Download PDF

Clinical Trial Results:
Phase 1/2 Study of PF-06463922 (an ALK/ROS1 Tyrosine Kinase Inhibitor) in Patients With Advanced Non-Small Cell Lung Cancer Harboring Specific Molecular Alterations

Summary
EudraCT number	2013-002620-17
Trial protocol	ES DE GB IT BE
Global end of trial date	24 May 2023

Results information
Results version number	v2(current)
This version publication date	08 Jun 2024
First version publication date	24 Mar 2018
Other versions	v1
Version creation reason

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

B7461001

ISRCTN number

US NCT number

NCT01970865

WHO universal trial number (UTN)

Sponsor organisation name

Pfizer, Inc.

Sponsor organisation address

235 E 42nd Street, New York, United States, NY 10017

Public contact

Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

31 Oct 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

24 May 2023

Was the trial ended prematurely?

Main objective of the trial

The primary objective of Phase 1 of the study was to assess safety and tolerability of PF-06463922 as a single agent at increasing dose levels in participants with advanced anaplastic lymphoma kinase (ALK) positive or advanced ROS1-positive non-small cell lung cancer (NSCLC) in order to estimate the Maximum Tolerated Dose (MTD) and select the Recommended Phase 2 Dose (RP2D). Primary objective of Phase 2 of the study was to evaluate overall (intra- and extra-cranial) and intra-cranial anti-tumor activity of single-agent PF-06463922 at RP2D in participants with advanced ALK-positive NSCLC and advanced ROS1-positive NSCLC.

Protection of trial subjects

This study was conducted in compliance with the ethical principles originating in or derived from the Declaration of Helsinki and in compliance with all International Council for Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. In addition, all local regulatory requirements were followed, in particular, those affording greater protection to the safety of participants.

Background therapy

Evidence for comparator

Actual start date of recruitment

08 Jan 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 26

Country: Number of subjects enrolled

Canada: 7

Country: Number of subjects enrolled

France: 31

Country: Number of subjects enrolled

Germany: 1

Country: Number of subjects enrolled

Hong Kong: 2

Country: Number of subjects enrolled

Italy: 36

Country: Number of subjects enrolled

Japan: 42

Country: Number of subjects enrolled

Korea, Republic of: 9

Country: Number of subjects enrolled

Singapore: 29

Country: Number of subjects enrolled

Spain: 31

Country: Number of subjects enrolled

Switzerland: 7

Country: Number of subjects enrolled

Taiwan: 11

Country: Number of subjects enrolled

United States: 132

Worldwide total number of subjects

364

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

295

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

Screening details

A total of 364 participants were enrolled in this study.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

10 mg QD (Phase 1)

Arm description

PF-06463922 10 mg was orally given once daily (QD) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.

Arm type

Experimental

Investigational medicinal product name

PF-06463922

Investigational medicinal product code

Other name

Lorlatinib

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PF-06463922 10 mg was administered QD with at least 240 mL of water on an empty stomach. No food or liquids other than water were consumed for 2 hours before and 2 hours following each dose.

25 mg QD (Phase 1)

Arm description

PF-06463922 25 mg was orally given QD in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.

Arm type

Experimental

Investigational medicinal product name

PF-06463922

Investigational medicinal product code

Other name

Lorlatinib

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PF-06463922 25 mg was administered QD with at least 240 mL of water on an empty stomach. No food or liquids other than water were consumed for 2 hours before and 2 hours following each dose.

Investigational medicinal product name

Midazolam

Investigational medicinal product code

Other name

Pharmaceutical forms

Syrup

Routes of administration

Oral use

Dosage and administration details

Midazolam 2 mg was administered alone on Day -7 and concurrently with PF-06463922 on Cycle 1 Day 15.

50 mg QD (Phase 1)

Arm description

PF-06463922 50 mg was orally given QD on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.

Arm type

Experimental

Investigational medicinal product name

PF-06463922

Investigational medicinal product code

Other name

Lorlatinib

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PF-06463922 50 mg was administered QD with at least 240 mL of water on an empty stomach. No food or liquids other than water were consumed for 2 hours before and 2 hours following each dose.

75 mg QD (Phase 1)

Arm description

PF-06463922 75 mg was orally given QD on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.

Arm type

Experimental

Investigational medicinal product name

PF-06463922

Investigational medicinal product code

Other name

Lorlatinib

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PF-06463922 75 mg was administered QD with at least 240 mL of water on an empty stomach. No food or liquids other than water were consumed for 2 hours before and 2 hours following each dose.

100 mg QD (Phase 1)

Arm description

PF-06463922 100 mg was orally given QD on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.

Arm type

Experimental

Investigational medicinal product name

PF-06463922

Investigational medicinal product code

Other name

Lorlatinib

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PF-06463922 100 mg was administered BID with at least 240 mL of water on an empty stomach. No food or liquids other than water were consumed for 2 hours before and 2 hours following each dose.

150 mg QD (Phase 1)

Arm description

PF-06463922 150 mg was orally given QD in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.

Arm type

Experimental

Investigational medicinal product name

PF-06463922

Investigational medicinal product code

Other name

Lorlatinib

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PF-06463922 150 mg was administered QD with at least 240 mL of water on an empty stomach. No food or liquids other than water were consumed for 2 hours before and 2 hours following each dose.

Investigational medicinal product name

Midazolam

Investigational medicinal product code

Other name

Pharmaceutical forms

Syrup

Routes of administration

Oral use

Dosage and administration details

Midazolam 2 mg was administered alone on Day -7 and concurrently with PF-06463922 on Cycle 1 Day 15.

200 mg QD (Phase 1)

Arm description

PF-06463922 200 mg was orally given QD on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.

Arm type

Experimental

Investigational medicinal product name

PF-06463922

Investigational medicinal product code

Other name

Lorlatinib

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PF-06463922 200 mg was administered QD with at least 240 mL of water on an empty stomach. No food or liquids other than water were consumed for 2 hours before and 2 hours following each dose.

35 mg BID (Phase 1)

Arm description

PF-06463922 35 mg was orally given twice daily (BID) on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.

Arm type

Experimental

Investigational medicinal product name

PF-06463922

Investigational medicinal product code

Other name

Lorlatinib

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PF-06463922 35 mg was administered BID with at least 240 mL of water on an empty stomach. No food or liquids other than water were consumed for 2 hours before and 2 hours following each dose.

75 mg BID (Phase 1)

Arm description

PF-06463922 75 mg was orally given BID on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.

Arm type

Experimental

Investigational medicinal product name

PF-06463922

Investigational medicinal product code

Other name

Lorlatinib

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PF-06463922 75 mg was administered BID with at least 240 mL of water on an empty stomach. No food or liquids other than water were consumed for 2 hours before and 2 hours following each dose.

100 mg BID (Phase 1)

Arm description

PF-06463922 100 mg was orally given BID on Day -7 and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.

Arm type

Experimental

Investigational medicinal product name

PF-06463922

Investigational medicinal product code

Other name

Lorlatinib

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PF-06463922 100 mg was administered BID with at least 240 mL of water on an empty stomach. No food or liquids other than water were consumed for 2 hours before and 2 hours following each dose.

EXP-1 (Phase 2)

Arm description

Treatment-naïve participants with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally QD on Day -7 (only participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.

Arm type

Experimental

Investigational medicinal product name

PF-06463922

Investigational medicinal product code

Other name

Lorlatinib

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PF-06463922 100 mg was administered QD with at least 240 mL of water on an empty stomach. No food or liquids other than water were consumed for 2 hours before and 2 hours following each dose.

EXP-2 (Phase 2)

Arm description

Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally QD on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.

Arm type

Experimental

Investigational medicinal product name

PF-06463922

Investigational medicinal product code

Other name

Lorlatinib

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PF-06463922 100 mg was administered QD with at least 240 mL of water on an empty stomach. No food or liquids other than water were consumed for 2 hours before and 2 hours following each dose.

EXP-3 (Phase 2)

Arm description

Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after crizotinib therapy and 1 or 2 prior regimens of chemotherapy given before or after crizotinib therapy, or participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 1 ALK inhibitor therapy other than crizotinib with or without any number of prior chemotherapy regimens in any disease setting were given PF-06463922 100 mg orally QD on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.

Arm type

Experimental

Investigational medicinal product name

PF-06463922

Investigational medicinal product code

Other name

Lorlatinib

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PF-06463922 100 mg was administered QD with at least 240 mL of water on an empty stomach. No food or liquids other than water were consumed for 2 hours before and 2 hours following each dose.

EXP-4 (Phase 2)

Arm description

Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 2 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.

Arm type

Experimental

Investigational medicinal product name

PF-06463922

Investigational medicinal product code

Other name

Lorlatinib

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PF-06463922 100 mg was administered QD with at least 240 mL of water on an empty stomach. No food or liquids other than water were consumed for 2 hours before and 2 hours following each dose.

EXP-5 (Phase 2)

Arm description

Participants with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after 3 prior lines of ALK inhibitor therapies were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participant scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.

Arm type

Experimental

Investigational medicinal product name

PF-06463922

Investigational medicinal product code

Other name

Lorlatinib

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PF-06463922 100 mg was administered QD with at least 240 mL of water on an empty stomach. No food or liquids other than water were consumed for 2 hours before and 2 hours following each dose.

EXP-6 (Phase 2)

Arm description

Participants with advanced ROS1-positive NSCLC who were treatment naïve or had any number of prior cancer therapies with or without asymptomatic CNS metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for participants scheduled for pharmacokinetic evaluation) and in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal.

Arm type

Experimental

Investigational medicinal product name

PF-06463922

Investigational medicinal product code

Other name

Lorlatinib

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PF-06463922 100 mg was administered QD with at least 240 mL of water on an empty stomach. No food or liquids other than water were consumed for 2 hours before and 2 hours following each dose.

Japan Lead-In Cohort (LIC)

Arm description

Few Japanese participants were given PF-06463922 100 mg orally once daily (QD) in 21-day cycles from Cycle 1 Day 1 until progression of disease (unless clinical benefit was still achievable), unacceptable toxicity, death or consent withdrawal to evaluate safety of PF-06463922 in Japanese participants, in order to support inclusion of Japanese participants in Phase 2.

Arm type

Experimental

Investigational medicinal product name

PF-06463922

Investigational medicinal product code

Other name

Lorlatinib

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

PF-06463922 100 mg was administered QD with at least 240 mL of water on an empty stomach. No food or liquids other than water were consumed for 2 hours before and 2 hours following each dose.

DDI Substudy

Arm description

Participants with advanced ALK positive or ROS1-positive NSCLC who were treatment naïve or had any number of prior cancer therapies with or without asymptomatic CNS metastases were administered a single dose of a probe substrate alone on Day -2. Participants were given PF-06463922 100 mg orally QD starting on Cycle1 Day 1 and along with probe substrate on Day 15 Cycle 1.

Arm type

Experimental

Investigational medicinal product name

PF-06463922

Investigational medicinal product code

Other name

Lorlatinib

Pharmaceutical forms

Tablet

Routes of administration

Intratumoral use, Oral use

Dosage and administration details

PF-06463922 100 mg was administered QD with at least 240 mL of water on an empty stomach. No food or liquids other than water were consumed for 2 hours before and 2 hours following each dose.

Number of subjects in period 1	10 mg QD (Phase 1)	25 mg QD (Phase 1)	50 mg QD (Phase 1)	75 mg QD (Phase 1)	100 mg QD (Phase 1)	150 mg QD (Phase 1)	200 mg QD (Phase 1)	35 mg BID (Phase 1)	75 mg BID (Phase 1)	100 mg BID (Phase 1)	EXP-1 (Phase 2)	EXP-2 (Phase 2)	EXP-3 (Phase 2)	EXP-4 (Phase 2)	EXP-5 (Phase 2)	EXP-6 (Phase 2)	Japan Lead-In Cohort (LIC)	DDI Substudy
Started	3	3	3	12	17	3	3	3	3	4	30	27	60	65	46	47	3	32
Completed	0	0	0	2	3	0	0	0	1	2	18	7	18	8	3	7	2	6
Not completed	3	3	3	10	14	3	3	3	2	2	12	20	42	57	43	40	1	26
Death	3	2	3	6	9	3	2	3	2	2	8	13	25	46	37	22	1	17
Study terminated by sponsor	-	-	-	-	-	-	-	-	-	-	-	-	-	1	-	-	-	-
Unspecified	-	1	-	1	1	-	1	-	-	-	2	3	8	2	2	3	-	2
Subject refused further follow-up	-	-	-	2	3	-	-	-	-	-	1	4	7	8	3	11	-	6
Lost to follow-up	-	-	-	1	1	-	-	-	-	-	1	-	2	-	1	4	-	1

Baseline characteristics

Top of page

Reporting group title

10 mg QD (Phase 1)

Reporting group description

Reporting group title

25 mg QD (Phase 1)

Reporting group description

Reporting group title

50 mg QD (Phase 1)

Reporting group description

Reporting group title

75 mg QD (Phase 1)

Reporting group description

Reporting group title

100 mg QD (Phase 1)

Reporting group description

Reporting group title

150 mg QD (Phase 1)

Reporting group description

Reporting group title

200 mg QD (Phase 1)

Reporting group description

Reporting group title

35 mg BID (Phase 1)

Reporting group description

Reporting group title

75 mg BID (Phase 1)

Reporting group description

Reporting group title

100 mg BID (Phase 1)

Reporting group description

Reporting group title

EXP-1 (Phase 2)

Reporting group description

Reporting group title

EXP-2 (Phase 2)

Reporting group description

Reporting group title

EXP-3 (Phase 2)

Reporting group description

Reporting group title

EXP-4 (Phase 2)

Reporting group description

Reporting group title

EXP-5 (Phase 2)

Reporting group description

Reporting group title

EXP-6 (Phase 2)

Reporting group description

Reporting group title

Japan Lead-In Cohort (LIC)

Reporting group description

Reporting group title

DDI Substudy

Reporting group description

Reporting group values	10 mg QD (Phase 1)	25 mg QD (Phase 1)	50 mg QD (Phase 1)	75 mg QD (Phase 1)	100 mg QD (Phase 1)	150 mg QD (Phase 1)	200 mg QD (Phase 1)	35 mg BID (Phase 1)	75 mg BID (Phase 1)	100 mg BID (Phase 1)	EXP-1 (Phase 2)	EXP-2 (Phase 2)	EXP-3 (Phase 2)	EXP-4 (Phase 2)	EXP-5 (Phase 2)	EXP-6 (Phase 2)	Japan Lead-In Cohort (LIC)	DDI Substudy	Total
Number of subjects	3	3	3	12	17	3	3	3	3	4	30	27	60	65	46	47	3	32	364
Age Categorical
Units: Participants
<18 years	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
18-44 years	0	1	0	5	7	1	1	0	0	2	4	5	14	19	13	12	2	5	91
45-64 years	1	1	3	6	9	1	2	2	2	1	18	13	34	37	26	27	1	20	204
>=65 years	2	1	0	1	1	1	0	1	1	1	8	9	12	9	7	8	0	7	69
Sex: Female, Male
Units: Participants
Female	2	0	1	7	11	2	2	2	3	2	13	17	38	37	25	27	2	15	206
Male	1	3	2	5	6	1	1	1	0	2	17	10	22	28	21	20	1	17	158
Race/Ethnicity, Customized
Units: Subjects
WHITE	2	2	3	7	13	2	2	1	2	3	10	13	25	32	27	25	0	21	190
BLACK	1	0	0	0	0	1	0	1	0	0	1	0	1	0	0	1	0	0	6
ASIAN	0	1	0	3	2	0	1	0	0	0	17	10	23	23	14	16	3	11	124
OTHER	0	0	0	0	1	0	0	0	0	0	1	2	1	3	2	3	0	0	13
UNSPECIFIED	0	0	0	2	1	0	0	1	1	1	1	2	10	7	3	2	0	0	31

End points

Top of page

Reporting group title

10 mg QD (Phase 1)

Reporting group description

Reporting group title

25 mg QD (Phase 1)

Reporting group description

Reporting group title

50 mg QD (Phase 1)

Reporting group description

Reporting group title

75 mg QD (Phase 1)

Reporting group description

Reporting group title

100 mg QD (Phase 1)

Reporting group description

Reporting group title

150 mg QD (Phase 1)

Reporting group description

Reporting group title

200 mg QD (Phase 1)

Reporting group description

Reporting group title

35 mg BID (Phase 1)

Reporting group description

Reporting group title

75 mg BID (Phase 1)

Reporting group description

Reporting group title

100 mg BID (Phase 1)

Reporting group description

Reporting group title

EXP-1 (Phase 2)

Reporting group description

Reporting group title

EXP-2 (Phase 2)

Reporting group description

Reporting group title

EXP-3 (Phase 2)

Reporting group description

Reporting group title

EXP-4 (Phase 2)

Reporting group description

Reporting group title

EXP-5 (Phase 2)

Reporting group description

Reporting group title

EXP-6 (Phase 2)

Reporting group description

Reporting group title

Japan Lead-In Cohort (LIC)

Reporting group description

Reporting group title

DDI Substudy

Reporting group description

Subject analysis set title

ALK Positive Population (Phase 1)

Subject analysis set type

Sub-group analysis

Subject analysis set description

This reporting arm includes all Phase 1 participants who had documented ALK rearrangement.

Subject analysis set title

ROS1 Positive Population (Phase 1)

Subject analysis set type

Sub-group analysis

Subject analysis set description

This reporting arm includes all Phase 1 participants who had documented ROS1 rearrangement.

Subject analysis set title

ALK Positive Population (Phase 1)

Subject analysis set type

Sub-group analysis

Subject analysis set description

This reporting arm includes all Phase 1 participants who had documented ALK rearrangement.

Subject analysis set title

ROS1 Positive Population (Phase 1)

Subject analysis set type

Sub-group analysis

Subject analysis set description

This reporting arm includes all Phase 1 participants who had documented ROS1 rearrangement.

Subject analysis set title

Phase 1 ITT Population

Subject analysis set type

Sub-group analysis

Subject analysis set description

This reporting group includes all Phase 1 participants in the ITT analysis set.

Subject analysis set title

ALK Positive Population (Phase 1)

Subject analysis set type

Sub-group analysis

Subject analysis set description

This reporting arm includes all Phase 1 participants who had documented ALK rearrangement.

Subject analysis set title

Phase 1 PRO Evaluable Population

Subject analysis set type

Sub-group analysis

Subject analysis set description

This reporting group includes all Phase 1 participants who received at least 1 dose of PF-06463922 and completed a baseline and at least 1 post-baseline PRO assessment.

Subject analysis set title

Phase 2 ITT Population

Subject analysis set type

Sub-group analysis

Subject analysis set description

This reporting group includes all Phase 2 participants in the ITT analysis set.

Subject analysis set title

Phase 2 and Japan LIC PK Analysis Set

Subject analysis set type

Sub-group analysis

Subject analysis set description

PK parameters of PF-06463922 were determined for a small subset of Phase 2 participants and Japan LIC. These participants received PF-06463922 100 mg orally QD and were combined into 1 reporting group for PK analysis. Japan LIC was not included in single-dose PK analysis, ie, they did not contribute to Day -7 data.

Subject analysis set title

Phase 2 and Japan LIC PK Analysis Set

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Phase 2 and Japan LIC PK Analysis Set

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Phase 2 and Japan LIC PK Analysis Set

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subject analysis set title

Phase 2

Subject analysis set type

Sub-group analysis

Subject analysis set description

Primary: Number of Participants with Cycle 1 Dose-Limiting Toxicities (DLTs) in Phase 1

Top of page

End point title

Number of Participants with Cycle 1 Dose-Limiting Toxicities (DLTs) in Phase 1 ^[1] ^[2]

End point description

DLT: any of following AEs:hematologic: grade (G)4 neutropenia for >7 days; febrile neutropenia; grade >=3 neutropenic infection; grade >=3 thrombocytopenia with bleeding; G4 thrombocytopenia; non-hematologic: grade >=3 pancreatitis; grade >=3 toxicities (excluding grade >=3 laboratory abnormalities not requiring dose modifications) persisting after optimal treatment with standard medical therapy; symptomatic grade >=3 QTc prolongation, or asymptomatic grade >=3 prolongation confirmed by repeat testing, persisted after correction of reversible causes; >=20% decrease from baseline in left ventricular ejection fraction (LVEF); other: failure to deliver at least 16 out of 21 prescribed daily total doses due to toxicite; failure to restart dosing after 21 days (1 cycle) delay due to toxicity. MTD evaluable population: all enrolled participants who received at least 75% of planned PF-06463922 dose in Cycle 1 and who received <75% of planned PF-06463922 doses in Cycle 1 due to DLT.

End point type

Primary

End point timeframe

Cycle 1 (21 days)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	10 mg QD (Phase 1)	25 mg QD (Phase 1)	50 mg QD (Phase 1)	75 mg QD (Phase 1)	100 mg QD (Phase 1)	150 mg QD (Phase 1)	200 mg QD (Phase 1)	35 mg BID (Phase 1)	75 mg BID (Phase 1)	100 mg BID (Phase 1)
Number of subjects analysed	3	3	3	11	16	3	3	2	3	3
Units: Participants
With DLT	0	0	0	0	0	0	1	0	0	0
No DLT	3	2	3	6	8	2	1	2	3	2
Data missing	0	1	0	5	8	1	1	0	0	1

No statistical analyses for this end point

Primary: Percentage of Participants with Overall and Intracranial Objective Response (Phase 2)

Top of page

End point title

Percentage of Participants with Overall and Intracranial Objective Response (Phase 2) ^[3] ^[4]

End point description

Objective response (OR): confirmed CR or PR according to Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. Intracranial OR: confirmed CR or PR considering only lesions within brain. CR: disappearance of all non-lymph node target lesions (where all target lesions are recorded with a length of 0 milliliter (mm) on Target Lesions eCRF). Any pathological lymph nodes (recorded as target lesion) must have reduction in short axis to <10 mm. PR:30% or more decrease in sum of lesion dimensions (SLD) of target lesions, taking as reference the baseline SLD. Results presented here were based on independent central review.ITT analysis set: all enrolled participants with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922; participants with central nervous system (CNS) metastases in ITT analysis set were used for intracranial response assessment. "Number Analyzed": participants evaluable for specified rows.

End point type

Primary

End point timeframe

3 years

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis was planned
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	EXP-1 (Phase 2)	EXP-2 (Phase 2)	EXP-3 (Phase 2)	EXP-4 (Phase 2)	EXP-5 (Phase 2)	EXP-6 (Phase 2)
Number of subjects analysed	30	27	60	65	46	47
Units: Percentage of participants
number (confidence interval 95%)
OR, n=30,27,59,65,46, 47,32	90.0 (73.5 to 97.9)	74.1 (53.7 to 88.9)	50.8 (37.5 to 64.1)	41.5 (29.4 to 54.4)	34.8 (21.4 to 50.2)	36.2 (22.7 to 51.5)
Intracranial OR,n=8,17,32,45,38, 25	75.0 (34.9 to 96.8)	58.8 (32.9 to 81.6)	62.5 (43.7 to 78.9)	55.6 (40.0 to 70.4)	39.5 (24.0 to 56.6)	56.0 (34.9 to 75.6)

No statistical analyses for this end point

Secondary: Percentage of Participants With Overall and Intracranial Objective Response (Phase 1)

Top of page

End point title

Percentage of Participants With Overall and Intracranial Objective Response (Phase 1)

End point description

Objective response (OR) refers to confirmed CR or PR according to RECIST version 1.1. Intracranial OR refers to confirmed CR or PR considering only lesions within brain. CR was defined as the disappearance of all non-lymph node target lesions (where all target lesions are recorded with a length of 0 mm on Target Lesions eCRF). Any pathological lymph nodes (recorded as target lesion) must have reduction in short axis to <10 mm. PR was defined as a 30 % or more decrease in SLD of target lesions, taking as reference the baseline SLD. Results presented here were based on independent central review.The ITT analysis set was used for overall response assessment and included all enrolled participants with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922; participants with CNS metastases in the ITT analysis set was used for intracranial response assessment. Here, "Number Analyzed" signifies participants analyzed for this outcome measure.

End point type

Secondary

End point timeframe

From start of study treatment until CR or PR (maximum of 96.58 months of treatment exposure)

End point values	ALK Positive Population (Phase 1)	ROS1 Positive Population (Phase 1)
Number of subjects analysed	41	12
Units: Percentage of participants
number (confidence interval 95%)
OR, n= 41, 12	39.0 (24.2 to 55.5)	50.0 (21.1 to 78.9)
Intracranial OR, n=34, 8	41.2 (24.6 to 59.3)	50.0 (15.7 to 84.3)

No statistical analyses for this end point

Secondary: Time to Tumor Response (TTR) and Intracranial TTR (Phase 1)

Top of page

End point title

Time to Tumor Response (TTR) and Intracranial TTR (Phase 1)

End point description

TTR: time from first dose of study treatment to first documentation of objective tumor response (CR or PR). For participants whose objective response proceeded from PR to CR, onset of PR was taken as onset of response. CR:disappearance of all non-lymph node target lesions (where all target lesions are recorded with a length of 0 mm on Target Lesions eCRF). Any pathological lymph nodes (recorded as target lesion) must have reduction in short axis to <10 mm. PR: 30 % or more decrease in SLD of target lesions, taking as reference the baseline SLD. TTR was calculated for subgroup of participants with confirmed objective tumor response. Intracranial TTR was only calculated for participants with confirmed intracranial OR. Results presented here were based on independent central review.TTR analysis set:all ITT participants who had confirmed objective response; intracranial TTR analysis set:all ITT participants who had CNS metastases and achieved confirmed intracranial objective response

End point type

Secondary

End point timeframe

From start of study treatment to the first documentation of objective tumor response (CR or PR) (maximum of 96.58 months of treatment exposure)

End point values	ALK Positive Population (Phase 1)	ROS1 Positive Population (Phase 1)
Number of subjects analysed	16	6
Units: Months
median (full range (min-max))
TTR, n=16, 6	1.4 (1.2 to 15.2)	1.4 (1.2 to 2.8)
Intracranial TTR, n=14, 4	1.4 (1.2 to 20.1)	1.4 (1.1 to 2.8)

No statistical analyses for this end point

Secondary: Number of Participants With Duration of Response (DOR) and Intracranial DOR (Phase 1)

Top of page

End point title

Number of Participants With Duration of Response (DOR) and Intracranial DOR (Phase 1)

End point description

DOR: time from first documentation of objective tumor response (CR/PR) to first documentation of disease progression (PD) or death due to any cause. Intracranial DOR:calculated for participants with confirmed intracranial (IC) OR. CR:disappearance of all non-lymph node target lesions (where all target lesions are recorded with length of 0mm on Target Lesion eCRF). Pathological lymph node (recorded as target lesion) must have reduction in short axis to <10mm. PR:30% or more decrease in SLD of target lesion, taking as reference baseline SLD. PD:20% or more increase in SLD of target lesion relative to baseline/smallest SLD (nadir) recorded since first dose,demonstrate absolute increase of atleast 5mm(>=5mm) relative to baseline/smallest SLD recorded since first dose.DOR analysis set: ITT participant who had confirmed OR; IC DOR set: ITT participant who had CNS metastases, achieved confirmed IC OR.99999:Number of participant with confirmed OR was too small to provide summary statistics.

End point type

Secondary

End point timeframe

From start of study treatment to first documentation of disease progression (PD) or to death due to any cause, whichever occurred first (maximum of 96.58 months of treatment exposure)

End point values	ALK Positive Population (Phase 1)	ROS1 Positive Population (Phase 1)
Number of subjects analysed	16	6
Units: Participants
number (not applicable)
DOR, <3 Months, n=16,6	1	0
DOR,3 Months < 6 Months, n=16,6	6	0
DOR, 6 Months -< 9 Months, n=16,6	0	1
DOR, 9 Months -< 12 Months, n=16,6	0	1
DOR,12 Months -< 15 Months, n=16,6	1	0
DOR, 15 Months -< 18 Months, n=16,6	0	0
DOR, 18 Months -< 21 Months, n=16, 6	0	0
DOR, 21 Months -< 24 Months, n=16, 6	1	0
DOR,>= 24 Months, n=16, 6	1	2
Intracranial DOR, <3 Months, n=14, 4	1	0
Intracranial DOR, 3 Months < 6 Months, n=14, 4	0	0
Intracranial DOR, 6 Months -< 9 Months, n=14, 4	1	0
Intracranial DOR, 9 Months -< 12 Months, n=14, 4	0	0
Intracranial DOR, 12 Months -< 15 Months, n=14, 4	1	0
Intracranial DOR, 15 Months -< 18 Months, n=14, 4	0	0
Intracranial DOR, 18 Months -< 21 Months, n=14, 4	0	0
Intracranial DOR, 21 Months -< 24 Months, n=14, 4	0	0
Intracranial DOR, >= 24 Months, n=14, 4	0	0

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving Disease Control and Intracranial Disease Control at 12 and 24 Weeks (Phase 1)

Top of page

End point title

Percentage of Participants Achieving Disease Control and Intracranial Disease Control at 12 and 24 Weeks (Phase 1)

End point description

Tumor response was evaluated as per to RECIST v1.1, disease control: confirmed CR, confirmed PR, or stable disease (SD). Intracranial assessment was only performed for participants CNS metastases. CR:disappearance of all non-lymph node target lesions (where all target lesions are recorded with length of 0mm on Target Lesions eCRF). Any pathological lymph nodes (recorded as target lesion) must have reduction in short axis to <10 mm. PR: 30% or more decrease in SLD of target lesion, taking as reference baseline SLD. Progressive disease: 20% or more increase in SLD of target lesions relative to baseline or smallest SLD (nadir) recorded since first dose. SLD must demonstrate absolute increase of atleast 5mm (>=5mm) relative to baseline or smallest SLD (nadir). ITT analysis set: all enrolled participants with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922; participants with CNS metastases in ITT analysis set was used for intracranial response assessment.

End point type

Secondary

End point timeframe

12 and 24 weeks

End point values	ALK Positive Population (Phase 1)	ROS1 Positive Population (Phase 1)
Number of subjects analysed	41	12
Units: Percentage of participants
number (confidence interval 95%)
DCR at Week 12, n=41,12	53.7 (37.4 to 69.3)	58.3 (27.7 to 84.8)
DCR at Week 24, n=41,12	39.0 (24.2 to 55.5)	50.0 (21.1 to 78.9)
Intracranial DCR at Week 12, n=34, 8	50.0 (32.4 to 67.6)	37.5 (8.5 to 75.5)
Intracranial DCR at Week 24, n=34, 8	41.2 (24.6 to 59.3)	37.5 (8.5 to 75.5)

No statistical analyses for this end point

Secondary: Probability of First Event Being a Central Nervous System (CNS) Progression, Non CNS Progression, or Death (Phase 1)

Top of page

End point title

Probability of First Event Being a Central Nervous System (CNS) Progression, Non CNS Progression, or Death (Phase 1)

End point description

Probability of first event being a CNS progression, a non-CNS progression, or death was evaluated with a competing risk approach by estimating cumulative incidence functions (range: 0-1) relative to the analysis set. The time to first event being a Competing Event (either “CNS progression” or “non CNS progression” or “Death”) was defined as time from first dose until the date of that specific event. Participants not known to have any of the Competing Events were censored on the date they were last assessed for disease status for PFS. Participants who presented one type of event were counted as a competing cause of failure for the analysis of other type of events. For each type of event, the cumulative incidence function corresponding to the nearest time point preceding 1 year is presented. Results are based on independent central review. intent-to-treat (ITT) analysis set: all enrolled participants with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922.

End point type

Secondary

End point timeframe

From start of study treatment until first event of CNS progression (maximum of 96.58 months of treatment exposure)

End point values	Phase 1 ITT Population
Number of subjects analysed	53
Units: Probability of events
number (not applicable)
CNS progression	0.260
Non CNS progression	0.352
Death	0.060

No statistical analyses for this end point

Secondary: Progression-Free Survival (PFS) (Phase 1)

Top of page

End point title

Progression-Free Survival (PFS) (Phase 1)

End point description

PFS was defined as the time from the first dose of study treatment to the first documentation of objective disease progression or to death on study due to any cause, whichever came first. Progressive disease was defined by a 20% or more increase in the SLD of target lesions relative to baseline or the smallest SLD (nadir) recorded since first dose. In addition to the relative increase of 20%, SLD must also demonstrate an absolute increase of at least 5 mm (>= 5 mm) relative to baseline or the smallest SLD (nadir) recorded since the first dose. Results presented here were based on independent central review. PFS analysis set included all participants with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922.

End point type

Secondary

End point timeframe

From start of study treatment to first documentation of disease progression (PD) or to death due to any cause, whichever occurred first (maximum of 96.58 months of treatment exposure)

End point values	ALK Positive Population (Phase 1)	ROS1 Positive Population (Phase 1)
Number of subjects analysed	41	12
Units: Months
median (confidence interval 95%)	5.4 (2.7 to 11.8)	10.1 (1.6 to 33.0)

No statistical analyses for this end point

Secondary: Overall Survival (OS) (Phase 1)

Top of page

End point title

Overall Survival (OS) (Phase 1)

End point description

OS was defined as the time from first dose to the date of death due to any cause. For participants still alive at the time of analysis, the OS time was censored on the last date the participants were known to be alive. Estimates of OS and its 95% confidence interval were determined using Kaplan-Meier method. ITT analysis set: all enrolled participants with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922."Number Analyzed": participants analyzed for this outcome measure. 99999 represents “A large proportion of participants in the analysis set had their OS data censored, and number of participants dead by the cutoff date of this report was small, so it's impossible to derive such summary statistics.”

End point type

Secondary

End point timeframe

3 years

End point values	ALK Positive Population (Phase 1)	ROS1 Positive Population (Phase 1)
Number of subjects analysed	41	12
Units: Months
median (confidence interval 95%)	22.3 (11.4 to 99999)	99999 (4.7 to 99999)

No statistical analyses for this end point

Secondary: Maximum Observed Plasma Concentration (Cmax) of PF-06463922 Following Single Oral Doses (Phase 1)

Top of page

End point title

Maximum Observed Plasma Concentration (Cmax) of PF-06463922 Following Single Oral Doses (Phase 1) ^[5]

End point description

Maximum observed plasma concentration (Cmax) of PF-06463922 was observed directly from data. PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922. 99999 represents “Summary statistics were not calculated when fewer than 3 participants had reportable values. Individual values are 390 and 423 ng/mL, respectively.”

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 1 for 25 mg QD and 150 mg QD groups; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 for all other groups.

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	10 mg QD (Phase 1)	25 mg QD (Phase 1)	50 mg QD (Phase 1)	75 mg QD (Phase 1)	100 mg QD (Phase 1)	150 mg QD (Phase 1)	200 mg QD (Phase 1)	35 mg BID (Phase 1)	75 mg BID (Phase 1)	100 mg BID (Phase 1)
Number of subjects analysed	3	3	2	12	16	3	3	3	3	4
Units: Nanograms per milliliter (ng/mL)
geometric mean (geometric coefficient of variation)	50.80 ( 17 )	149.2 ( 71 )	99999 ( 99999 )	489.1 ( 45 )	595.5 ( 37 )	760.0 ( 58 )	1201 ( 19 )	202.2 ( 57 )	594.9 ( 27 )	507.2 ( 51 )

No statistical analyses for this end point

Secondary: Maximum Observed Plasma Concentration (Cmax) of PF-06463922 Following Multiple Oral Doses (Phase 1)

Top of page

End point title

Maximum Observed Plasma Concentration (Cmax) of PF-06463922 Following Multiple Oral Doses (Phase 1) ^[6]

End point description

Maximum Observed Plasma Concentration (Cmax) of PF-06463922 was observed directly from data. PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922. 99999 represents “Summary statistics were not calculated when fewer than 3 participants had reportable values. Individual values are 760 and 1430 ng/mL, respectively.” and “when fewer than 3 participants had reportable values. The individual value is 370 ng/mL”

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups).

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	10 mg QD (Phase 1)	25 mg QD (Phase 1)	50 mg QD (Phase 1)	75 mg QD (Phase 1)	100 mg QD (Phase 1)	150 mg QD (Phase 1)	200 mg QD (Phase 1)	35 mg BID (Phase 1)	75 mg BID (Phase 1)	100 mg BID (Phase 1)
Number of subjects analysed	3	3	3	12	16	3	3	3	3	3
Units: ng/mL
geometric mean (geometric coefficient of variation)	67.29 ( 18 )	138.1 ( 35 )	359.7 ( 27 )	429.6 ( 48 )	550.2 ( 32 )	541.0 ( 42 )	99999 ( 99999 )	99999 ( 99999 )	550.0 ( 23 )	600.5 ( 27 )

No statistical analyses for this end point

Secondary: Time for Cmax (Tmax) of PF-06463922 Following Single Oral Doses (Phase 1)

Top of page

End point title

Time for Cmax (Tmax) of PF-06463922 Following Single Oral Doses (Phase 1) ^[7]

End point description

End point type

Secondary

End point timeframe

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	10 mg QD (Phase 1)	25 mg QD (Phase 1)	50 mg QD (Phase 1)	75 mg QD (Phase 1)	100 mg QD (Phase 1)	150 mg QD (Phase 1)	200 mg QD (Phase 1)	35 mg BID (Phase 1)	75 mg BID (Phase 1)	100 mg BID (Phase 1)
Number of subjects analysed	3	3	2	12	16	3	3	3	3	4
Units: Hours
median (full range (min-max))	1.98 (1.00 to 2.97)	2.00 (0.50 to 2.05)	1.25 (0.50 to 2.00)	1.09 (0.50 to 4.03)	1.96 (0.517 to 4.33)	1.05 (1.00 to 3.00)	2.00 (1.18 to 3.00)	1.20 (0.50 to 1.97)	1.23 (1.00 to 2.00)	2.00 (1.10 to 3.07)

No statistical analyses for this end point

Secondary: Time for Cmax (Tmax) of PF-06463922 Following Multiple Oral Doses (Phase 1)

Top of page

End point title

Time for Cmax (Tmax) of PF-06463922 Following Multiple Oral Doses (Phase 1) ^[8]

End point description

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups).

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	10 mg QD (Phase 1)	25 mg QD (Phase 1)	50 mg QD (Phase 1)	75 mg QD (Phase 1)	100 mg QD (Phase 1)	150 mg QD (Phase 1)	200 mg QD (Phase 1)	35 mg BID (Phase 1)	75 mg BID (Phase 1)	100 mg BID (Phase 1)
Number of subjects analysed	3	3	3	12	16	3	3	3	3	3
Units: Hours
median (full range (min-max))	1.00 (1.00 to 1.08)	1.00 (1.00 to 2.00)	2.00 (1.92 to 2.75)	1.03 (0.50 to 2.00)	1.13 (1.00 to 4.00)	1.30 (1.00 to 24.0)	1.61 (1.22 to 2.00)	0.50 (0.50 to 0.50)	0.55 (0.50 to 2.05)	2.00 (1.00 to 2.00)

No statistical analyses for this end point

Secondary: Area under the Plasma Concentration-Time profile from Time Zero to Time Tau (AUCtau) of PF-06463922 Following Single Oral Doses (Phase 1)

Top of page

End point title

Area under the Plasma Concentration-Time profile from Time Zero to Time Tau (AUCtau) of PF-06463922 Following Single Oral Doses (Phase 1) ^[9]

End point description

Tau refers to the dosing interval, and it equals to 12 or 24 hours for BID or QD dosing, respectively. AUCtau was determined using linear/log trapezoidal method. PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922. 99999 represents “Summary statistics were not calculated when fewer than 3 participants had reportable values. Individual values are 3310 and 3880 ng*hr/mL, respectively.”

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 1 for 25 mg QD and 150 mg QD groups; pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, and 24 hours post-dose on Day -7 for all other groups.

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	10 mg QD (Phase 1)	25 mg QD (Phase 1)	50 mg QD (Phase 1)	75 mg QD (Phase 1)	100 mg QD (Phase 1)	150 mg QD (Phase 1)	200 mg QD (Phase 1)	35 mg BID (Phase 1)	75 mg BID (Phase 1)	100 mg BID (Phase 1)
Number of subjects analysed	3	3	2	12	16	3	3	3	3	4
Units: Nanogramhour/milliliter (nghr/mL)
geometric mean (geometric coefficient of variation)	488.2 ( 21 )	1387 ( 35 )	99999 ( 99999 )	3990 ( 55 )	5110 ( 28 )	7474 ( 73 )	11410 ( 43 )	982.4 ( 9 )	2996 ( 20 )	2925 ( 47 )

No statistical analyses for this end point

Secondary: Area under the Plasma Concentration-Time profile from Time Zero to Time Tau (AUCtau) of PF-06463922 Following Multiple Oral Doses (Phase 1)

Top of page

End point title

Area under the Plasma Concentration-Time profile from Time Zero to Time Tau (AUCtau) of PF-06463922 Following Multiple Oral Doses (Phase 1) ^[10]

End point description

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups)

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	10 mg QD (Phase 1)	25 mg QD (Phase 1)	50 mg QD (Phase 1)	75 mg QD (Phase 1)	100 mg QD (Phase 1)	150 mg QD (Phase 1)	200 mg QD (Phase 1)	35 mg BID (Phase 1)	75 mg BID (Phase 1)	100 mg BID (Phase 1)
Number of subjects analysed	3	3	3	12	16	3	2	1	3	3
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)	752.1 ( 26 )	1701 ( 29 )	3367 ( 39 )	4107 ( 53 )	5121 ( 30 )	6157 ( 9 )	99999 ( 99999 )	99999 ( 99999 )	3574 ( 35 )	4058 ( 33 )

No statistical analyses for this end point

Secondary: Area under the Plasma Concentration-Time Profile from Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06463922 Following Single Oral Doses (Phase 1)

Top of page

End point title

Area under the Plasma Concentration-Time Profile from Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06463922 Following Single Oral Doses (Phase 1) ^[11]

End point description

AUCinf was calculated as AUClast+(Clast*/kel),where AUClast was area under plasma concentration-time profile from time 0 to time of last quantifiable concentration,Clast* was predicted plasma concentration at last quantifiable time point estimated from log-linear regression analysis, kel was rate constant for terminal phase.PK parameter analysis set for PF-06463922:all enrolled participants who received at least 1 dose of PF-06463922,had sufficient information to estimate at least one of PK parameter.Overall Number of Participants Analyzed: participants evaluable for this outcome measure.99999:Summary statistics were not calculated when fewer than 3 participants had reportable value.Individual value:698 ng*hr/mL;when fewer than 3 participant had reportable value.Individual values are 7210 and 7240 ng*hr/mL; when fewer than 3 participant had reportable value.Individual values are 2630 and 3690 ng*hr/mL. when fewer than 3 participant had reportable value.Individual value:6860 ng*hr/mL.

End point type

Secondary

End point timeframe

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	10 mg QD (Phase 1)	50 mg QD (Phase 1)	75 mg QD (Phase 1)	100 mg QD (Phase 1)	200 mg QD (Phase 1)	35 mg BID (Phase 1)	75 mg BID (Phase 1)	100 mg BID (Phase 1)
Number of subjects analysed	1	2	11	15	3	2	1	4
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)	99999 ( 99999 )	99999 ( 99999 )	7663 ( 79 )	8236 ( 25 )	18340 ( 61 )	99999 ( 99999 )	99999 ( 99999 )	6318 ( 56 )

No statistical analyses for this end point

Secondary: Apparent Oral Clearance (CL/F) of PF-06463922 Following Single Oral Doses (Phase 1)

Top of page

End point title

Apparent Oral Clearance (CL/F) of PF-06463922 Following Single Oral Doses (Phase 1) ^[12]

End point description

Clearance of drug is measure of rate at which drug is metabolized or eliminated by normal biological processes. CL/F was calculated as dose/AUCinf, where AUCinf was area under plasma concentration-time profile from time 0 extrapolated to infinite time. PK parameter analysis set for PF-06463922: all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of PK parameters of interest for PF-06463922.Overall Number of Participants Analyzed: participants evaluable for this outcome measure. Summary statistics were not calculated when fewer than 3 participants had reportable values. individual value is 14.3 L/hr; when fewer than 3 participants had reportable values. Individual values are 6.91 and 6.94 L/hr, respectively; when fewer than 3 participants had reportable values. Individual values are 9.48 and 13.3 L/hr, respectively; when fewer than 3 participants had reportable values. The individual value is 10.9 L/hr.

End point type

Secondary

End point timeframe

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	10 mg QD (Phase 1)	50 mg QD (Phase 1)	75 mg QD (Phase 1)	100 mg QD (Phase 1)	200 mg QD (Phase 1)	35 mg BID (Phase 1)	75 mg BID (Phase 1)	100 mg BID (Phase 1)
Number of subjects analysed	1	2	11	15	3	2	1	4
Units: Liter/hour (L/hr)
geometric mean (geometric coefficient of variation)	99999 ( 99999 )	99999 ( 99999 )	9.788 ( 79 )	12.14 ( 25 )	10.90 ( 61 )	99999 ( 99999 )	99999 ( 99999 )	15.83 ( 56 )

No statistical analyses for this end point

Secondary: Apparent Oral Clearance (CL/F) of PF-06463922 Following Multiple Oral Doses (Phase 1)

Top of page

End point title

Apparent Oral Clearance (CL/F) of PF-06463922 Following Multiple Oral Doses (Phase 1) ^[13]

End point description

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as dose/AUCinf, where AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time. PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922. 99999: Summary statistics were not calculated when fewer than 3 participants had reportable values. Individual values are 15.5 and 44.6 L/hr, respectively and when fewer than 3 participants had reportable values. The individual value is 16.3 L/hr.

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups)

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	10 mg QD (Phase 1)	25 mg QD (Phase 1)	50 mg QD (Phase 1)	75 mg QD (Phase 1)	100 mg QD (Phase 1)	150 mg QD (Phase 1)	200 mg QD (Phase 1)	35 mg BID (Phase 1)	75 mg BID (Phase 1)	100 mg BID (Phase 1)
Number of subjects analysed	3	3	3	12	16	3	2	1	3	3
Units: L/hr
geometric mean (geometric coefficient of variation)	13.27 ( 26 )	14.72 ( 29 )	14.84 ( 39 )	17.66 ( 48 )	19.52 ( 30 )	24.37 ( 9 )	99999 ( 99999 )	99999 ( 99999 )	20.99 ( 35 )	22.37 ( 47 )

No statistical analyses for this end point

Secondary: Apparent Volume of Distribution (Vz/F) of PF-06463922 Following Single Oral Doses (Phase 1)

Top of page

End point title

Apparent Volume of Distribution (Vz/F) of PF-06463922 Following Single Oral Doses (Phase 1) ^[14]

End point description

Vz/F was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug, and calculated as dose/(AUCinf*kel), where AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time, kel was the rate constant for terminal phase. Summary statistics were not calculated when fewer than 3 participants had reportable values. The individual value is 373 L; when fewer than 3 participants had reportable values. Individual values are 166 and 307 L, respectively; when fewer than 3 participants had reportable values. Individual values are 362 and 472 L, respectively. Summary statistics were not calculated when fewer than 3 participants had reportable values. The individual value is 410 L.

End point type

Secondary

End point timeframe

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	10 mg QD (Phase 1)	50 mg QD (Phase 1)	75 mg QD (Phase 1)	100 mg QD (Phase 1)	200 mg QD (Phase 1)	35 mg BID (Phase 1)	75 mg BID (Phase 1)	100 mg BID (Phase 1)
Number of subjects analysed	1	2	11	15	3	2	1	4
Units: Liters (L)
geometric mean (geometric coefficient of variation)	99999 ( 99999 )	99999 ( 99999 )	367.9 ( 54 )	356.3 ( 39 )	307.8 ( 41 )	99999 ( 99999 )	99999 ( 99999 )	378.3 ( 54 )

No statistical analyses for this end point

Secondary: Observed Accumulation Ratio (Rac) of PF-06463922 Following Multiple Oral Doses (Phase 1)

Top of page

End point title

Observed Accumulation Ratio (Rac) of PF-06463922 Following Multiple Oral Doses (Phase 1) ^[15]

End point description

Rac was calculated as Day 15 AUCtau/Day -7 AUCtau or Day 1 AUCtau, where AUCtau was the area under the plasma concentration-time profile from time 0 to time tau (12 and 24 hours for BID and QD dosing regimen, respectively). PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922. Here, "Overall Number of Participants Analyzed" signifies participants evaluable for this outcome measure.Standard deviation was not calculated when fewer than 3 participants had reportable values and when fewer than 3 participants had reportable values. The individual value is 2.09.

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups)

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	10 mg QD (Phase 1)	25 mg QD (Phase 1)	50 mg QD (Phase 1)	75 mg QD (Phase 1)	100 mg QD (Phase 1)	150 mg QD (Phase 1)	200 mg QD (Phase 1)	35 mg BID (Phase 1)	75 mg BID (Phase 1)	100 mg BID (Phase 1)
Number of subjects analysed	3	3	2	12	15	3	2	1	3	3
Units: Ratio
arithmetic mean (standard deviation)	1.543 ( 0.075056 )	1.237 ( 0.20817 )	1.105 ( 99999 )	1.121 ( 0.44575 )	1.071 ( 0.31138 )	1.000 ( 0.79137 )	0.6500 ( 99999 )	99999 ( 99999 )	1.231 ( 0.35228 )	1.523 ( 0.29569 )

No statistical analyses for this end point

Secondary: Terminal Half-Life of PF-06463922 Following Single Oral Doses (Phase 1)

Top of page

End point title

Terminal Half-Life of PF-06463922 Following Single Oral Doses (Phase 1) ^[16]

End point description

Terminal plasma half-life: time measured for plasma concentration to decrease by one half, and calculated as loge(2)/kel, where kel was rate constant for terminal phase. PK parameter analysis set for PF-06463922: all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of PK parameters of interest for PF-06463922. "Overall Number of Participants Analyzed" signifies participants evaluable for this outcome measure. 99999: Summary statistics were not calculated when fewer than 3 participants had reportable values. Individual value is 18.0 hr; when fewer than 3 participants had reportable values. Individual values are 16.6 and 30.8 hr, respectively; Standard deviation was not calculated when fewer than 3 participants had reportable values. Individual values are 24.6 and 26.5 hr, respectively; Summary statistics were not calculated when fewer than 3 participants had reportable values. individual value is 26.0 hr.

End point type

Secondary

End point timeframe

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	10 mg QD (Phase 1)	50 mg QD (Phase 1)	75 mg QD (Phase 1)	100 mg QD (Phase 1)	200 mg QD (Phase 1)	35 mg BID (Phase 1)	75 mg BID (Phase 1)	100 mg BID (Phase 1)
Number of subjects analysed	1	2	11	15	3	2	1	4
Units: Hours (hr)
arithmetic mean (standard deviation)	99999 ( 99999 )	23.70 ( 99999 )	27.22 ( 8.2961 )	20.89 ( 5.0308 )	19.80 ( 3.3045 )	25.55 ( 99999 )	99999 ( 99999 )	17.18 ( 5.1874 )

No statistical analyses for this end point

Secondary: Steady State Accumulation Ratio (Rss) of PF-06463922 Following Multiple Oral Doses (Phase 1)

Top of page

End point title

Steady State Accumulation Ratio (Rss) of PF-06463922 Following Multiple Oral Doses (Phase 1) ^[17]

End point description

Rss was calculated as Day 15 AUCtau/Day -7 AUCinf, where AUCtau was area under plasma concentration-time profile from time 0 to time tau (12 and 24 hours for BID and QD dosing regimen, respectively).PK parameter analysis set for PF-06463922: all enrolled participants who received at least 1 dose of PF-06463922, had sufficient information to estimate at least one of PK parameters of interest. Overall Number of Participants Analyzed: participants evaluable for this outcome measure. 99999: summary statistics were not calculated when fewer than 3 participants had reportable values,individual value:0.993; SD was not calculated when fewer than 3 participants had reportable values. Individual values:0.401 and 0.719,when fewer than 3 participants had reportable values. Individual values:0.384 and 0.403, summary statistics were not calculated when fewer than 3 participants had reportable values. individual value:0.815; fewer than 3 participants had reportable values. individual value:0.542.

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24 hours post-dose on Cycle 1 Day 15 (24-hour samples not collected for BID groups)

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	10 mg QD (Phase 1)	50 mg QD (Phase 1)	75 mg QD (Phase 1)	100 mg QD (Phase 1)	200 mg QD (Phase 1)	35 mg BID (Phase 1)	75 mg BID (Phase 1)	100 mg BID (Phase 1)
Number of subjects analysed	1	2	11	14	2	1	1	3
Units: Ratio
arithmetic mean (standard deviation)	99999 ( 99999 )	0.5600 ( 99999 )	0.6131 ( 0.29021 )	0.6603 ( 0.18604 )	0.3935 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	0.7687 ( 0.13552 )

No statistical analyses for this end point

Secondary: Renal Clearance (CLr) of PF-06463922 (Phase 1)

Top of page

End point title

Renal Clearance (CLr) of PF-06463922 (Phase 1) ^[18]

End point description

Renal clearance was calculated as Aetau/AUCtau, where Aetau was cumulative amount of drug recovered unchanged in urine up to dosing interval tau (24 hours for QD dosing regimen), and AUCtau was area under plasma concentration-time profile from time 0 to time tau (24 hours for QD dosing regimen). PK parameter analysis set for PF-06463922: all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of PK parameters of interest for PF-06463922. "Overall Number of Participants Analyzed" signifies participants evaluable for this outcome measure.

End point type

Secondary

End point timeframe

0-4 hours, 4-12 hours and 12-24 hours post-dose on Cycle 1 Day 15

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	100 mg QD (Phase 1)
Number of subjects analysed	3
Units: ml/hour
geometric mean (geometric coefficient of variation)	61.31 ( 58 )

No statistical analyses for this end point

Secondary: Percent of PF-06463922 Recovered Unchanged in Urine up to Dosing Interval (AEtau%) (Phase 1)

Top of page

End point title

Percent of PF-06463922 Recovered Unchanged in Urine up to Dosing Interval (AEtau%) (Phase 1) ^[19]

End point description

Dosing interval was 24 hours for QD dosing regimen. Aetau% was calculated as 100*Ae24/dose, where Ae24 was the cumulative amount of drug recovered unchanged in urine up to 24 hours post-dose. PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922. As planned, this parameter was only analyzed for 100 mg QD group. Here, "Overall Number of Participants Analyzed" signifies participants evaluable for this outcome measure.

End point type

Secondary

End point timeframe

0-4 hours, 4-12 hours and 12-24 hours post-dose on Cycle 1 Day 15

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	100 mg QD (Phase 1)
Number of subjects analysed	3
Units: Percentage of recovered PF-06463922
arithmetic mean (standard deviation)	0.4017 ( 0.11074 )

No statistical analyses for this end point

Secondary: Maximum Observed Plasma Concentration (Cmax) of Midazolam (Phase 1)

Top of page

End point title

Maximum Observed Plasma Concentration (Cmax) of Midazolam (Phase 1) ^[20]

End point description

Cmax of midazolam was observed directly from data. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflected the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflected the PK assessment after multiple doses of PF-06463922 were administered. PK parameter analysis set for PF-06463922: all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922.

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	25 mg QD (Phase 1)	150 mg QD (Phase 1)
Number of subjects analysed	3	3
Units: ng/mL
geometric mean (geometric coefficient of variation)
Day -7	16.06 ( 42 )	11.56 ( 48 )
Cycle 1 Day 15	9.697 ( 40 )	5.734 ( 43 )

No statistical analyses for this end point

Secondary: Time for Cmax (Tmax) of Midazolam (Phase 1)

Top of page

End point title

Time for Cmax (Tmax) of Midazolam (Phase 1) ^[21]

End point description

Tmax of midazolam was observed directly from data as time of first occurrence. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflect the PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect the PK assessment after multiple doses of PF-06463922 were administered. PK parameter analysis set for midazolam: all participants who received at least 1 dose of midazolam and for which at least 1 midazolam PK parameter of interest was available.

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	25 mg QD (Phase 1)	150 mg QD (Phase 1)
Number of subjects analysed	3	3
Units: Hours
median (full range (min-max))
Day -7	0.50 (0.50 to 1.00)	0.50 (0.50 to 0.50)
Cycle 1 Day 15	0.50 (0.50 to 1.00)	0.50 (0.50 to 0.533)

No statistical analyses for this end point

Secondary: Area under the Plasma Concentration-Time profile from Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Midazolam (Phase 1)

Top of page

End point title

Area under the Plasma Concentration-Time profile from Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Midazolam (Phase 1) ^[22]

End point description

Area under plasma concentration-time profile from time 0 to time of last quantifiable concentration (AUClast) of midazolam was determined using linear/log trapezoidal method. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflect PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect PK assessment after multiple doses of PF-06463922 were administered. PK parameter analysis set for midazolam: all participants who received at least 1 dose of midazolam and for which at least 1 midazolam PK parameter of interest was available

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	25 mg QD (Phase 1)	150 mg QD (Phase 1)
Number of subjects analysed	3	3
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)
Day -7	51.30 ( 47 )	36.49 ( 20 )
Cycle 1 Day 15	20.43 ( 18 )	14.44 ( 25 )

No statistical analyses for this end point

Secondary: Area under the Plasma Concentration-Time Profile from Time Zero Extrapolated to Infinite Time (AUCinf) of Midazolam (Phase 1)

Top of page

End point title

Area under the Plasma Concentration-Time Profile from Time Zero Extrapolated to Infinite Time (AUCinf) of Midazolam (Phase 1) ^[23]

End point description

AUCinf was calculated as AUClast + (Clast*/kel), where AUClast was area under plasma concentration-time profile from time 0 to time of last quantifiable concentration, Clast* was predicted plasma concentration at last quantifiable time point estimated from the log-linear regression analysis, and kel was rate constant for terminal phase. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflect PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect PK assessment after multiple doses of PF-06463922 were administered. PK parameter analysis set for midazolam: all participants who received at least 1 dose of midazolam and for which at least 1 midazolam PK parameter of interest was available. 99999: Summary statistics were not calculated when fewer than 3 participants had reportable values. Individual values are 42.2 and 46.8 ng*hr/mL, respectively.

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	25 mg QD (Phase 1)	150 mg QD (Phase 1)
Number of subjects analysed	3	3
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)
Day -7, n=3, 2	54.53 ( 43 )	99999 ( 99999 )
Cycle 1 Day 15, n=3 ,3	21.32 ( 18 )	16.09 ( 29 )

No statistical analyses for this end point

Secondary: Apparent Oral Clearance (CL/F) of Midazolam (Phase 1)

Top of page

End point title

Apparent Oral Clearance (CL/F) of Midazolam (Phase 1) ^[24]

End point description

Clearance of drug is measure of rate at which drug is metabolized or eliminated by normal biological processes. CL/F was calculated as dose/AUCinf, where AUCinf was area under plasma concentration-time profile from time 0 extrapolated to infinite time. Only participants in 25 and 150 mg QD groups were given midazolam. Day -7 data reflect PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect PK assessment after multiple doses of PF-06463922 were administered.PK parameter analysis set: all participants who received at least 1 dose of midazolam and for which at least 1 midazolam PK parameter of interest was available.Number Analyzed:participants evaluable for specified rows.99999: Summary statistics were not calculated when fewer than 3 participants had reportable values. Individual values are 42.7 and 47.4 L/hr.

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	25 mg QD (Phase 1)	150 mg QD (Phase 1)
Number of subjects analysed	3	3
Units: L/hr
geometric mean (geometric coefficient of variation)
Day -7, n=3, 2	36.68 ( 43 )	99999 ( 99999 )
Cycle 1 Day 15, n=3, 3	93.86 ( 18 )	124.2 ( 29 )

No statistical analyses for this end point

Secondary: Apparent Volume of Distribution (Vz/F) of Midazolam (Phase 1)

Top of page

End point title

Apparent Volume of Distribution (Vz/F) of Midazolam (Phase 1) ^[25]

End point description

Vz/F was defined as theoretical volume in which total amount of drug would need to be uniformly distributed to produce desired plasma concentration of drug, and calculated as dose/(AUCinf*kel), where AUCinf was area under plasma concentration-time profile from time 0 extrapolated to infinite time, kel was rate constant for terminal phase. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflect PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect PK assessment after multiple doses of PF-06463922 were administered. PK parameter analysis set for midazolam: all participants who received at least 1 dose of midazolam and for which at least 1 midazolam PK parameter of interest was available. Here, 'Number Analyzed' signifies participants evaluable for specified rows. 99999:Summary statistics were not calculated when fewer than 3 participants had reportable values. Individual values are 161 and 486 L, respectively

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	25 mg QD (Phase 1)	150 mg QD (Phase 1)
Number of subjects analysed	3	3
Units: Liters
geometric mean (geometric coefficient of variation)
Day -7, n=3, 2	229.0 ( 7 )	99999 ( 99999 )
Cycle 1 Day 15, n=3, 3	404.4 ( 51 )	702.2 ( 100 )

No statistical analyses for this end point

Secondary: Terminal Half-Life of Midazolam (Phase 1)

Top of page

End point title

Terminal Half-Life of Midazolam (Phase 1) ^[26]

End point description

Terminal plasma half-life was defined as time measured for plasma concentration to decrease by one half, and calculated as loge(2)/kel, where kel was rate constant for terminal phase. Only participants in 25 mg and 150 mg QD groups were given midazolam. Day -7 data reflect PK assessment before administration of PF-06463922, and Cycle 1 Day 15 data reflect PK assessment after multiple doses of PF-06463922 were administered. PK parameter analysis set for midazolam: all participants who received at least 1 dose of midazolam and for which at least 1 midazolam PK parameter of interest was available. Here, 'Number Analyzed' signifies participants evaluable for specified rows.99999 represents “Standard deviation was not calculated when fewer than 3 participants had reportable values. Individual values are 2.35 and 7.89 hr, respectively”

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	25 mg QD (Phase 1)	150 mg QD (Phase 1)
Number of subjects analysed	3	3
Units: Hour
arithmetic mean (standard deviation)
Day -7, n=3, 2	4.620 ( 1.9328 )	5.120 ( 99999 )
Cycle 1 Day 15, n=3, 3	3.343 ( 2.0358 )	5.257 ( 5.0639 )

No statistical analyses for this end point

Secondary: Number of Participants with ALK Mutation Based on Plasma CNA Analysis (Phase 1)

Top of page

End point title

Number of Participants with ALK Mutation Based on Plasma CNA Analysis (Phase 1)

End point description

Plasma circulating nucleic acid (CNA) samples were analyzed for ALK kinase domain mutations by digital polymerase chain reaction (PCR) BEAMing technology. Number of participants with one or more ALK mutations is presented.

End point type

Secondary

End point timeframe

Screening (up to 28 days)

End point values	ALK Positive Population (Phase 1)
Number of subjects analysed	40
Units: Participants	14

No statistical analyses for this end point

Secondary: Number of Participants with ALK Mutation Based on Tumor Tissue Analysis (Phase 1)

Top of page

End point title

Number of Participants with ALK Mutation Based on Tumor Tissue Analysis (Phase 1)

End point description

Tumor tissues from archived tissue specimens and/or a de novo biopsy were analyzed for ALK kinase domain mutations. Number of participants with one or more ALK mutations is presented.

End point type

Secondary

End point timeframe

Screening (up to 28 days)

End point values	ALK Positive Population (Phase 1)
Number of subjects analysed	40
Units: Participants	7

No statistical analyses for this end point

Secondary: Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-C30 (Phase 1)

Top of page

End point title

Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-C30 (Phase 1)

End point description

European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ)-C30 (version 3.0) consists of 30 questions assessing 5 functional domains (physical, role, emotional, cognitive and social), global quality of life (QoL), disease/treatment related symptoms (fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, constipation and diarrhea), and the perceived financial impact of disease. Each scale was transformed to a range of 0 to 100 using standard EORTC algorithm. For global QoL and functional scales, higher score indicate better performance, and improvement was defined as an increase of at least 10 points, worsening was defined as a decrease of at least 10 points. For symptom scales, higher score indicates worse symptoms, and improvement was defined as a decrease of at least 10 points, worsening was defined as an increase of at least 10 points. All scales which had not improved nor worsened were considered stable.

End point type

Secondary

End point timeframe

From start of study treatment until end of treatment (maximum of 96.58 months of treatment exposure)

End point values	Phase 1 PRO Evaluable Population
Number of subjects analysed	43
Units: participants
Improved in global QoL	19
Stable in global QoL	13
Worsened in global QoL	11
Improved in physical functioning	5
Stable in physical functioning	29
Worsened in physical functioning	9
Improved in role functioning	14
Stable in role functioning	15
Worsened in role functioning	14
Improved in emotional functioning	15
Stable in emotional functioning	21
Worsened in emotional functioning	7
Improved in cognitive functioning	8
Stable in cognitive functioning	21
Worsened in cognitive functioning	14
Improved in social functioning	13
Stable in social functioning	17
Worsened in social functioning	13
Improved in fatigue	17
Stable in fatigue	19
Worsened in fatigue	7
Improved in nausea and vomiting	10
Stable in nausea and vomiting	32
worsened in nausea and vomiting	1
Improved in pain	17
Stable in pain	16
Worsened in pain	10
Improved in dyspnea	13
Stable in dyspnea	19
Worsened in dyspnea	11
Improved in insomnia	19
Stable in insomnia	17
Worsened in insomnia	7
Improved in appetite loss	14
Stable in appetite loss	27
Worsened in appetite loss	2
Improved in constipation	10
Stable in constipation	28
Worsened in constipation	5
Improved in diarrhea	9
Stable in diarrhea	28
Worsened in diarrhea	6
Improved in financial difficulties	7
Stable in financial difficulties	20
Worsened in financial difficulties	16

No statistical analyses for this end point

Secondary: Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-LC13 (Phase 1)

Top of page

End point title

Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-LC13 (Phase 1)

End point description

EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. The scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms, and improvement was defined as a decrease of at least 10 points, worsening was defined as an increase of at least 10 points. All scales which had not improved nor worsened were considered stable.

End point type

Secondary

End point timeframe

From start of study treatment until end of treatment (maximum of 96.58 months of treatment exposure)

End point values	Phase 1 PRO Evaluable Population
Number of subjects analysed	43
Units: Participants
Improved in dyspnea	9
Stable in dyspnea	23
Worsened in dyspnea	11
Improved in coughing	23
Stable in coughing	12
Worsened in coughing	8
Improved in hemoptysis	1
Stable in hemoptysis	42
Worsened in hemoptysis	0
Improved in sore mouth	0
Stable in sore mouth	40
Worsened in sore mouth	3
Improved in dysphagia	4
Stable in dysphagia	37
Worsened in dysphagia	2
Improved in peripheral neuropathy	6
Stable in peripheral neuropathy	21
Worsened in peripheral neuropathy	16
Improved in alopecia	4
Stable in alopecia	29
Worsened in alopecia	9
Improved in chest pain	16
Stable in chest pain	22
Worsened in chest pain	5
Improved in arm or shoulder pain	10
Stable in arm or shoulder pain	27
Worsened in arm or shoulder pain	6
Improved in pain in other parts	20
Stable in pain in other parts	12
Worsened in pain in other parts	11

No statistical analyses for this end point

Secondary: Change from Baseline in Mini Mental State Examination (MMSE) Score (Phase 1)

Top of page

End point title

Change from Baseline in Mini Mental State Examination (MMSE) Score (Phase 1) ^[27]

End point description

In Phase 1, MMSE was collected to assess mental status. MMSE is 30 item questionnaire that tests 5 areas of cognitive function: orientation, registration, attention and calculation, recall and language. Maximum score is 30 and minimum score is 0. Highest score indicates no cognitive impairment, lowest score indicates severe cognitive impairment. MMSE was removed under Amendment 6 of study protocol, and not required for Phase 2, as tool was not considered meaningful for assessment of cognitive function. MMSE assessment evaluable analysis set: all participants in safety analysis set (all participants who received at least 1 dose of PF-06463922) who completed baseline and at least 1 post-baseline assessment. Overall Number of Participants Analyzed: participants evaluable for this outcome measure. Number Analyzed: participants evaluable for specified rows. 99999:SD could not be calculated as only 1 participant was analyzed.

End point type

Secondary

End point timeframe

Baseline, Day 1 of Cycle 1-52, and end of treatment (up to 3 years)

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	10 mg QD (Phase 1)	25 mg QD (Phase 1)	50 mg QD (Phase 1)	75 mg QD (Phase 1)	100 mg QD (Phase 1)	150 mg QD (Phase 1)	200 mg QD (Phase 1)	35 mg BID (Phase 1)	75 mg BID (Phase 1)	100 mg BID (Phase 1)
Number of subjects analysed	2	3	3	9	16	3	2	2	3	4
Units: Units on a scale
arithmetic mean (standard deviation)
Cycle 1 Day 1, n=2,0,2,7,9,0,0,0,1,1	1.0 ( 1.41 )	99999 ( 99999 )	-0.5 ( 0.71 )	-0.9 ( 2.27 )	0.8 ( 1.39 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	0.0 ( 99999 )	0.0 ( 99999 )
Cycle 2 Day 1, n=1,3,1,9,16,3,2,2,2,3	2.0 ( 99999 )	-0.3 ( 0.58 )	2.0 ( 99999 )	0.3 ( 1.41 )	0.0 ( 1.79 )	4.7 ( 8.08 )	4.0 ( 4.24 )	0.0 ( 0.00 )	0.0 ( 0.00 )	-0.3 ( 1.15 )
Cycle 3 Day 1,2,3,2,8,15,2,2,0,1,3	2.0 ( 0.00 )	0.3 ( 0.58 )	-0.5 ( 0.71 )	-0.6 ( 1.85 )	0.2 ( 1.52 )	5.0 ( 8.49 )	3.0 ( 2.83 )	99999 ( 99999 )	0.0 ( 99999 )	-1.0 ( 1.00 )
Cycle 4 Day 1, n=1,2,2,8,14,3,2,0,1,3	5.0 ( 99999 )	0.5 ( 0.71 )	1.5 ( 2.12 )	-1.1 ( 1.81 )	0.0 ( 1.47 )	2.0 ( 6.24 )	-0.5 ( 3.54 )	99999 ( 99999 )	0.0 ( 99999 )	-0.7 ( 1.15 )
Cycle 5 Day 1, n=2,2,2,7,11,3,2,0,1,3	0.5 ( 3.54 )	0.5 ( 0.71 )	1.5 ( 2.12 )	0.3 ( 1.25 )	-0.2 ( 1.72 )	4.7 ( 8.14 )	0.5 ( 6.36 )	99999 ( 99999 )	0.0 ( 99999 )	-0.5 ( 0.71 )
Cycle 6 Day 1, =1,2,2,7,12,3,2,0,1,3	2.5 ( 2.12 )	0.5 ( 0.71 )	1.0 ( 1.41 )	-0.4 ( 2.70 )	0.3 ( 0.90 )	4.3 ( 5.86 )	2.0 ( 4.24 )	99999 ( 99999 )	0.0 ( 99999 )	-1.3 ( 2.31 )
Cycle 7 Day 1, n=0,2,1,7,11,2,1,0,0,3	2.0 ( 99999 )	0.5 ( 0.71 )	1.5 ( 2.12 )	-0.1 ( 1.21 )	0.4 ( 0.90 )	4.7 ( 8.33 )	3.0 ( 4.24 )	99999 ( 99999 )	0.0 ( 99999 )	-0.7 ( 1.15 )
Cycle 8 Day 1, n=1,2,1,5,10,2,1,0,1,3	-4.0 ( 99999 )	0.5 ( 0.71 )	1.5 ( 2.12 )	-0.1 ( 2.34 )	0.2 ( 1.34 )	3.0 ( 7.81 )	4.0 ( 4.24 )	99999 ( 99999 )	0.0 ( 99999 )	0.0 ( 0.00 )
Cycle 9 Day 1, n=0,2,1,7,11,2,1,0,0,3	99999 ( 99999 )	0.0 ( 0.00 )	0.0 ( 99999 )	-1.0 ( 2.31 )	0.3 ( 2.10 )	6.0 ( 8.49 )	6.0 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	-0.3 ( 0.58 )
Cycle 10 Day 1, n=1,2,1,5,10,2,1,0,1,3	-5.0 ( 99999 )	0.5 ( 0.71 )	0.0 ( 99999 )	0.0 ( 0.00 )	-0.1 ( 0.88 )	6.5 ( 9.19 )	6.0 ( 99999 )	99999 ( 99999 )	0.0 ( 99999 )	-1.7 ( 1.53 )
Cycle 11 Day 1, n=0,2,1,7,12,2,2,0,1,3	99999 ( 99999 )	-0.5 ( 0.71 )	0.0 ( 99999 )	0.3 ( 1.70 )	-0.2 ( 1.53 )	7.0 ( 8.49 )	3.5 ( 3.54 )	99999 ( 99999 )	0.0 ( 99999 )	0.0 ( 0.00 )
Cycle 12 Day 1, n=0,2,0,5,12,2,2,0,1,2	99999 ( 99999 )	0.5 ( 0.71 )	99999 ( 99999 )	-0.6 ( 2.19 )	-0.2 ( 2.33 )	6.5 ( 9.19 )	3.5 ( 3.54 )	99999 ( 99999 )	0.0 ( 99999 )	-0.7 ( 0.58 )
Cycle 13 Day 1, n=0,2,0,5,10,2,2,0,1,2	99999 ( 99999 )	0.5 ( 0.71 )	99999 ( 99999 )	0.8 ( 1.79 )	0.5 ( 2.22 )	5.5 ( 7.78 )	3.0 ( 4.24 )	99999 ( 99999 )	0.0 ( 99999 )	-0.5 ( 0.71 )
Cycle 14 Day 1, n=0,2,0,6,11,2,2,0,1,3	99999 ( 99999 )	0.5 ( 0.71 )	99999 ( 99999 )	-0.3 ( 3.20 )	0.3 ( 0.79 )	6.0 ( 8.49 )	2.5 ( 3.54 )	99999 ( 99999 )	0.0 ( 99999 )	0.0 ( 0.00 )
Cycle 15 Day 1, n=0,2,0,6,9,0,2,0,1,3	99999 ( 99999 )	0.5 ( 0.71 )	99999 ( 99999 )	-1.7 ( 5.43 )	0.1 ( 1.36 )	99999 ( 99999 )	4.0 ( 4.24 )	99999 ( 99999 )	0.0 ( 99999 )	-0.3 ( 0.58 )
Cycle 16 Day 1, n=0,2,0,5,9,1,2,0,1,2	99999 ( 99999 )	0.0 ( 1.41 )	99999 ( 99999 )	-0.2 ( 2.49 )	-0.2 ( 1.99 )	1.0 ( 99999 )	1.5 ( 6.36 )	99999 ( 99999 )	0.0 ( 99999 )	0.0 ( 0.00 )
Cycle 17 Day 1, n=0,2,0,5,9,1,2,0,1,3	99999 ( 99999 )	-2.0 ( 2.83 )	99999 ( 99999 )	0.6 ( 1.95 )	0.1 ( 1.17 )	-3.0 ( 99999 )	4.0 ( 4.24 )	99999 ( 99999 )	0.0 ( 99999 )	-1.3 ( 1.53 )
Cycle 18 Day 1, n=0,2,0,5,9,1,2,0,0,2	99999 ( 99999 )	-0.5 ( 0.71 )	99999 ( 99999 )	0.8 ( 1.79 )	0.0 ( 1.73 )	-2.0 ( 99999 )	3.0 ( 4.24 )	99999 ( 99999 )	99999 ( 99999 )	0.0 ( 0.00 )
Cycle 19 Day 1, n=0,2,0,5,9,1,2,0,1,2	99999 ( 99999 )	-0.5 ( 0.71 )	99999 ( 99999 )	0.8 ( 1.79 )	-0.6 ( 2.65 )	0.0 ( 99999 )	3.5 ( 4.95 )	99999 ( 99999 )	0.0 ( 99999 )	-0.5 ( 0.71 )
Cycle 20 Day 1, n=0,2,0,5,9,1,2,0,1,2	99999 ( 99999 )	0.0 ( 0.00 )	99999 ( 99999 )	0.0 ( 1.41 )	0.7 ( 2.12 )	0.0 ( 99999 )	3.5 ( 3.54 )	99999 ( 99999 )	0.0 ( 99999 )	-0.5 ( 0.71 )
Cycle 21 Day 1, n=0,2,0,5,9,1,2,0,1,2	99999 ( 99999 )	-0.5 ( 0.71 )	99999 ( 99999 )	0.0 ( 1.41 )	0.1 ( 2.09 )	99999 ( 99999 )	4.0 ( 4.24 )	99999 ( 99999 )	0.0 ( 99999 )	-0.5 ( 0.71 )
Cycle 22 Day 1, n=0,2,0,5,9,1,2,0,1,3	99999 ( 99999 )	0.0 ( 0.00 )	99999 ( 99999 )	0.4 ( 1.52 )	0.1 ( 1.45 )	0.0 ( 99999 )	3.5 ( 3.54 )	99999 ( 99999 )	-1.0 ( 99999 )	-0.3 ( 0.58 )
Cycle 23 Day 1, n=0,2,0,5,8,1,2,0,1,2	99999 ( 99999 )	0.5 ( 0.71 )	99999 ( 99999 )	0.0 ( 1.41 )	0.1 ( 1.81 )	-1.0 ( 99999 )	1.5 ( 3.54 )	99999 ( 99999 )	0.0 ( 99999 )	-2.3 ( 4.04 )
Cycle 24 Day 1, n=0,2,0,5,8,1,2,0,1,2	99999 ( 99999 )	0.5 ( 0.71 )	99999 ( 99999 )	-0.4 ( 0.89 )	0.6 ( 0.74 )	1.0 ( 99999 )	1.5 ( 4.95 )	99999 ( 99999 )	0.0 ( 99999 )	0.0 ( 0.00 )
Cycle 25 Day 1, n=0,2,0,5,7,1,2,0,1,2	99999 ( 99999 )	0.0 ( 0.00 )	99999 ( 99999 )	0.8 ( 1.79 )	-0.9 ( 2.27 )	-2.0 ( 99999 )	2.5 ( 4.95 )	99999 ( 99999 )	0.0 ( 99999 )	0.0 ( 0.00 )
Cycle 26 Day 1, n=0,2,0,5,8,1,2,0,1,3	99999 ( 99999 )	0.5 ( 0.71 )	99999 ( 99999 )	0.8 ( 1.79 )	-0.4 ( 2.77 )	-1.0 ( 99999 )	2.0 ( 4.24 )	99999 ( 99999 )	0.0 ( 99999 )	-0.3 ( 0.58 )
Cycle 27 Day 1, n=0,2,0,5,7,1,2,0,1,2	99999 ( 99999 )	0.5 ( 0.71 )	99999 ( 99999 )	0.8 ( 1.79 )	-0.1 ( 2.67 )	-1.0 ( 99999 )	3.5 ( 3.54 )	99999 ( 99999 )	0.0 ( 99999 )	-1.0 ( 1.41 )
Cycle 28 Day 1, n=0,2,0,4,7,1,2,0,1,3	99999 ( 99999 )	0.5 ( 0.71 )	99999 ( 99999 )	1.0 ( 2.00 )	0.7 ( 0.76 )	-2.0 ( 99999 )	3.0 ( 2.83 )	99999 ( 99999 )	0.0 ( 99999 )	0.0 ( 0.00 )
Cycle 29 Day 1, n=0,2,0,4,8,1,2,0,1,3	99999 ( 99999 )	-1.5 ( 2.12 )	99999 ( 99999 )	0.5 ( 1.73 )	0.1 ( 1.81 )	0.0 ( 99999 )	3.5 ( 3.54 )	99999 ( 99999 )	0.0 ( 99999 )	0.0 ( 0.00 )
Cycle 30 Day 1, n=0,2,0,4,5,1,2,0,1,3	99999 ( 99999 )	0.0 ( 0.00 )	99999 ( 99999 )	0.8 ( 1.50 )	0.4 ( 0.55 )	0.0 ( 99999 )	3.0 ( 2.83 )	99999 ( 99999 )	0.0 ( 99999 )	-1.0 ( 1.00 )
Cycle 31 Day 1, n=0,2,0,3,6,1,2,0,0,3	99999 ( 99999 )	0.5 ( 0.71 )	99999 ( 99999 )	1.0 ( 2.65 )	0.7 ( 0.82 )	0.0 ( 99999 )	3.0 ( 4.24 )	99999 ( 99999 )	99999 ( 99999 )	0.0 ( 0.00 )
Cycle 32 Day 1, n=0,2,0,3,5,0,2,0,1, 2	99999 ( 99999 )	0.0 ( 0.00 )	99999 ( 99999 )	1.3 ( 2.31 )	0.4 ( 0.55 )	99999 ( 99999 )	3.5 ( 3.54 )	99999 ( 99999 )	0.0 ( 99999 )	0.0 ( 0.00 )
Cycle 33 Day 1, n=0,2,0,3,4,0,2,0,1, 2	99999 ( 99999 )	0.0 ( 0.00 )	99999 ( 99999 )	1.3 ( 2.31 )	0.5 ( 0.58 )	99999 ( 99999 )	3.5 ( 3.54 )	99999 ( 99999 )	0.0 ( 99999 )	0.0 ( 0.00 )
Cycle 34 Day 1, n=0,2,0,2,4,0,2,0,1, 2	99999 ( 99999 )	0.0 ( 0.00 )	99999 ( 99999 )	0.0 ( 0.00 )	0.3 ( 0.50 )	99999 ( 99999 )	4.0 ( 4.24 )	99999 ( 99999 )	0.0 ( 99999 )	0.0 ( 0.00 )
Cycle 35 Day 1, n=0,2,0,1,4,0,2,0,1, 1	99999 ( 99999 )	0.5 ( 0.71 )	99999 ( 99999 )	0.0 ( 99999 )	0.3 ( 0.50 )	99999 ( 99999 )	4.0 ( 4.24 )	99999 ( 99999 )	0.0 ( 99999 )	0.0 ( 99999 )
Cycle 36 Day 1, n=0,2,0,1,3,0,2,0,1, 1	99999 ( 99999 )	-0.5 ( 0.71 )	99999 ( 99999 )	0.0 ( 99999 )	0.0 ( 0.00 )	99999 ( 99999 )	4.0 ( 4.24 )	99999 ( 99999 )	0.0 ( 99999 )	0.0 ( 99999 )
Cycle 37 Day 1, n=0,2,0,1,2,0,2,0,0,0	99999 ( 99999 )	0.0 ( 0.00 )	99999 ( 99999 )	-1.0 ( 99999 )	0.0 ( 0.00 )	99999 ( 99999 )	3.5 ( 4.95 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Cycle 38 Day 1, n=0,2,0,1,2,0,2,0,1,0	99999 ( 99999 )	0.0 ( 0.00 )	99999 ( 99999 )	0.0 ( 99999 )	0.0 ( 0.00 )	99999 ( 99999 )	3.0 ( 2.83 )	99999 ( 99999 )	0.0 ( 99999 )	99999 ( 99999 )
Cycle 39 Day 1, n=0,1,0,1,2,0,2,0,0,0	99999 ( 99999 )	0.0 ( 99999 )	99999 ( 99999 )	0.0 ( 99999 )	-0.5 ( 0.71 )	99999 ( 99999 )	3.5 ( 4.95 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Cycle 40 Day 1, n=0,1,0,1,1,0,2,0,0,0	99999 ( 99999 )	0.5 ( 0.71 )	99999 ( 99999 )	-1.0 ( 99999 )	0.0 ( 99999 )	99999 ( 99999 )	4.0 ( 4.24 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Cycle 41 Day 1, n=0,2,0,1,1,0,2,0,0,0	99999 ( 99999 )	0.5 ( 0.71 )	99999 ( 99999 )	0.0 ( 99999 )	0.0 ( 99999 )	99999 ( 99999 )	1.5 ( 6.36 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Cycle 42 Day 1, n=0,2,0,1,1,0,2,0,0,0	99999 ( 99999 )	-0.5 ( 0.71 )	99999 ( 99999 )	0.0 ( 99999 )	0.0 ( 99999 )	99999 ( 99999 )	4.0 ( 4.24 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Cycle 43 Day 1, n=0,2,0,1,0,0,2,0,0,0	99999 ( 99999 )	0.0 ( 0.00 )	99999 ( 99999 )	0.0 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	4.0 ( 4.24 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Cycle 44 Day 1, n=0,2,0,1,0,0,2,0,0,0	99999 ( 99999 )	1.0 ( 99999 )	99999 ( 99999 )	-1.0 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	3.0 ( 4.24 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Cycle 45 Day 1, n=0,1,0,1,0,0,1,0,0,0	99999 ( 99999 )	1.0 ( 99999 )	99999 ( 99999 )	0.0 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	1.0 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Cycle 46 Day 1, n=0,1,0,1,0,0,0,0,0,0	99999 ( 99999 )	0.0 ( 99999 )	99999 ( 99999 )	-1.0 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Cycle 47 Day 1, n=0,1,0,1,0,0,0,0,0,0	99999 ( 99999 )	0.0 ( 99999 )	99999 ( 99999 )	0.0 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Cycle 48 Day 1, n=0,1,0,1,0,0,0,0,0,0	99999 ( 99999 )	-3.0 ( 99999 )	99999 ( 99999 )	0.0 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Cycle 49 Day 1, n=0,2,0,0,0,0,0,0,0,0	99999 ( 99999 )	0.5 ( 0.71 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Cycle 50 Day 1, n=0,1,0,0,0,0,0,0,0,0	99999 ( 99999 )	-3.0 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Cycle 51 Day 1, n=0,1,0,0,0,0,0,0,0,0	99999 ( 99999 )	-0.5 ( 0.71 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
Cycle 52 Day 1, n=0,1,0,0,0,0,0,0,0,0	99999 ( 99999 )	1.0 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
End of treatment, n=1,0,3,1,4,0,0,1,1	-8.0 ( 99999 )	99999 ( 99999 )	0.7 ( 1.15 )	-2.0 ( 99999 )	-2.3 ( 5.19 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	-15.0 ( 99999 )	0.0 ( 99999 )

No statistical analyses for this end point

Secondary: Time to Tumor Response (TTR) and Intracranial TTR (Phase 2 and DDI sub-study)

Top of page

End point title

Time to Tumor Response (TTR) and Intracranial TTR (Phase 2 and DDI sub-study) ^[28]

End point description

TTR: time from first dose of study treatment to first documentation of objective tumor response (CR or PR). For participants whose objective response proceeded from PR to CR, onset of PR was taken as onset of response. TTR was calculated for subgroup of participants with confirmed objective tumor response. Intracranial TTR was calculated for participants with confirmed intracranial objective response. CR: disappearance of all non-lymph node target lesions (where all target lesions are recorded with length of 0 mm on Target Lesions eCRF). Any pathological lymph nodes (recorded as target lesion) must have reduction in short axis to <10 mm. PR: 30% or more decrease in SLD of target lesions, taking as reference baseline SLD. TTR analysis set: ITT participants who had confirmed objective response; intracranial TTR analysis set:all ITT participants who had CNS metastases,achieved confirmed intracranial objective response."Number Analyzed": participants evaluable for specified rows.

End point type

Secondary

End point timeframe

From first dose of study treatment until CR or PR (maximum of 89.65 months of treatment exposure for Phase 2 and maximum of 68.69 months of treatment exposure for DDI participants)

Notes
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	EXP-1 (Phase 2)	EXP-2 (Phase 2)	EXP-3 (Phase 2)	EXP-4 (Phase 2)	EXP-5 (Phase 2)	EXP-6 (Phase 2)	DDI Substudy
Number of subjects analysed	27	21	34	26	17	18	13
Units: Months
median (full range (min-max))
TTR, n=27,21,34,26,17,18,13	1.4 (1.2 to 5.4)	1.4 (1.2 to 18.0)	1.4 (1.1 to 16.6)	2.6 (1.2 to 16.4)	1.4 (1.2 to 9.3)	1.4 (1.3 to 29.7)	1.4 (1.2 to 11.0)
Intracranial TTR, n=6,10,22,24,16,14,4	2.1 (1.2 to 2.8)	1.4 (1.2 to 1.5)	1.4 (1.1 to 5.7)	1.7 (1.2 to 17.5)	1.4 (1.2 to 10.6)	1.4 (1.2 to 28.9)	2.0 (1.1 to 4.2)

No statistical analyses for this end point

Secondary: Duration of Response (DOR) and Intracranial DOR (Phase 2 and DDI Substudy)

Top of page

End point title

Duration of Response (DOR) and Intracranial DOR (Phase 2 and DDI Substudy) ^[29]

End point description

DOR: time from first documentation of objective tumor response (CR/PR) to first documentation of PD or to death due to any cause, whichever occurred first. DOR: calculated for subgroup of participants with confirmed objective tumor response. Intracranial(IC) DOR: calculated for participants with confirmed IC OR. CR:disappearance of all non-lymph node target lesions (where all target lesions are recorded with length of 0mm on Target Lesion eCRF). Any pathological lymph node (recorded as target lesion) must have reduction in short axis to <10mm. PR:30% or more decrease in SLD of target lesion, taking as reference baseline SLD. PD:20% or more increase in SLD of target lesion relative to baseline or smallest SLD (nadir) recorded since first dose, demonstrate absolute increase of at least 5mm (>=5mm) relative to baseline or smallest SLD.99999: Upper limit could not be calculated due to insufficient number of participants with events.

End point type

Secondary

End point timeframe

From first dose of study treatment to first documentation of PD or to death due to any cause, whichever occurred first (maximum of 89.65 months of treatment exposure for Phase 2 and maximum of 68.69 months of treatment exposure for DDI participants)

Notes
[29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	EXP-1 (Phase 2)	EXP-2 (Phase 2)	EXP-3 (Phase 2)	EXP-4 (Phase 2)	EXP-5 (Phase 2)	EXP-6 (Phase 2)	DDI Substudy
Number of subjects analysed	27	21	34	26	17	18	13
Units: Months
median (confidence interval 95%)
DOR, n=27,21,34,26,17,18,13	17.16 (12.45 to 35.09)	16.56 (4.20 to 99999)	11.10 (5.55 to 99999)	15.08 (5.55 to 26.28)	7.03 (4.17 to 11.01)	19.61 (11.10 to 99999)	5.19 (4.17 to 99999)
Intra-cranial DOR, n=6,10,22,24,16,14,4	99999 (8.28 to 99999)	99999 (20.99 to 99999)	37.12 (8.38 to 99999)	14.52 (11.07 to 99999)	10.32 (6.90 to 14.98)	17.62 (4.99 to 99999)	99999 (2.76 to 99999)

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving Disease Control and Intracranial Disease Control at Week 12 and 24 (Phase 2 and DDI Substudy)

Top of page

End point title

Percentage of Participants Achieving Disease Control and Intracranial Disease Control at Week 12 and 24 (Phase 2 and DDI Substudy) ^[30]

End point description

Tumor response was evaluated according to RECIST version 1.1, and disease control:confirmed CR, PR, or stable disease (SD). CR: disappearance of all non-lymph node target lesions (where all target lesions are recorded with length of 0 mm on Target Lesions eCRF). Any pathological lymph nodes (recorded as target lesion) must have reduction in short axis to <10 mm. PR: 30 % or more decrease in SLD of target lesions, taking as reference the baseline SLD. SD= when neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD is observed, taking as reference smallest sum diameters while on study. Intracranial assessment was only performed for participants CNS metastases. ITT analysis set:all enrolled participants with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922; participants with CNS metastases in ITT analysis set was used for intracranial response assessment. 'Number Analyzed': participants evaluable for specified rows.

End point type

Secondary

End point timeframe

Weeks 12 and 24

Notes
[30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	EXP-1 (Phase 2)	EXP-2 (Phase 2)	EXP-3 (Phase 2)	EXP-4 (Phase 2)	EXP-5 (Phase 2)	EXP-6 (Phase 2)	DDI Substudy
Number of subjects analysed	30	27	60	65	46	47	32
Units: Percentage of participants
number (confidence interval 95%)
DCR at Week 12, n=30,27,60,65,47,47,32	93.3 (77.9 to 99.2)	85.2 (66.3 to 95.8)	68.3 (55.0 to 79.7)	64.6 (51.8 to 76.1)	50.0 (34.9 to 65.1)	66.0 (50.7 to 79.1)	56.3 (37.7 to 73.6)
DCR at Week 24, n=30,27,60,65,47,47,32	83.3 (65.3 to 94.4)	63.0 (42.4 to 80.6)	51.7 (38.4 to 64.8)	49.2 (36.6 to 61.9)	32.6 (19.5 to 48.0)	48.9 (34.1 to 63.9)	34.4 (18.6 to 53.2)
Intra-cranial DCR at Week 12,n=8,17,33,45,37,25,16	87.5 (47.3 to 99.7)	94.1 (71.3 to 99.9)	75.8 (57.7 to 88.9)	75.6 (60.5 to 87.1)	67.6 (50.2 to 82.0)	72.0 (50.6 to 87.9)	56.3 (29.9 to 80.2)
Intra-cranial DCR at Week 24,n=8,17,33,45,37,25,16	75.0 (34.9 to 96.8)	70.6 (44.0 to 89.7)	60.6 (42.1 to 77.1)	62.2 (46.5 to 76.2)	48.6 (31.9 to 65.6)	52.0 (31.3 to 72.2)	43.8 (19.8 to 70.1)

No statistical analyses for this end point

Secondary: Time to Progression on the Last Prior Therapy (Phase 2)

Top of page

End point title

Time to Progression on the Last Prior Therapy (Phase 2) ^[31]

End point description

TTP on last prior therapy was defined as time from first dose date of last prior treatment regimen to date of progression. Progressive disease: 20% or more increase in SLD of target lesions relative to baseline or smallest SLD (nadir) recorded since first dose. SLD must also demonstrate an absolute increase of at least 5 mm (>= 5 mm) relative to baseline or smallest SLD (nadir) recorded since first dose.ITT analysis set: all enrolled participants with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922. As planned in SAP, this outcome measure was not analyzed for EXP-1 and EXP-6 groups. Number Analyzed: participants evaluable for specified rows. 99999: Upper limit could not be calculated due to insufficient number of participants with events.

End point type

Secondary

End point timeframe

From first dose of study treatment until progression (maximum of 89.65 months of treatment exposure for Phase 2 and maximum of 68.69 months of treatment exposure for DDI participants)

Notes
[31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	EXP-2 (Phase 2)	EXP-3 (Phase 2)	EXP-4 (Phase 2)	EXP-5 (Phase 2)
Number of subjects analysed	27	60	65	46
Units: Months
median (confidence interval 95%)
Prior systemic therapy before PF-06463922	11.5 (7.2 to 19.6)	12.8 (10.9 to 16.9)	10.2 (7.6 to 15.9)	3.7 (2.1 to 6.4)
Prior ALK+/ROS1+ TKI treatment	11.5 (7.2 to 19.6)	13.8 (11.2 to 18.1)	12.1 (7.9 to 16.4)	3.7 (2.1 to 6.6)
Prior systemic therapy other than ALK+/ROS1+ TKI	19.6 (16.1 to 99999)	8.5 (5.0 to 12.6)	5.0 (3.1 to 10.0)	5.6 (3.5 to 11.2)

No statistical analyses for this end point

Secondary: Time to Tumor Progression (TTP) and Intracranial TTP (Phase 2 and DDI Substudy)

Top of page

End point title

Time to Tumor Progression (TTP) and Intracranial TTP (Phase 2 and DDI Substudy) ^[32]

End point description

TTP: time from first dose of study treatment to first documentation of objective PD. Intracranial TTP: time from first dose of study treatment to date of first documentation of objective progression of intracranial disease, based on either new brain metastases or progression of existing brain metastases.PD: 20% or more increase in SLD of target lesions relative to baseline or smallest SLD (nadir) recorded since first dose. SLD must also demonstrate absolute increase of at least 5 mm (>= 5 mm) relative to baseline or the smallest SLD (nadir) recorded since first dose. ITT analysis set: all enrolled participants with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922; ITT participants with CNS metastases were analyzed for intracranial TTP.99999: Upper limit could not be calculated due to insufficient number of participants with events. Median and Upper limit could not be calculated due to insufficient number of participants with events.

End point type

Secondary

End point timeframe

From first dose of study treatment until progression (maximum of 89.65 months of treatment exposure for Phase 2 and maximum of 68.69 months of treatment exposure for DDI participants)

Notes
[32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	EXP-1 (Phase 2)	EXP-2 (Phase 2)	EXP-3 (Phase 2)	EXP-4 (Phase 2)	EXP-5 (Phase 2)	EXP-6 (Phase 2)	DDI Substudy
Number of subjects analysed	30	27	60	65	46	47	32
Units: Months
median (confidence interval 95%)
TTP	17.7 (12.5 to 40.5)	20.6 (5.5 to 99999)	8.2 (5.5 to 12.5)	8.4 (5.6 to 13.7)	5.6 (4.0 to 8.3)	12.5 (8.2 to 26.2)	5.7 (4.1 to 8.3)
Intracranial TTP	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (15.0 to 99999)	22.1 (15.7 to 99999)	16.4 (12.7 to 99999)	99999 (34.5 to 99999)	99999 (6.9 to 99999)

No statistical analyses for this end point

Secondary: Probability of First Event Being a Central Nervous System (CNS) Progression, Non CNS Progression, or Death (Phase 2)

Top of page

End point title

Probability of First Event Being a Central Nervous System (CNS) Progression, Non CNS Progression, or Death (Phase 2)

End point description

Probability of first event being CNS progression, non-CNS progression, or death was evaluated with competing risk approach by estimating cumulative incidence functions (range: 0-1) relative to analysis set. Time to first event being Competing Event (either CNS progression or non CNS progression or Death)=time from first dose until date of that specific event. Participants not known to have any of Competing Events were censored on date they were last assessed for disease status for PFS. Participants who presented one type of event were counted as competing cause of failure for analysis of other type of events. PD:20% or more increase in SLD of target lesion relative to baseline or smallest SLD (nadir) recorded since first dose. SLD must demonstrate absolute increase of atleast 5mm(>=5 mm) relative to baseline or smallest SLD (nadir) recorded since first dose.ITT analysis set: all enrolled participants with documented ALK or ROS1 rearrangement & received at least 1 dose of PF-06463922.

End point type

Secondary

End point timeframe

From first dose of study treatment until progression (maximum of 89.65 months of treatment exposure for Phase 2 and maximum of 68.69 months of treatment exposure for DDI participants)

End point values	Phase 2 ITT Population
Number of subjects analysed	274
Units: Probability of events
number (not applicable)
CNS progression	0.179
Non CNS progression	0.325
Death	0.055

No statistical analyses for this end point

Secondary: Progression-Free Survival (PFS) (Phase 2 and DDI Substudy)

Top of page

End point title

Progression-Free Survival (PFS) (Phase 2 and DDI Substudy) ^[33]

End point description

PFS was defined as time from first dose of study treatment to first documentation of objective disease progression or to death on study due to any cause, whichever came first. Progressive disease was defined by a 20% or more increase in SLD of target lesions relative to baseline or smallest SLD (nadir) recorded since first dose. In addition to relative increase of 20%, SLD must also demonstrate an absolute increase of at least 5 mm (>= 5 mm) relative to baseline or smallest SLD (nadir) recorded since first dose. Results presented here were based on independent central review. PFS analysis set included all participants with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922. 99999: Upper limit could not be calculated due to insufficient number of participants with events.

End point type

Secondary

End point timeframe

From first dose of study treatment to first documentation of objective disease progression or death due to any cause, whichever came first(maximum of 89.65 month of treatment exposure-Phase 2, maximum of 68.69 month of treatment exposure-DDI participant)

Notes
[33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	EXP-1 (Phase 2)	EXP-2 (Phase 2)	EXP-3 (Phase 2)	EXP-4 (Phase 2)	EXP-5 (Phase 2)	EXP-6 (Phase 2)	DDI Substudy
Number of subjects analysed	30	27	60	65	46	47	32
Units: Months
median (confidence interval 95%)	16.6 (11.8 to 28.3)	20.6 (5.5 to 99999)	6.9 (5.5 to 11.0)	7.3 (4.2 to 11.1)	5.5 (3.9 to 8.2)	9.9 (5.5 to 21.0)	5.7 (4.0 to 7.1)

No statistical analyses for this end point

Secondary: Overall Survival (Phase 2 and DDI Substudy)

Top of page

End point title

Overall Survival (Phase 2 and DDI Substudy) ^[34]

End point description

OS was defined as the time from first dose to the date of death due to any cause. For participants still alive at the time of analysis, the OS time was censored on the last date the participants were known to be alive. Estimates of OS and its 95% confidence interval were determined using Kaplan-Meier method. ITT analysis set: all enrolled participants with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922. 99999: Median and upper limit could not be calculated due to insufficient number of participants with events.

End point type

Secondary

End point timeframe

From first dose of study treatment until date of death (maximum of 89.65 months of treatment exposure for Phase 2 and maximum of 68.69 months of treatment exposure for DDI participants)

Notes
[34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	EXP-1 (Phase 2)	EXP-2 (Phase 2)	EXP-3 (Phase 2)	EXP-4 (Phase 2)	EXP-5 (Phase 2)	EXP-6 (Phase 2)	DDI Substudy
Number of subjects analysed	30	27	60	65	46	47	32
Units: Months
median (confidence interval 95%)	99999 (99999 to 99999)	52.5 (24.4 to 99999)	99999 (38.5 to 99999)	18.7 (15.1 to 34.1)	20.4 (10.5 to 31.6)	49.7 (21.0 to 99999)	19.8 (11.1 to 99999)

No statistical analyses for this end point

Secondary: Maximum Observed Plasma Concentration (Cmax) of PF-06463922 (Phase 2)

Top of page

End point title

Maximum Observed Plasma Concentration (Cmax) of PF-06463922 (Phase 2)

End point description

Maximum observed plasma concentration (Cmax) of PF-06463922 was observed directly from data. PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922. Here, "Overall Number Analyzed" signifies participants analyzed for this outcome measure. Here, 'Number Analyzed' signifies participants evaluable for specified rows.

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15

End point values	Phase 2 and Japan LIC PK Analysis Set
Number of subjects analysed	22
Units: ng/mL
geometric mean (geometric coefficient of variation)
Day -7, n=19	695.2 ( 40 )
Cycle 1 Day 15, n=22	576.5 ( 42 )

No statistical analyses for this end point

Secondary: Time for Cmax (Tmax) of PF-06463922 (Phase 2)

Top of page

End point title

Time for Cmax (Tmax) of PF-06463922 (Phase 2)

End point description

Tmax of PF-06463922 was observed directly from data as time of first occurrence. PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922. Here, "Number Analyzed" signifies participants analyzed for this outcome measure. Here, 'Number Analyzed' signifies participants evaluable for specified rows.

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15

End point values	Phase 2 and Japan LIC PK Analysis Set
Number of subjects analysed	22
Units: Hours
median (full range (min-max))
Day -7, n=19	1.15 (0.50 to 4.02)
Cycle 1 Day 15, n=22	1.96 (0.50 to 22.7)

No statistical analyses for this end point

Secondary: Area under the Plasma Concentration-Time Profile from Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06463922 (Phase 2)

Top of page

End point title

Area under the Plasma Concentration-Time Profile from Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06463922 (Phase 2)

End point description

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7

End point values	Phase 2 and Japan LIC PK Analysis Set
Number of subjects analysed	16
Units: ng*hour/mL
geometric mean (geometric coefficient of variation)	9088 ( 35 )

No statistical analyses for this end point

Secondary: Area under the Plasma Concentration-Time profile from Time Zero to Time Tau (AUCtau) of PF-06463922 (Phase 2)

Top of page

End point title

Area under the Plasma Concentration-Time profile from Time Zero to Time Tau (AUCtau) of PF-06463922 (Phase 2)

End point description

Tau refers to the dosing interval, and it equals to 24 hours for QD dosing which was adopted in Phase 2. AUCtau was determined using linear/log trapezoidal method. PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922. Here, 'Number Analyzed' signifies participants evaluable for specified row.

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15

End point values	Phase 2 and Japan LIC PK Analysis Set
Number of subjects analysed	22
Units: ng*hour/mL
geometric mean (geometric coefficient of variation)
Day -7, n=19	5308 ( 36 )
Cycle 1 Day 15, n=22	5650 ( 39 )

No statistical analyses for this end point

Secondary: Apparent Volume of Distribution (Vz/F) of PF-06463922 (Phase 2)

Top of page

End point title

Apparent Volume of Distribution (Vz/F) of PF-06463922 (Phase 2)

End point description

Vz/F was defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug, and calculated as dose/(AUCinf*kel), where AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time, kel was the rate constant for terminal phase. PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922. Here, "Overall Number of Participants Analyzed" signifies participants evaluable for this outcome measure.

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7

End point values	Phase 2 and Japan LIC PK Analysis Set
Number of subjects analysed	16
Units: Liters
geometric mean (geometric coefficient of variation)	351.5 ( 37 )

No statistical analyses for this end point

Secondary: Apparent Oral Clearance (CL/F) of PF-06463922 (Phase 2)

Top of page

End point title

Apparent Oral Clearance (CL/F) of PF-06463922 (Phase 2)

End point description

Clearance of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL/F was calculated as dose/AUCinf, where AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time.PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922. Here, 'Number Analyzed' signifies participants evaluable for specified row.

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7 and pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15

End point values	Phase 2 and Japan LIC PK Analysis Set
Number of subjects analysed	22
Units: Liter/hour
geometric mean (geometric coefficient of variation)
Day -7, n=16	11.01 ( 35 )
Cycle 1 Day 15, n=22	17.70 ( 39 )

No statistical analyses for this end point

Secondary: Terminal Half-Life of PF-06463922 (Phase 2)

Top of page

End point title

Terminal Half-Life of PF-06463922 (Phase 2)

End point description

Terminal plasma half-life was defined as the time measured for the plasma concentration to decrease by one half, and calculated as loge(2)/kel, where kel was the rate constant for terminal phase. PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922. Here, "Overall Number of Participants Analyzed" signifies participants evaluable for this outcome measure.

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9, 24, 48, 72, 96 and 120 hours post-dose on Day -7

End point values	Phase 2 and Japan LIC PK Analysis Set
Number of subjects analysed	16
Units: Hours
arithmetic mean (standard deviation)	23.58 ( 9.3743 )

No statistical analyses for this end point

Secondary: Observed Accumulation Ratio (Rac) of PF-06463922 Following Multiple Oral Doses (Phase 2)

Top of page

End point title

Observed Accumulation Ratio (Rac) of PF-06463922 Following Multiple Oral Doses (Phase 2)

End point description

Rac was calculated as Day 15 AUCtau/Day -7 AUCtau, where AUCtau was the area under the plasma concentration-time profile from time 0 to time tau (24 hours for QD dosing regimen which was adopted in Phase 2). PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922. Here, "Overall Number of Participants Analyzed" signifies participants evaluable for this outcome measure.

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15

End point values	Phase 2 and Japan LIC PK Analysis Set
Number of subjects analysed	20
Units: Ratio
arithmetic mean (standard deviation)	1.082 ( 0.42701 )

No statistical analyses for this end point

Secondary: Steady State Accumulation Ratio (Rss) of PF-06463922 Following Multiple Oral Doses (Phase 2)

Top of page

End point title

Steady State Accumulation Ratio (Rss) of PF-06463922 Following Multiple Oral Doses (Phase 2)

End point description

Rss was calculated as Day 15 AUCtau/Day -7 AUCinf, where AUCtau was the area under the plasma concentration-time profile from time 0 to time tau (24 hours for QD dosing regimen which was adopted in Phase 2), and AUCinf was the area under the plasma concentration-time profile from time 0 extrapolated to infinite time. PK parameter analysis set for PF-06463922 included all enrolled participants who received at least 1 dose of PF-06463922 and had sufficient information to estimate at least one of the PK parameters of interest for PF-06463922. Here, "Overall Number of Participants Analyzed" signifies participants evaluable for this outcome measure.

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cycle 1 Day 15

End point values	Phase 2 and Japan LIC PK Analysis Set
Number of subjects analysed	14
Units: Ratio
arithmetic mean (standard deviation)	0.6577 ( 0.28627 )

No statistical analyses for this end point

Secondary: Number of Participants with ALK Mutation Based on Tumor Tissue Analysis (Phase 2)

Top of page

End point title

Number of Participants with ALK Mutation Based on Tumor Tissue Analysis (Phase 2) ^[35]

End point description

Tumor tissues from archived tissue specimens and/or a de novo biopsy were analyzed for ALK kinase domain mutations. Number of participants with one or more ALK mutations is presented. Tumor Tissue analysis set included all participants of the ITT analysis set who had at least 1 molecular tumor biomarker assayed from either the screening archival or screening de novo tumor biopsy sample (or both). Tumor Tissue analysis set included all participants of the ITT analysis set who had at least 1 molecular tumor biomarker assayed from either the screening archival or screening de novo tumor biopsy sample (or both).

End point type

Secondary

End point timeframe

Screening (up to 28 days)

Notes
[35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	EXP-1 (Phase 2)	EXP-2 (Phase 2)	EXP-3 (Phase 2)	EXP-4 (Phase 2)	EXP-5 (Phase 2)
Number of subjects analysed	29	26	58	63	44
Units: Participants	0	7	8	12	13

No statistical analyses for this end point

Secondary: Number of Participants with ALK Mutation Based on Plasma CNA Analysis (Phase 2)

Top of page

End point title

Number of Participants with ALK Mutation Based on Plasma CNA Analysis (Phase 2) ^[36]

End point description

Plasma CNA samples were analyzed for ALK kinase domain mutations by Next Generation Sequencing (NGS). Number of participants with one or more ALK mutations is presented. CNA peripheral blood analysis set included all participants of the ITT analysis set who had at least 1 molecular biomarker assayed. CNA peripheral blood analysis set included all participants of the ITT analysis set who had at least 1 molecular biomarker assayed. Here, "Overall Number of Participants Analyzed" signifies participants evaluable for this outcome measure.

End point type

Secondary

End point timeframe

Screening (up to 28 days)

Notes
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	EXP-1 (Phase 2)	EXP-2 (Phase 2)	EXP-3 (Phase 2)	EXP-4 (Phase 2)	EXP-5 (Phase 2)
Number of subjects analysed	30	26	59	61	46
Units: Participants	0	6	8	17	14

No statistical analyses for this end point

Secondary: Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-C30 (Phase 2 and DDI sub-study)

Top of page

End point title

Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-C30 (Phase 2 and DDI sub-study) ^[37]

End point description

EORTC QLQ-C30 (v3.0) consists of 30 questions assessing 5 functional domains (physical, role, emotional, cognitive and social), global QoL, disease/treatment related symptoms (fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, constipation and diarrhea), and the perceived financial impact of disease. Each scale was transformed to a range of 0 to 100 using standard EORTC algorithm. For global QoL and functional scales, higher score indicate better performance, and improvement: increase of at least 10 points, worsening: decrease of at least 10 points. For symptom scales, higher score indicates worse symptoms, and improvement: decrease of at least 10 points, worsening: increase of at least 10 points. All scales which had not improved nor worsened were considered stable.PRO evaluable analysis set: all enrolled participants who received at least 1 dose of PF-06463922 and completed baseline, at least 1 post-baseline PRO assessment.

End point type

Secondary

End point timeframe

From first dose of study treatment to end of treatment (maximum of 89.65 months of treatment exposure for Phase 2 and maximum of 68.69 months of treatment exposure for DDI participants)

Notes
[37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	EXP-1 (Phase 2)	EXP-2 (Phase 2)	EXP-3 (Phase 2)	EXP-4 (Phase 2)	EXP-5 (Phase 2)	EXP-6 (Phase 2)	DDI Substudy
Number of subjects analysed	30	26	55	60	43	41	32
Units: Participants
Improved in global QoL, n=30,26,55,60,43,41,32	17	11	18	25	17	19	12
Stable in global QoL,n=30,26,55,60,43,41,32	10	12	24	22	16	15	18
Worsened in global QoL,n=30,26,55,60,43,41,32	3	3	13	13	10	6	2
Improved physical function,n=30,26,55,60,43,41,32	11	8	13	24	8	11	5
Stable physical function,n=30,26,55,60,43,41,32	13	17	38	24	25	23	23
Worsened physical function,n=30,26,55,60,43,41,32	6	1	4	12	10	6	4
Improved in role function,n=30,26,55,60,43,39,32	12	7	15	25	18	17	10
Stable role function,n=30,26,55,60,43,39,32	9	16	33	18	13	17	15
Worsened role function,n=30,26,55,60,43,39,32	9	3	7	17	12	5	7
Improved emotional function,n=30,26,55,60,43,41,32	13	12	13	20	17	16	10
Stable emotional function,n=30,26,55,60,43,41,32	13	14	32	34	20	22	20
Worsened emotional function,n=30,26,55,60,43,41,32	4	0	10	6	6	2	2
Improved cognitive function,n=30,26,55,60,43,41,32	9	4	5	12	12	12	9
Stable cognitive function,n=30,26,55,60,43,41,32	12	14	36	34	19	20	11
Worsened cognitive function,n=30,26,55,60,43,41,32	9	8	14	14	12	8	12
Improved social function,n=30,26,55,60,43,41,32	14	7	16	20	11	13	13
Stable in social function,n=30,26,55,60,43,41,32	11	16	33	29	21	18	13
Worsened social function,n=30,26,55,60,43,41,32	5	3	6	11	11	9	6
Improved fatigue,n=30,26,55,60,43,41,32	18	14	22	28	26	16	17
Stable in fatigue,n=30,26,55,60,43,41,32	8	11	25	23	9	20	9
Worsened in fatigue,n=30,26,55,60,43,41,32	4	1	8	9	8	4	6
Improved nausea & vomiting,n=30,26,55,60,43,41,32	8	5	10	16	13	10	6
Stable nausea & vomiting,n=30,26,55,60,43,41,32	22	21	44	39	28	28	24
Worsened nausea & vomiting,n=30,26,55,60,43,41,32	0	0	1	5	2	2	2
Improved in pain,n=30,26,55,60,43,41,32	13	10	20	23	19	21	14
Stable in pain,n=30,26,55,60,43,41,32	10	14	25	28	19	12	13
Worsened in pain,n=30,26,55,60,43,41,32	7	2	10	9	5	7	5
Improved in dyspnea,n=30,26,55,60,43,41,32	16	10	10	23	14	14	9
Stable in dyspnea,n=30,26,55,60,43,41,32	10	14	33	22	18	17	15
Worsened in dyspnea,n=30,26,55,60,43,41,32	4	2	12	15	11	9	8
Improved in insomnia,n=30,26,55,60,43,41,32	20	8	18	30	21	19	12
Stable in insomnia,n=30,26,55,60,43,41,32	9	13	28	22	16	18	15
Worsened in insomnia,n=30,26,55,60,43,41,32	1	5	9	8	6	3	5
Improved in appetite loss,n=30,26,55,60,43,41,32	14	4	18	29	22	20	10
Stable in appetite loss,n=30,26,55,60,43,41,32	16	22	36	26	21	20	20
Worsened in appetite loss,n=30,26,55,60,43,41,32	0	0	1	5	0	0	2
Improved in constipation,n=30,26,55,60,43,41,32	10	5	9	16	11	13	10
Stable in constipation,n=30,26,55,60,43,41,32	14	19	33	33	29	22	12
Worsened in constipation,n=30,26,55,60,43,41,32	6	2	13	11	3	5	10
Improved in diarrhea,n=30,26,55,60,43,41,32	5	3	10	10	10	8	6
Stable in diarrhea,n=30,26,55,60,43,41,32	18	21	40	39	27	28	21
Worsened in diarrhea,n=30,26,55,60,43,41,32	7	2	5	11	6	4	5
Improved finance difficulty,n=30,26,55,60,43,41,32	10	6	11	13	10	10	9
Stable financial difficulty,n=30,26,55,60,43,41,32	17	19	34	38	22	26	16
Worsen financial difficulty,n=30,26,55,60,43,41,32	3	1	10	9	11	4	7

No statistical analyses for this end point

Secondary: Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-LC13 (Phase 2 and DDI sub-study)

Top of page

End point title

Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-LC13 (Phase 2 and DDI sub-study) ^[38]

End point description

EORTC QLQ-LC13 is the lung cancer module of EORTC QLQ-C30 and includes questions specific to the disease associated symptoms (dyspnea, cough, hemoptysis, and site specific pain), treatment-related symptoms (sore mouth, dysphagia, neuropathy and alopecia), and analgesic use of lung cancer patients. Scale was transformed to a range of 0 to 100 using standard EORTC algorithm. Higher score indicates worse symptoms, and improvement: decrease of at least 10 points, worsening was defined as an increase of at least 10 points. All scales which had not improved nor worsened were considered stable. PRO evaluable analysis set: all enrolled participants who received at least 1 dose of PF-06463922 and completed a baseline and at least 1 post-baseline PRO assessment. Here, "Overall Number of Participants Analyzed" signifies participants evaluable for this outcome measure.

End point type

Secondary

End point timeframe

From first dose of study treatment to end of treatment (maximum of 89.65 months of treatment exposure for Phase 2 and maximum of 68.69 months of treatment exposure for DDI participants)

Notes
[38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	EXP-1 (Phase 2)	EXP-2 (Phase 2)	EXP-3 (Phase 2)	EXP-4 (Phase 2)	EXP-5 (Phase 2)	EXP-6 (Phase 2)	DDI Substudy
Number of subjects analysed	30	26	55	60	43	41	32
Units: Participants
Improved in dyspnea	11	5	9	21	12	12	6
Stable in dyspnea	16	18	36	25	21	23	18
Worsened in dyspnea	3	3	10	14	9	6	8
Improved in coughing	18	9	22	26	18	17	16
Stable in coughing	9	13	26	28	15	18	15
Worsened in coughing	3	4	7	6	9	6	1
Improved in hemoptysis	4	0	7	5	5	4	1
Stable in hemoptysis	24	25	47	52	34	36	31
Worsened in hemoptysis	2	1	1	3	3	1	0
Improved in sore mouth	0	2	4	9	2	5	4
Stable in sore mouth	25	20	44	41	33	28	26
Worsened in sore mouth	5	4	7	10	7	8	2
Improved in dysphagia	3	1	3	7	4	5	3
Stable in dysphagia	23	24	46	48	33	30	27
Worsened in dysphagia	4	1	6	5	5	6	2
Improved in peripheral neuropathy	4	5	9	5	6	9	9
Stable in peripheral neuropathy	10	13	27	33	22	18	16
Worsened in peripheral neuropathy	16	8	19	22	14	14	7
Improved in alopecia	2	1	2	10	10	9	4
Stable in alopecia	18	22	41	40	24	27	21
Worsened in alopecia	10	3	12	10	8	5	7
Improved in chest pain	11	7	13	18	14	14	13
Stable in chest pain	17	17	35	33	25	24	17
Worsened in chest pain	2	2	6	9	3	3	2
Improved in arm or shoulder pain	10	5	14	14	12	12	9
Stable in arm or shoulder pain	15	19	30	36	21	22	19
Worsened in arm or shoulder pain	5	2	11	10	9	7	4
Improved in pain in other parts	9	6	17	20	15	17	9
Stable in pain in other parts	14	15	23	24	9	18	10
Worsened in pain in other parts	7	5	15	16	17	6	12

No statistical analyses for this end point

Secondary: Number of Participants with Treatment-Emergent Adverse Events (Phase 1, Phase 2 and DDI sub-study)

Top of page

End point title

Number of Participants with Treatment-Emergent Adverse Events (Phase 1, Phase 2 and DDI sub-study) ^[39]

End point description

AE: any untoward medical occurrence in clinical investigation participant administered product or medical device, regardless of causal relationship to study treatment. Treatment-emergent AEs (TEAE): AE which occurred for first time during effective duration of treatment or AE that increased in severity during treatment. Serious AE (SAE): any untoward medical occurrence at any dose that resulted in death; was life-threatening, required inpatient hospitalization or caused prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity (substantial disruption of ability to conduction normal life function). Severity graded as per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.Grade (G)1: mild, G2:moderate, G3:severe, G4:Life threatening consequences; urgent intervention indicated, G5:death related to AE. Safety analysis set: all enrolled participants who received atleast 1 dose of PF-06463922.

End point type

Secondary

End point timeframe

From first dose of study treatment to end of treatment (maximum of 96.58 months of treatment exposure for Phase 1, maximum of 89.65 months of treatment exposure for Phase 2 and maximum of 68.69 months of treatment exposure for DDI participants)

Notes
[39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	10 mg QD (Phase 1)	25 mg QD (Phase 1)	50 mg QD (Phase 1)	75 mg QD (Phase 1)	100 mg QD (Phase 1)	150 mg QD (Phase 1)	200 mg QD (Phase 1)	35 mg BID (Phase 1)	75 mg BID (Phase 1)	100 mg BID (Phase 1)	DDI Substudy	Phase 2
Number of subjects analysed	3	3	3	12	17	3	3	3	3	4	32	275
Units: Participants
AEs (all causality)	3	3	3	12	17	3	3	3	3	4	32	274
AEs (treatment-related)	3	3	3	11	16	3	3	1	3	4	31	262
SAEs (all causality)	3	2	1	6	10	3	2	2	2	2	13	135
SAEs (treatment-related)	1	1	0	1	1	3	0	0	0	1	1	27
Grade 3 or 4 (all causality)	3	3	0	6	12	3	2	2	1	4	24	209
Grade 3 or 4 (treatment-related)	2	2	0	3	6	2	0	0	1	3	16	137
Grade 5 (all causality)	1	1	0	1	4	2	0	0	1	0	5	43
Grade 5 (treatment-related)	0	0	0	0	0	0	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: Number of Participants with Laboratory Abnormalities (Phase 1, Phase 2 and DDI sub-study) – Hematology

Top of page

End point title

Number of Participants with Laboratory Abnormalities (Phase 1, Phase 2 and DDI sub-study) – Hematology ^[40]

End point description

Hematology evaluation included hemoglobin, platelets, white blood cell, absolute neutrophils, absolute lymphocytes, absolute monocytes, absolute eosinophils and absolute basophils. Hematology parameters with any abnormalities were reported in this outcome measure. Safety analysis set included all enrolled participants who received at least 1 dose of PF-06463922. Here, 'Number Analyzed' signifies participants evaluable for specified rows. All participants in Phase 2 received 100 mg of PF-06463922, hence combined data is presented for Phase 2.

End point type

Secondary

End point timeframe

Notes
[40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	10 mg QD (Phase 1)	25 mg QD (Phase 1)	50 mg QD (Phase 1)	75 mg QD (Phase 1)	100 mg QD (Phase 1)	150 mg QD (Phase 1)	200 mg QD (Phase 1)	35 mg BID (Phase 1)	75 mg BID (Phase 1)	100 mg BID (Phase 1)	DDI Substudy	Phase 2
Number of subjects analysed	3	3	3	12	17	3	3	3	3	4	32	275
Units: Participants
Anemia, n=3,3,3,12,17,3,3,3,3,4,273,32	3	3	3	10	16	3	3	3	3	4	25	218
Hb increased, n=3,3,3,12,17,3,3,3,3,4,273,32	0	0	0	0	0	0	0	0	0	0	1	7
LC decreased, n=3,3,3,12,17,3,3,3,3,4,272,32	2	2	2	7	4	3	3	0	0	2	15	134
LC increased, n=3,3,3,12,17,3,3,3,3,4,272,32	0	0	0	0	3	1	0	0	0	0	2	15
NC decreased, n=3,3,3,12,17,3,3,3,3,4,272,32	1	0	0	4	2	0	1	0	0	1	3	37
PC decreased, n=3,3,3,12,17,3,3,3,3,4,273,32	2	2	0	4	5	1	0	0	0	1	8	74
WBC decreased, n=3,3,3,12,17,3,3,3,3,4,273,32	2	1	0	4	2	2	2	0	0	1	4	54

No statistical analyses for this end point

Secondary: Number of Participants with Laboratory Abnormalities (Phase 1, Phase 2 and DDI sub-study) – Chemistry

Top of page

End point title

Number of Participants with Laboratory Abnormalities (Phase 1, Phase 2 and DDI sub-study) – Chemistry ^[41]

End point description

Chemistry evaluation included alanine aminotransferase (ALT), alkaline phosphatase, aspartate aminotransferase (AST), blood bilirubin, creatine phosphokinase (CPK), creatinine, gamma-glutamyl transferase (GGT), calcium, sodium, potassium, magnesium, albumin, glucose (non-fasted), albumin, phosphorus or phosphate, serum amylase and lipase. The safety analysis set included all enrolled participants who received at least 1 dose of PF-06463922. Here, "Overall Number of Participants Analyzed" signifies participants evaluable for this outcome measure. Here, 'Number Analyzed' signifies participants evaluable for specified rows. All participants in Phase 2 received 100 mg of PF-06463922, hence combined data is presented for Phase 2.

End point type

Secondary

End point timeframe

Notes
[41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	10 mg QD (Phase 1)	25 mg QD (Phase 1)	50 mg QD (Phase 1)	75 mg QD (Phase 1)	100 mg QD (Phase 1)	150 mg QD (Phase 1)	200 mg QD (Phase 1)	35 mg BID (Phase 1)	75 mg BID (Phase 1)	100 mg BID (Phase 1)	DDI Substudy	Phase 2
Number of subjects analysed	3	3	3	12	17	3	3	3	3	4	32	273
Units: Participants
ALT increased, n=3,3,3,12,17,3,3,3,3,4,272,32	2	1	1	6	9	2	2	0	0	3	10	109
ALP increased, n=3,3,3,12,17,3,3,3,3,4,272,32	1	1	3	6	10	3	1	0	2	3	9	118
AST increased, n=3,3,3,12,17,3,3,3,3,4,272,32	2	2	2	5	8	2	2	0	1	3	11	139
Bilirubin increased,n=3,3,3,12,17,3,3,3,3,4,272,32	1	0	0	1	0	0	0	0	0	1	1	8
CPK increased, n=0,0,0,0,3,1,0,0,1,0,18,2	99999	99999	99999	99999	1	1	99999	99999	1	99999	1	9
Creat. increased, n=3,3,3,12,17,3,3,3,3,4,273,32	3	2	3	10	13	3	3	2	2	3	20	209
GGT increased, n=1,0,0,0,4,1,1,0,1,2,13,1	0	99999	99999	99999	1	0	1	99999	0	2	0	8
Hypercalcemia, n=3,3,3,12,17,3,3,3,3,4,273,32	0	0	0	0	3	1	0	0	0	1	5	33
Hyperglycemia, n=3,3,3,12,17,3,3,3,3,4,273,32	3	3	2	7	8	2	1	1	2	1	23	185
Hyperkalemia, n=3,3,3,12,17,3,3,3,3,4,273,32	0	1	2	3	6	1	1	1	1	2	5	71
Hypermagnesemia, n=3,3,3,12,17,3,3,3,3,4,272,32	2	0	0	2	2	0	0	0	0	0	0	14
Hypernatremia, n=3,3,3,12,17,3,3,3,3,4,273,32	0	1	0	0	4	2	0	0	0	1	3	35
Hypoalbuminemia, n=3,3,3,12,17,3,3,3,3,4,271,32	2	1	3	4	7	3	1	1	3	1	18	180
Hypocalcemia, n=3,3,3,12,17,3,3,3,3,4,273,32	1	0	1	4	5	2	1	0	0	1	6	53
Hypoglycemia, n=3,3,3,12,17,3,3,3,3,4,273,32	0	0	1	3	4	0	1	0	1	0	6	33
Hypokalemia, n=3,3,3,12,17,3,3,3,3,4,273,32	0	0	2	4	3	3	1	1	0	2	7	57
Hypomagnesemia, n=3,3,3,12,17,3,3,3,3,4,272,32	0	1	2	4	2	3	0	1	1	3	15	89
Hyponatremia, n=3,3,3,12,17,3,3,3,3,4,273,32	2	1	1	2	4	1	1	0	2	2	10	78
Hypophosphatemia, n=3,3,3,12,17,3,3,3,3,4,272,32	1	2	0	3	3	2	1	1	2	1	9	82
Lipase increased, n=3,3,3,12,17,3,3,3,3,4,270,32	3	0	0	8	6	0	1	0	2	2	7	80
S.amylase increased,n=3,3,1,11,16,3,3,3,2,4,265,32	3	0	0	2	5	0	1	0	0	2	4	83

No statistical analyses for this end point

Secondary: Number of Participants with Laboratory Abnormalities (Phase 1, Phase 2 and DDI sub-study) – Coagulation, Lipids and Urinalysis

Top of page

End point title

Number of Participants with Laboratory Abnormalities (Phase 1, Phase 2 and DDI sub-study) – Coagulation, Lipids and Urinalysis ^[42]

End point description

Coagulation evaluation included activated partial thromboplastin time, international normalized ratio (INR), and prothrombin time. Lipid evaluation included Cholesterol and triglycerides. The safety analysis set included all enrolled participants who received at least 1 dose of PF-06463922. Here, "Overall Number of Participants Analyzed" signifies participants evaluable for this outcome measure. Here, 'Number Analyzed' signifies participants evaluable for specified rows. All participants in Phase 2 received 100 mg of PF-06463922, hence combined data is presented for Phase 2.

End point type

Secondary

End point timeframe

Notes
[42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	10 mg QD (Phase 1)	25 mg QD (Phase 1)	50 mg QD (Phase 1)	75 mg QD (Phase 1)	100 mg QD (Phase 1)	150 mg QD (Phase 1)	200 mg QD (Phase 1)	35 mg BID (Phase 1)	75 mg BID (Phase 1)	100 mg BID (Phase 1)	DDI Substudy	Phase 2
Number of subjects analysed	3	3	3	12	17	3	3	3	3	4	32	272
Units: Participants
APTT prolonged, n=3,3,3,11,14,3,3,3,3,3,82,21	1	0	1	3	2	0	0	0	0	0	2	14
Cholesterol high, n=2,2,12,17,2,3,3,3,4,272,32	2	2	2	10	16	2	3	3	2	3	31	267
Hypertriglyceridemia, n=1,2,12,17,2,3,3,3,4,272,32	0	2	2	11	16	2	3	2	1	3	31	261
INR increased, n=3,3,3,11,14,3,3,3,3,3,113,24	2	1	1	2	2	1	0	0	0	0	3	21
Prothrombin time, n=3,3,3,11,14,3,3,3,3,3,103,21	2	1	1	3	3	1	0	0	1	1	6	25

No statistical analyses for this end point

Secondary: Number of Participants with Vital Signs Data Meeting Pre-defined Criteria (Phase 1, Phase 2 and DDI sub-study)

Top of page

End point title

Number of Participants with Vital Signs Data Meeting Pre-defined Criteria (Phase 1, Phase 2 and DDI sub-study) ^[43]

End point description

Blood pressure (BP), including systolic BP (SBP) and diastolic BP (DBP), and pulse rate were recorded in sitting position. Body weight was also measured. The safety analysis set included all enrolled participants who received at least 1 dose of PF-06463922. Here, "Overall Number of Participants Analyzed" signifies participants evaluable for this outcome measure. 'Number Analyzed' signifies participants evaluable for specified row. All participants in Phase 2 received 100 mg of PF-06463922, hence combined data is presented for Phase 2.

End point type

Secondary

End point timeframe

Notes
[43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	10 mg QD (Phase 1)	25 mg QD (Phase 1)	50 mg QD (Phase 1)	75 mg QD (Phase 1)	100 mg QD (Phase 1)	150 mg QD (Phase 1)	200 mg QD (Phase 1)	35 mg BID (Phase 1)	75 mg BID (Phase 1)	100 mg BID (Phase 1)	DDI Substudy	Phase 2
Number of subjects analysed	3	3	3	12	17	3	3	3	3	4	32	273
Units: Participants
Increa.SBP>=40mmHg,n=3,3,3,12,17,3,3,3,3,4,270,32	0	0	0	0	3	2	0	0	1	0	4	45
Increa.SBP>=60mmHg,n=3,3,3,12,17,3,3,3,3,4,270,32	0	0	0	0	0	0	0	0	0	0	0	2
Decrea.SBP>=40mmHg,n=3,3,3,12,17,3,3,3,3,4,270,32	0	0	0	3	2	1	0	0	0	0	1	14
Decrea.SBP>=60mmHg, n=3,3,3,12,17,3,3,3,3,4,270,32	0	0	0	0	0	0	0	0	0	0	0	0
Increa.DBP>=20mmHg,n=3,3,3,12,17,3,3,3,3,4,270,32	0	2	0	0	7	3	1	0	1	0	7	86
Increa.DBP>=40mmHg,n=3,3,3,12,17,3,3,3,3,4,270,32	0	0	0	0	0	0	0	0	0	0	0	8
Decrea.DBP>=20mmHg,n=3,3,3,12,17,3,3,3,3,4,270,32	2	1	0	5	3	2	2	0	1	2	8	58
Decrea.DBP>=40mmHg,n=3,3,3,12,17,3,3,3,3,4,270,32	0	0	0	0	0	0	0	0	0	0	0	1
PR <50 bpm, n=3,3,3,12,17,3,3,3,3,4,273,32	0	1	0	0	0	0	0	0	0	0	2	11
PR>120 bpm,n=3,3,3,12,17,3,3,3,3,4,273,32	0	0	1	1	2	2	0	0	0	0	3	23
Increase PR>=30 bpm,n=3,3,3,12,17,3,3,3,3,4,269,32	0	1	0	2	7	1	0	0	0	1	8	74
Decrease PR>=30bpm,n=3,3,3,12,17,3,3,3,3,4,269,32	0	0	1	2	0	1	0	1	1	2	4	36
Increase W:10-<20%,n=3,3,3,12,17,3,3,3,3,4,262,32	1	0	0	8	6	2	2	0	0	0	9	80
Increased W:>=20%,n=3,3,3,12,17,3,3,3,3,4,262,32	0	2	1	1	5	1	0	0	1	1	3	58
Decreased W>=10%,n=3,3,3,12,17,3,3,3,3,4,262,32	0	0	0	0	0	0	0	0	0	2	1	14

No statistical analyses for this end point

Secondary: Number of Participants with Maximum Decrease from Baseline Greater than or Equal to 20 Percent in Left Ventricular Ejection Fraction (LVEF) (Phase 1, Phase 2 and DDI sub-study)

Top of page

End point title

Number of Participants with Maximum Decrease from Baseline Greater than or Equal to 20 Percent in Left Ventricular Ejection Fraction (LVEF) (Phase 1, Phase 2 and DDI sub-study) ^[44]

End point description

Left Ventricular Ejection Fraction (LVEF) was determined by echocardiogram. Baseline was defined as the measurement prior to the first dose of study treatment. The safety analysis set included all enrolled participants who received at least 1 dose of PF-06463922.

End point type

Secondary

End point timeframe

Notes
[44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	10 mg QD (Phase 1)	25 mg QD (Phase 1)	50 mg QD (Phase 1)	75 mg QD (Phase 1)	100 mg QD (Phase 1)	150 mg QD (Phase 1)	200 mg QD (Phase 1)	35 mg BID (Phase 1)	75 mg BID (Phase 1)	100 mg BID (Phase 1)	DDI Substudy	Phase 2
Number of subjects analysed	3	3	3	12	17	3	3	3	3	4	32	275
Units: Participants	1	0	1	3	5	2	1	0	0	2	2	41

No statistical analyses for this end point

Secondary: Number of Participants with Absolute Values and Change from Baseline in QTcF Meeting Pre-defined Criteria (Phase 1, Phase 2 and DDI sub-study)

Top of page

End point title

Number of Participants with Absolute Values and Change from Baseline in QTcF Meeting Pre-defined Criteria (Phase 1, Phase 2 and DDI sub-study) ^[45]

End point description

Triplicate 12-lead electrocardiograms (ECGs) were performed approximately 2 minutes apart to determine mean QTc interval (QT interval corrected for heart rate). QT interval was corrected for heart rate using Fridericia’s formula to provide QTcF. Absolute values and changes from baseline were summarized according to pre-defined criteria. Baseline was defined as the last evaluation on or prior to the first dose of study treatment. The safety analysis set included all enrolled participants who received at least 1 dose of PF-06463922.

End point type

Secondary

End point timeframe

Notes
[45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	10 mg QD (Phase 1)	25 mg QD (Phase 1)	50 mg QD (Phase 1)	75 mg QD (Phase 1)	100 mg QD (Phase 1)	150 mg QD (Phase 1)	200 mg QD (Phase 1)	35 mg BID (Phase 1)	75 mg BID (Phase 1)	100 mg BID (Phase 1)	DDI Substudy	Phase 2
Number of subjects analysed	3	3	3	12	17	3	3	3	3	4	32	275
Units: Participants
QTcF: 450 to <480 msec	1	0	0	2	1	1	0	2	0	1	7	55
QTcF: 480 to <500 msec	1	0	0	0	0	0	0	0	0	1	1	7
QTcF: >=500 msec	0	0	0	0	0	0	0	0	0	0	1	3
QTcF Increase: 30 to <60 msec	0	0	1	3	3	0	0	1	0	1	7	75
QTcF: >=60 msec	0	0	0	0	0	0	0	0	0	1	1	6

No statistical analyses for this end point

Secondary: Number of Participants with Suicidal Ideation and Suicidal Behavior (Phase 2)

Top of page

End point title

Number of Participants with Suicidal Ideation and Suicidal Behavior (Phase 2) ^[46]

End point description

The Columbia Suicide Severity Rating Scale (C-SSRS) was used to analyze participants' suicidal ideation and behavior, and it is a unique, simple and short method of assessing both behavior and ideation that tracks all suicidal events and provides a summary of suicidality. It assesses the lethality of attempts and other features of ideation (frequency, duration, controllability, reasons for ideation and deterrents), all of which are significantly predictive of completed suicide. Maximum score of 4 or 5 indicates maximum suicidal ideation and minimum score of “0” indicates no suicidal ideation. The safety analysis set included all enrolled participants who received at least 1 dose of PF-06463922.

End point type

Secondary

End point timeframe

Notes
[46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	EXP-1 (Phase 2)	EXP-2 (Phase 2)	EXP-3 (Phase 2)	EXP-4 (Phase 2)	EXP-5 (Phase 2)	EXP-6 (Phase 2)
Number of subjects analysed	26	24	52	43	30	25
Units: Participants
Suicidal ideation	1	0	2	1	1	2
Suicidal behavior	0	0	0	0	0	1

No statistical analyses for this end point

Secondary: Change from Baseline in Total Scores for Beck Depression Inventory (BDI)-II (Mood Assessment) (Phase 2)

Top of page

End point title

Change from Baseline in Total Scores for Beck Depression Inventory (BDI)-II (Mood Assessment) (Phase 2) ^[47]

End point description

Beck Depression Inventory (BDI)-II is a 21-item self-report scale, with each item rated by participants on a 4-point scale (ranging from 0-3, where 0 indicated lowest depression and 3 indicated severe depression). Scale includes items capturing mood, (loss of pleasure, sadness, and irritability), suicidal ideation, and cognitive signs (punitive thoughts, self-criticism, self-dislike, pessimism, and poor concentration) as well as somatic signs (appetite, sleep, fatigue and libido). Scores were obtained by adding up the total points from the series of answers. Higher total scores indicate more severe depressive symptoms. The standardized cutoffs are as follows: 0-13: minimal depression; 14-19: mild depression; 20-28: moderate depression; 29-63: severe depression. PRO evaluable analysis set: all enrolled participants who received study treatment, had baseline test assessment and at least 1 on-study test assessment. 'Number Analyzed' signifies participants evaluable for specified row.

End point type

Secondary

End point timeframe

Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years)

Notes
[47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	EXP-1 (Phase 2)	EXP-2 (Phase 2)	EXP-3 (Phase 2)	EXP-4 (Phase 2)	EXP-5 (Phase 2)	EXP-6 (Phase 2)
Number of subjects analysed	24	24	53	41	28	26
Units: Units on scale
least squares mean (confidence interval 95%)
Cycle 2 Day 1, n=24,24,53,41,28,26	-2.59 (-4.82 to -0.37)	-3.27 (-5.52 to -1.01)	-2.26 (-3.77 to -0.76)	-2.17 (-3.89 to -0.46)	-1.52 (-3.60 to 0.56)	-2.43 (-4.57 to -0.29)
Cycle 3 Day 1, n=24,24,53,41,28,26	-3.34 (-5.57 to -1.12)	-3.18 (-5.43 to -0.93)	-3.03 (-4.55 to -1.51)	-3.10 (-4.85 to -1.35)	-0.46 (-2.61 to 1.69)	-1.24 (-3.37 to 0.90)
Cycle 4 Day 1, n=24,24,53,41,28,26	-3.84 (-6.07 to -1.62)	-4.10 (-6.38 to -1.82)	-2.59 (-4.14 to -1.05)	-1.95 (-3.72 to -0.19)	-1.19 (-3.38 to 1.01)	-1.94 (-4.12 to 0.24)
Cycle 5 Day 1, n=24,24,53,41,28,26	-4.47 (-6.69 to -2.24)	-3.96 (-6.27 to -1.66)	-2.75 (-4.33 to -1.16)	-3.03 (-4.82 to -1.25)	-1.51 (-3.74 to 0.72)	-1.25 (-3.46 to 0.95)
Cycle 6 Day 1, n=24,24,53,41,28,26	-3.51 (-5.73 to -1.28)	-4.25 (-6.56 to -1.94)	-3.31 (-4.90 to -1.72)	-3.79 (-5.61 to -1.98)	-0.42 (-2.64 to 1.81)	-0.29 (-2.54 to 1.96)
Cycle 8 Day 1, n=24,24,53,41,28,26	-4.17 (-6.41 to -1.92)	-4.86 (-7.23 to -2.50)	-2.26 (-3.86 to -0.66)	-4.06 (-5.90 to -2.22)	-1.09 (-3.34 to 1.17)	0.17 (-2.10 to 2.45)
Cycle 10 Day 1, n=24,24,53,41,28,26	-3.09 (-5.38 to -0.80)	-4.92 (-7.28 to -2.55)	-1.94 (-3.54 to -0.34)	-4.27 (-6.14 to -2.39)	-2.97 (-5.29 to -0.66)	-0.19 (-2.60 to 2.22)
Cycle 12 Day 1, n=24,24,53,41,28,26	-3.95 (-6.30 to -1.61)	-5.60 (-7.97 to -3.24)	-0.72 (-2.40 to 0.95)	-4.80 (-6.83 to -2.77)	-1.94 (-4.29 to 0.42)	-1.40 (-3.81 to 1.01)
Cycle 14 Day 1, n=24,24,53,41,28,26	-3.81 (-6.18 to -1.43)	-5.80 (-8.35 to -3.25)	-2.58 (-4.41 to -0.76)	-4.29 (-6.41 to -2.17)	-1.73 (-4.40 to 0.94)	-0.08 (-2.59 to 2.42)
Cycle 16 Day 1, n=24,24,53,41,28,26	-1.75 (-4.40 to 0.89)	-4.61 (-7.51 to -1.71)	-2.15 (-4.35 to 0.06)	-4.65 (-6.90 to -2.41)	-2.22 (-5.50 to 1.07)	0.03 (-2.65 to 2.71)
Cycle 18 Day 1, n=24,24,53,41,28,26	-4.49 (-7.49 to -1.49)	-7.02 (-10.59 to -3.46)	-1.96 (-4.22 to 0.31)	-2.86 (-5.21 to -0.51)	-1.11 (-8.25 to 6.03)	1.88 (-1.66 to 5.41)
Cycle 20 Day 1, n=24,24,53,41,0,26	-5.01 (-8.55 to -1.46)	-5.17 (-9.06 to -1.29)	-1.82 (-4.70 to 1.06)	-3.63 (-6.31 to -0.95)	99999 (99999 to 99999)	1.88 (-1.66 to 5.41)
Cycle 22 Day 1, n=24,24,53,41,0,26	-2.93 (-6.79 to 0.94)	-4.63 (-9.00 to -0.26)	-2.36 (-5.68 to 0.96)	-5.50 (-8.87 to -2.12)	99999 (99999 to 99999)	-2.39 (-6.73 to 1.94)
Cycle 24 Day 1, n=24,24,53,41,0,26	-7.31 (-11.66 to -2.96)	-5.63 (-10.00 to -1.26)	-2.88 (-7.04 to 1.28)	-3.89 (-8.10 to 0.32)	99999 (99999 to 99999)	2.27 (-2.06 to 6.61)
Cycle 26 Day 1, n=24,24,53,41,0,0	-5.50 (-10.67 to -0.33)	99999 (99999 to 99999)	-3.03 (-10.01 to 3.95)	-4.30 (-11.31 to 2.70)	99999 (99999 to 99999)	99999 (99999 to 99999)
End of treatment, n=24,24,53,41,28,26	-4.77 (-9.23 to -0.32)	-0.73 (-5.61 to 4.15)	-2.55 (-5.28 to 0.18)	-3.22 (-5.49 to -0.95)	0.74 (-2.70 to 4.17)	-2.08 (-5.65 to 1.50)

No statistical analyses for this end point

Secondary: Change from Baseline in Total Scores for Detection Test (Cognitive Function Assessment) (Phase 2)

Top of page

End point title

Change from Baseline in Total Scores for Detection Test (Cognitive Function Assessment) (Phase 2) ^[48]

End point description

Detection Test is measure of psychomotor function, uses well validated simple reaction time paradigm with playing card stimuli. In this test, on-screen instructions ask: “Has the card turned over?”.Playing card is presented face down in center of screen. Card flips over so it is face up. As soon as card flips over participant must press “Yes”. Participant is encouraged to work as quickly as they can, be as accurate as possible. Speed and accuracy of each response are recorded, mean of log10 transformed reaction times for correct responses is calculated. Lower values of least square mean change from baseline indicate performance decline. Upper limit of 95% confidence interval of -0.00 or lower indicate statistically significant decline of performance over baseline. PRO evaluable analysis set: all enrolled participants who received study treatment, had baseline test assessment, at least 1 on-study test assessment. 'Number Analyzed': participants evaluable for specified row.

End point type

Secondary

End point timeframe

Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years)

Notes
[48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	EXP-1 (Phase 2)	EXP-2 (Phase 2)	EXP-3 (Phase 2)	EXP-4 (Phase 2)	EXP-5 (Phase 2)	EXP-6 (Phase 2)
Number of subjects analysed	24	26	50	46	38	29
Units: Units on a scale
least squares mean (confidence interval 95%)
Cycle 2 Day 1, n=24,26,50,46,38,29	0.01 (-0.04 to 0.05)	0.04 (-0.01 to 0.08)	-0.01 (-0.04 to 0.02)	0.02 (-0.01 to 0.05)	-0.02 (-0.05 to 0.02)	0.01 (-0.03 to 0.05)
Cycle 3 Day 1, n=24,26,50,46,38,29	-0.01 (-0.05 to 0.03)	0.01 (-0.03 to 0.05)	0.01 (-0.02 to 0.04)	-0.01 (-0.04 to 0.02)	-0.01 (-0.05 to 0.02)	-0.01 (-0.05 to 0.03)
Cycle 4 Day 1, n=24,26,50,46,38,29	0.03 (-0.02 to 0.07)	0.00 (-0.04 to 0.04)	-0.03 (-0.06 to 0.00)	-0.02 (-0.05 to 0.01)	-0.04 (-0.07 to -0.00)	-0.01 (-0.06 to 0.03)
Cycle 5 Day 1, n=24,26,50,46,38,29	-0.01 (-0.05 to 0.03)	-0.01 (-0.06 to 0.03)	-0.00 (-0.03 to 0.03)	0.00 (-0.03 to 0.03)	-0.04 (-0.08 to -0.01)	-0.04 (-0.08 to 0.00)
Cycle 6 Day 1, n=24,26,50,46,38,29	-0.03 (-0.07 to 0.01)	0.01 (-0.03 to 0.06)	-0.02 (-0.05 to 0.01)	-0.00 (-0.04 to 0.03)	-0.01 (-0.05 to 0.02)	-0.02 (-0.07 to 0.02)
Cycle 8 Day 1, n=24,26,50,46,38,29	-0.02 (-0.06 to 0.02)	0.00 (-0.04 to 0.05)	-0.02 (-0.05 to 0.01)	-0.03 (-0.06 to 0.01)	-0.04 (-0.07 to 0.00)	0.00 (-0.04 to 0.05)
Cycle 10 Day 1, n=24,26,50,46,38,29	-0.02 (-0.06 to 0.02)	0.03 (-0.01 to 0.08)	-0.02 (-0.06 to 0.01)	-0.01 (-0.05 to 0.02)	-0.05 (-0.09 to -0.01)	-0.04 (-0.08 to 0.01)
Cycle 12 Day 1, n=24,26,50,46,38,29	-0.04 (-0.08 to 0.01)	-0.00 (-0.05 to 0.04)	-0.02 (-0.06 to 0.02)	-0.03 (-0.06 to 0.01)	-0.08 (-0.13 to -0.04)	-0.01 (-0.05 to 0.04)
Cycle 14 Day 1, n=24,26,50,46,38,29	0.02 (-0.04 to 0.07)	0.02 (-0.03 to 0.08)	-0.05 (-0.09 to -0.01)	-0.04 (-0.08 to -0.00)	-0.02 (-0.07 to 0.04)	0.01 (-0.05 to 0.06)
Cycle 16 Day 1, n=24,26,50,46,38,29	-0.03 (-0.09 to 0.03)	0.01 (-0.05 to 0.07)	0.02 (-0.03 to 0.07)	-0.03 (-0.08 to 0.01)	-0.04 (-0.14 to 0.06)	-0.01 (-0.07 to 0.06)
Cycle 18 Day 1, n=24,26,50,46,38,29	0.09 (0.01 to 0.18)	-0.02 (-0.09 to 0.05)	-0.03 (-0.09 to 0.02)	-0.06 (-0.11 to -0.01)	-0.09 (-0.23 to 0.04)	-0.01 (-0.08 to 0.05)
Cycle 20 Day 1, n=24,26,50,46,0,29	0.07 (-0.03 to 0.17)	0.02 (-0.06 to 0.09)	0.01 (-0.06 to 0.08)	-0.09 (-0.16 to -0.03)	99999 (99999 to 99999)	-0.03 (-0.11 to 0.04)
Cycle 22 Day 1, n=24,26,50,46,0,29	-0.02 (-0.12 to 0.08)	-0.02 (-0.10 to 0.07)	0.00 (-0.08 to 0.08)	-0.08 (-0.16 to 0.00)	99999 (99999 to 99999)	-0.05 (-0.13 to 0.03)
Cycle 24 Day 1, n=24,26,50,46,0,29	0.03 (-0.11 to 0.16)	99999 (99999 to 99999)	99999 (99999 to 99999)	-0.06 (-0.20 to 0.07)	99999 (99999 to 99999)	99999 (99999 to 99999)
End of treatment, n=24,26,50,46,38,29	-0.04 (-0.13 to 0.04)	-0.01 (-0.10 to 0.08)	-0.02 (-0.08 to 0.04)	-0.05 (-0.10 to -0.00)	-0.07 (-0.14 to -0.01)	-0.05 (-0.12 to 0.03)

No statistical analyses for this end point

Secondary: Change from Baseline in Total Scores for Identification Test (Cognitive Function Assessment) (Phase 2)

Top of page

End point title

Change from Baseline in Total Scores for Identification Test (Cognitive Function Assessment) (Phase 2) ^[49]

End point description

Identification Test: measure of visual attention and uses well validated choice reaction time paradigm with playing card stimuli. In this, playing cards are all red or black jokers. On-screen instructions ask: “Is card red?”. Playing card is presented face down in center of screen. Card flips over so it is face up. As soon as it flips over participant must decide whether card is red or not. If it is red participant should press “Yes”, if it is not red participant should press “No”. Speed and accuracy of each response are recorded.Mean of log10 transformed reaction time for correct response is calculated. Lower value of least square mean change from baseline=performance decline. Upper limit of 95% CI of -0.00/lower=statistically significant decline of performance over baseline. PRO evaluable analysis set: all enrolled participants who received study treatment, had baseline test assessment, atleast 1 on-study test assessment. Number Analyzed: participants evaluable for specified row.

End point type

Secondary

End point timeframe

Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years)

Notes
[49] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	EXP-1 (Phase 2)	EXP-2 (Phase 2)	EXP-3 (Phase 2)	EXP-4 (Phase 2)	EXP-5 (Phase 2)	EXP-6 (Phase 2)
Number of subjects analysed	24	26	50	46	38	29
Units: Units on a scale
least squares mean (confidence interval 95%)
Cycle 2 Day 1, n=24,26,50,46,38,29	-0.02 (-0.05 to 0.01)	-0.02 (-0.05 to 0.01)	-0.01 (-0.03 to 0.00)	-0.01 (-0.03 to 0.01)	-0.02 (-0.04 to 0.01)	-0.01 (-0.04 to 0.02)
Cycle 3 Day 1, n=24,26,50,46,38,29	-0.01 (-0.04 to 0.02)	-0.01 (-0.04 to 0.02)	-0.02 (-0.04 to 0.00)	-0.02 (-0.04 to 0.00)	-0.02 (-0.05 to 0.00)	-0.01 (-0.04 to 0.02)
Cycle 4 Day 1, n=24,26,50,46,38,29	-0.02 (-0.05 to 0.01)	-0.01 (-0.04 to 0.01)	-0.02 (-0.04 to 0.00)	-0.03 (-0.05 to -0.01)	-0.05 (-0.08 to -0.03)	-0.02 (-0.04 to 0.01)
Cycle 5 Day 1, n=24,26,50,46,38,29	-0.03 (-0.06 to -0.00)	-0.02 (-0.05 to 0.01)	-0.03 (-0.05 to -0.00)	-0.02 (-0.04 to 0.01)	-0.05 (-0.07 to -0.02)	-0.02 (-0.05 to 0.00)
Cycle 6 Day 1, n=24,26,50,46,38,29	-0.04 (-0.07 to -0.01)	-0.02 (-0.05 to 0.01)	-0.02 (-0.04 to 0.00)	-0.03 (-0.06 to -0.01)	-0.03 (-0.06 to -0.01)	-0.03 (-0.06 to -0.00)
Cycle 8 Day 1, n=24,26,50,46,38,29	-0.03 (-0.06 to -0.00)	-0.02 (-0.05 to 0.01)	-0.03 (-0.05 to -0.01)	-0.03 (-0.05 to -0.01)	-0.05 (-0.07 to -0.02)	-0.03 (-0.06 to 0.00)
Cycle 10 Day 1, n=24,26,50,46,38,29	-0.03 (-0.06 to 0.00)	-0.01 (-0.04 to 0.02)	-0.03 (-0.05 to -0.01)	-0.02 (-0.05 to 0.00)	-0.05 (-0.08 to -0.02)	-0.03 (-0.06 to 0.00)
Cycle 12 Day 1, n=24,26,50,46,38,29	-0.05 (-0.08 to -0.02)	-0.04 (-0.07 to -0.01)	-0.04 (-0.06 to -0.01)	-0.04 (-0.07 to -0.01)	-0.06 (-0.09 to -0.03)	-0.03 (-0.06 to 0.00)
Cycle 14 Day 1, n=24,26,50,46,38,29	-0.04 (-0.08 to 0.00)	-0.04 (-0.07 to -0.00)	-0.03 (-0.06 to -0.00)	-0.04 (-0.07 to -0.01)	-0.04 (-0.08 to -0.00)	-0.02 (-0.06 to 0.02)
Cycle 16 Day 1, n=24,26,50,46,38,29	-0.09 (-0.13 to -0.05)	-0.00 (-0.04 to 0.04)	-0.03 (-0.07 to 0.01)	-0.03 (-0.06 to 0.01)	-0.07 (-0.13 to 0.00)	-0.06 (-0.10 to -0.01)
Cycle 18 Day 1, n=24,26,50,46,38,29	-0.01 (-0.06 to 0.05)	-0.05 (-0.09 to 0.00)	-0.04 (-0.08 to 0.00)	-0.07 (-0.10 to -0.03)	-0.19 (-0.29 to -0.09)	-0.01 (-0.05 to 0.04)
Cycle 20 Day 1, n=24,26,50,46,0,29	-0.03 (-0.10 to 0.04)	-0.01 (-0.06 to 0.04)	-0.03 (-0.08 to 0.02)	-0.10 (-0.15 to -0.06)	99999 (99999 to 99999)	-0.03 (-0.08 to 0.02)
Cycle 22 Day 1, n=24,26,50,46,0,29	0.04 (-0.03 to 0.11)	-0.01 (-0.07 to 0.05)	-0.06 (-0.11 to 0.00)	-0.05 (-0.11 to 0.00)	99999 (99999 to 99999)	-0.08 (-0.14 to -0.03)
Cycle 24 Day 1, n=24,26,50,46,0,0	0.08 (-0.01 to 0.18)	99999 (99999 to 99999)	99999 (99999 to 99999)	-0.06 (-0.15 to 0.04)	99999 (99999 to 99999)	99999 (99999 to 99999)
End of treatment, n=24,26,50,46,38,29	-0.07 (-0.13 to -0.02)	-0.03 (-0.10 to 0.03)	-0.02 (-0.06 to 0.02)	-0.03 (-0.06 to 0.01)	-0.09 (-0.14 to -0.05)	-0.06 (-0.11 to -0.01)

No statistical analyses for this end point

Secondary: Change from Baseline in Total Scores for One Back Test (Cognitive Function Assessment) (Phase 2)

Top of page

End point title

Change from Baseline in Total Scores for One Back Test (Cognitive Function Assessment) (Phase 2) ^[50]

End point description

One Back Test: measure of working memory and uses well validated n back paradigm with playing cards. In this task, the on-screen instructions ask: “Is previous card same?”. Playing card is presented in center of screen. Participant must decide whether card is same as previous card. If it is same participant should press “Yes”, and if not press “No”. Speed and accuracy of each response are recorded, mean of log10 transformed reaction time for correct response is used to demonstrate speed of performance, arcsine transformation of square root of proportion of correct responses is for demonstrate accuracy. Lower value of least square mean change from baseline= performance decline. Upper limit of 95%CI of -0.00/ lower:statistically significant decline of performance over baseline. PRO evaluable analysis set: all enrolled participants who received study treatment, had baseline test assessment, at least 1 on-study test assessment. Number Analyzed:participants evaluable for specified row.

End point type

Secondary

End point timeframe

Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years)

Notes
[50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	EXP-1 (Phase 2)	EXP-2 (Phase 2)	EXP-3 (Phase 2)	EXP-4 (Phase 2)	EXP-5 (Phase 2)	EXP-6 (Phase 2)
Number of subjects analysed	24	26	50	46	38	29
Units: Units on a scale
least squares mean (confidence interval 95%)
Cycle 2 Day 1, n=24,26,50,46,38,29	0.01 (-0.02 to 0.05)	0.02 (-0.01 to 0.05)	0.02 (0.00 to 0.05)	0.01 (-0.01 to 0.04)	0.02 (-0.01 to 0.05)	0.01 (-0.02 to 0.04)
Cycle 3 Day 1, n=24,26,50,46,38,29	0.06 (0.02 to 0.09)	0.01 (-0.02 to 0.05)	0.01 (-0.01 to 0.04)	0.01 (-0.02 to 0.03)	-0.01 (-0.04 to 0.02)	-0.00 (-0.04 to 0.03)
Cycle 4 Day 1, n=24,26,50,46,38,29	0.04 (0.01 to 0.08)	0.03 (-0.00 to 0.06)	0.02 (-0.01 to 0.04)	-0.01 (-0.04 to 0.01)	-0.02 (-0.05 to 0.01)	-0.01 (-0.05 to 0.02)
Cycle 5 Day 1, n=24,26,50,46,38,29	0.02 (-0.01 to 0.06)	0.03 (-0.00 to 0.07)	0.03 (0.00 to 0.05)	-0.01 (-0.04 to 0.02)	-0.02 (-0.05 to 0.01)	0.02 (-0.01 to 0.05)
Cycle 6 Day 1, n=24,26,50,46,38,29	0.03 (-0.01 to 0.06)	0.03 (-0.00 to 0.07)	0.03 (0.01 to 0.06)	0.01 (-0.02 to 0.04)	-0.00 (-0.03 to 0.03)	0.01 (-0.03 to 0.04)
Cycle 8 Day 1, n=24,26,50,46,38,29	0.03 (-0.01 to 0.06)	0.02 (-0.02 to 0.06)	0.03 (0.00 to 0.05)	0.01 (-0.02 to 0.03)	-0.01 (-0.04 to 0.02)	0.01 (-0.02 to 0.05)
Cycle 10 Day 1, n=24,26,50,46,38,29	0.07 (0.03 to 0.11)	0.03 (-0.00 to 0.07)	0.03 (0.00 to 0.05)	0.02 (-0.01 to 0.05)	-0.01 (-0.05 to 0.02)	0.01 (-0.02 to 0.05)
Cycle 12 Day 1, n=24,26,50,46,38,29	0.05 (0.01 to 0.08)	0.01 (-0.03 to 0.05)	0.02 (-0.01 to 0.05)	0.01 (-0.02 to 0.04)	-0.00 (-0.04 to 0.03)	0.03 (-0.01 to 0.07)
Cycle 14 Day 1, n=24,26,50,46,38,29	0.00 (-0.05 to 0.05)	0.03 (-0.01 to 0.07)	0.03 (-0.01 to 0.07)	-0.00 (-0.04 to 0.03)	0.01 (-0.04 to 0.06)	0.02 (-0.03 to 0.07)
Cycle 16 Day 1, n=24,26,50,46,38,29	0.03 (-0.03 to 0.08)	0.05 (-0.01 to 0.10)	0.05 (0.00 to 0.09)	-0.02 (-0.05 to 0.02)	-0.01 (-0.10 to 0.08)	0.03 (-0.03 to 0.08)
Cycle 18 Day 1, n=24,26,50,46,38,29	0.02 (-0.06 to 0.09)	0.01 (-0.04 to 0.07)	0.06 (0.02 to 0.11)	-0.02 (-0.06 to 0.03)	-0.18 (-0.30 to -0.06)	0.05 (-0.01 to 0.10)
Cycle 20 Day 1, n=24,26,50,46,0,29	-0.06 (-0.15 to 0.03)	0.07 (0.00 to 0.13)	0.02 (-0.05 to 0.08)	-0.01 (-0.06 to 0.05)	99999 (99999 to 99999)	0.02 (-0.04 to 0.09)
Cycle 22 Day 1, n=24,26,50,46,0,29	0.02 (-0.07 to 0.11)	0.05 (-0.02 to 0.12)	0.04 (-0.03 to 0.11)	-0.07 (-0.14 to 0.00)	99999 (99999 to 99999)	0.03 (-0.04 to 0.11)
Cycle 24 Day 1, n=24,26,50,46,0,0	0.09 (-0.03 to 0.21)	99999 (99999 to 99999)	99999 (99999 to 99999)	0.01 (-0.11 to 0.13)	99999 (99999 to 99999)	99999 (99999 to 99999)
End of treatment, n=24,26,50,46,0,29	-0.03 (-0.10 to 0.05)	0.03 (-0.05 to 0.11)	0.03 (-0.02 to 0.07)	0.01 (-0.04 to 0.05)	-0.03 (-0.08 to 0.02)	0.02 (-0.05 to 0.08)

No statistical analyses for this end point

Secondary: Change from Baseline in Total Scores for International Shopping List Test (Cognitive Function Assessment) (Phase 2)

Top of page

End point title

Change from Baseline in Total Scores for International Shopping List Test (Cognitive Function Assessment) (Phase 2) ^[51]

End point description

International Shopping List task: measure of verbal learning,uses well validated list learning paradigm administered using computer. High frequencies, high imagery, concrete nouns (items from a shopping list) were read to participant at rate of one word every 2 seconds. Once all 12 words had been read, participant was asked to recall as many of words as quickly as possible. Words recalled by participant were marked on computer screen. When participant could recall no more words, same list was read again. Words recalled by participant were recorded. This was repeated third time. Total number of correct responses on 3 consecutive trials at single assessment was recorded. Upper limit of 95% CI of -0.00 or lower indicate statistically significant decline of performance over baseline. PRO evaluable analysis set: all enrolled participants who received study treatment, had baseline test assessment, atleast 1 on-study test assessment. Number Analyzed: participant evaluable for specified row.

End point type

Secondary

End point timeframe

Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years)

Notes
[51] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	EXP-1 (Phase 2)	EXP-2 (Phase 2)	EXP-3 (Phase 2)	EXP-4 (Phase 2)	EXP-5 (Phase 2)	EXP-6 (Phase 2)
Number of subjects analysed	24	26	50	46	38	29
Units: Units on a scale
least squares mean (confidence interval 95%)
Cycle 2 Day 1, n=24,26,50,46,0,29	-0.02 (-1.89 to 1.84)	-1.13 (-2.90 to 0.64)	0.25 (-1.01 to 1.52)	-0.45 (-1.76 to 0.86)	0.96 (-0.50 to 2.43)	0.16 (-1.51 to 1.83)
Cycle 3 Day 1, n=24,26,50,46,0,29	0.19 (-1.66 to 2.03)	-0.81 (-2.58 to 0.96)	0.14 (-1.15 to 1.43)	-1.04 (-2.36 to 0.29)	-0.08 (-1.59 to 1.44)	-0.56 (-2.21 to 1.09)
Cycle 4 Day 1, n=24,26,50,46,0,29	0.58 (-1.26 to 2.42)	0.26 (-1.54 to 2.05)	0.28 (-1.05 to 1.61)	0.24 (-1.12 to 1.60)	1.30 (-0.26 to 2.86)	-0.87 (-2.59 to 0.84)
Cycle 5 Day 1, n=24,26,50,46,0,29	1.30 (-0.51 to 3.12)	-0.66 (-2.53 to 1.21)	0.59 (-0.77 to 1.95)	-0.94 (-2.33 to 0.45)	1.23 (-0.36 to 2.82)	0.74 (-0.97 to 2.45)
Cycle 6 Day 1, n=24,26,50,46,0,29	0.18 (-1.64 to 1.99)	0.81 (-1.06 to 2.68)	0.50 (-0.87 to 1.87)	0.08 (-1.31 to 1.47)	0.82 (-0.83 to 2.46)	-0.51 (-2.31 to 1.29)
Cycle 8 Day 1, n=24,26,50,46,0,29	0.84 (-1.00 to 2.68)	0.60 (-1.30 to 2.50)	1.69 (0.29 to 3.08)	0.15 (-1.27 to 1.57)	0.44 (-1.23 to 2.11)	1.70 (-0.11 to 3.50)
Cycle 10 Day 1, n=24,26,50,46,0,29	0.26 (-1.68 to 2.21)	2.59 (0.65 to 4.52)	0.86 (-0.56 to 2.27)	0.13 (-1.46 to 1.72)	2.29 (0.53 to 4.05)	0.97 (-0.99 to 2.93)
Cycle 12 Day 1, n=24,26,50,46,0,29	2.87 (0.86 to 4.88)	0.02 (-2.06 to 2.10)	0.11 (-1.52 to 1.73)	0.69 (-0.98 to 2.35)	1.74 (-0.25 to 3.72)	3.10 (1.06 to 5.14)
Cycle 14 Day 1, n=24,26,50,46,0,29	1.91 (-0.71 to 4.53)	1.46 (-0.85 to 3.78)	2.27 (0.36 to 4.17)	0.94 (-0.86 to 2.73)	-4.43 (-7.11 to -1.75)	2.67 (0.09 to 5.25)
Cycle 16 Day 1, n=24,26,50,46,0,29	4.52 (1.58 to 7.46)	0.87 (-2.06 to 3.79)	1.36 (-1.11 to 3.84)	1.04 (-0.99 to 3.07)	3.46 (-1.26 to 8.18)	1.97 (-0.93 to 4.87)
Cycle 18 Day 1, n=24,26,50,46,0,29	4.77 (0.82 to 8.73)	0.66 (-2.50 to 3.81)	-0.27 (-2.89 to 2.36)	-0.52 (-2.77 to 1.73)	-0.35 (-6.90 to 6.21)	3.13 (0.00 to 6.27)
Cycle 20 Day 1, n=24,26,50,46,0,29	-2.72 (-7.47 to 2.03)	-1.44 (-4.91 to 2.03)	0.56 (-2.81 to 3.92)	1.20 (-1.84 to 4.24)	99999 (99999 to 99999)	0.56 (-2.89 to 4.01)
Cycle 22 Day 1, n=24,26,50,46,0,29	-5.72 (-10.47 to -0.97)	-0.28 (-4.22 to 3.66)	2.17 (-1.68 to 6.01)	-0.36 (-4.21 to 3.48)	99999 (99999 to 99999)	3.99 (0.07 to 7.91)
Cycle 24 Day 1, n=24,26,50,46,0,0	-8.49 (-15.06 to -1.92)	99999 (99999 to 99999)	99999 (99999 to 99999)	-3.35 (-9.86 to 3.16)	99999 (99999 to 99999)	99999 (99999 to 99999)
End of treatment, n=24,26,50,46,38,29	1.02 (-2.99 to 5.04)	-1.62 (-5.95 to 2.71)	0.80 (-1.80 to 3.40)	-0.27 (-2.47 to 1.92)	2.37 (-0.54 to 5.27)	-0.60 (-4.09 to 2.89)

No statistical analyses for this end point

Secondary: Change from Baseline in Total Scores for International Shopping List Test-Delayed Recall (Cognitive Function Assessment) (Phase 2)

Top of page

End point title

Change from Baseline in Total Scores for International Shopping List Test-Delayed Recall (Cognitive Function Assessment) (Phase 2) ^[52]

End point description

This test was performed in same way as the International Shopping List Test, with exception that, delayed recall condition required participant to recall words from list 15 30 minutes later without having list read again. During recognition condition, qualified personnel read a shopping list item that may or may not have been on original list and participant had to respond either affirmatively (if item was on original list) or negatively (if it was not). Total number of correct responses made in remembering word list after a delay was recorded. Lower values of least square mean change from baseline indicate performance decline. Upper limit of 95% CI of -0.00 or lower indicate statistically significant decline of performance over baseline at that cycle. PRO evaluable analysis: all enrolled participants who received study treatment, had a baseline test assessment and at least 1 on-study test assessment. Here, 'Number Analyzed' signifies participants evaluable for specified row.

End point type

Secondary

End point timeframe

Baseline, Day 1 of Cycles 2-5, Day 1 of every other cycle from Cycle 6, and end of treatment (up to 3 years)

Notes
[52] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	EXP-1 (Phase 2)	EXP-2 (Phase 2)	EXP-3 (Phase 2)	EXP-4 (Phase 2)	EXP-5 (Phase 2)	EXP-6 (Phase 2)
Number of subjects analysed	24	26	50	46	38	29
Units: Units on a scale
least squares mean (confidence interval 95%)
Cycle 2 Day 1, n=24,26,50,46,38,29	0.10 (-0.85 to 1.06)	-0.84 (-1.76 to 0.08)	-0.12 (-0.77 to 0.53)	-0.59 (-1.28 to 0.09)	-0.22 (-0.96 to 0.53)	-0.25 (-1.11 to 0.62)
Cycle 3 Day 1,n=24,26,50,46,38,29	-0.33 (-1.28 to 0.62)	-1.32 (-2.24 to -0.40)	-0.14 (-0.81 to 0.52)	-0.77 (-1.46 to -0.07)	-0.87 (-1.64 to -0.10)	-0.30 (-1.15 to 0.56)
Cycle 4 Day 1,n=24,26,50,46,38,29	-0.44 (-1.38 to 0.50)	-0.91 (-1.86 to 0.03)	0.03 (-0.66 to 0.72)	-0.25 (-0.97 to 0.47)	-0.02 (-0.82 to 0.78)	-1.06 (-1.95 to -0.18)
Cycle 5 Day 1,n=24,26,50,46,38,29	-0.35 (-1.29 to 0.59)	-0.57 (-1.54 to 0.40)	0.02 (-0.69 to 0.73)	-0.46 (-1.20 to 0.27)	0.09 (-0.74 to 0.92)	0.17 (-0.72 to 1.05)
Cycle 6 Day 1,n=24,26,50,46,38,29	0.48 (-0.46 to 1.42)	-0.38 (-1.35 to 0.59)	0.12 (-0.59 to 0.84)	-0.22 (-0.95 to 0.52)	0.30 (-0.55 to 1.15)	-0.28 (-1.21 to 0.66)
Cycle 8 Day 1,n=24,26,50,46,38,29	0.56 (-0.38 to 1.50)	-0.24 (-1.23 to 0.75)	0.02 (-0.70 to 0.74)	-0.49 (-1.24 to 0.25)	-1.08 (-1.94 to -0.22)	-0.16 (-1.10 to 0.77)
Cycle 10 Day 1, n=24,26,50,46,38,29	0.29 (-0.74 to 1.31)	0.80 (-0.22 to 1.82)	0.54 (-0.20 to 1.28)	0.23 (-0.61 to 1.08)	0.25 (-0.67 to 1.16)	-0.00 (-1.02 to 1.02)
Cycle 12 Day 1,n=24,26,50,46,38,29	0.90 (-0.15 to 1.95)	0.13 (-0.95 to 1.21)	0.22 (-0.63 to 1.07)	0.19 (-0.70 to 1.07)	0.60 (-0.43 to 1.64)	0.42 (-0.64 to 1.49)
Cycle 14 Day 1, n=24,26,50,46,38,29	0.38 (-0.99 to 1.75)	0.06 (-1.15 to 1.27)	1.06 (0.06 to 2.06)	0.11 (-0.85 to 1.07)	-1.80 (-3.31 to -0.30)	0.35 (-1.00 to 1.71)
Cycle 16 Day 1, n=24,26,50,46,38,29	0.89 (-0.66 to 2.43)	0.52 (-1.02 to 2.05)	0.68 (-0.62 to 1.98)	-0.12 (-1.22 to 0.98)	0.40 (-2.09 to 2.88)	-0.22 (-1.75 to 1.30)
Cycle 18 Day 1, n=24,26,50,46,38,29	1.06 (-1.02 to 3.14)	0.68 (-0.98 to 2.34)	0.38 (-1.00 to 1.76)	-0.24 (-1.54 to 1.07)	-0.39 (-3.85 to 3.07)	-0.33 (-1.97 to 1.32)
Cycle 20 Day 1,n=24,26,50,46,0,29	-1.22 (-3.73 to 1.28)	0.16 (-1.67 to 1.98)	-0.24 (-2.01 to 1.53)	-0.18 (-1.78 to 1.43)	99999 (99999 to 99999)	-0.70 (-2.52 to 1.11)
Cycle 22 Day 1, n=24,26,50,46,0,29	-3.22 (-5.73 to -0.72)	0.68 (-1.40 to 2.76)	0.80 (-1.23 to 2.83)	-0.64 (-2.67 to 1.39)	99999 (99999 to 99999)	0.37 (-1.70 to 2.43)
Cycle 24 Day 1, n=24,0,0,46,0,0	-2.43 (-5.89 to 1.04)	99999 (99999 to 99999)	99999 (99999 to 99999)	-0.80 (-4.25 to 2.64)	99999 (99999 to 99999)	99999 (99999 to 99999)
End of treatment,n=24,26,50,46,38,29	-0.87 (-2.99 to 1.24)	-2.31 (-4.58 to -0.04)	0.52 (-0.84 to 1.89)	-0.85 (-2.06 to 0.35)	-0.19 (-1.71 to 1.34)	0.11 (-1.72 to 1.95)

No statistical analyses for this end point

Secondary: Number of Participants with Absolute Values and Change from Baseline in PR Interval Meeting Pre-defined Criteria (Phase 2 and DDI Substudy)

Top of page

End point title

Number of Participants with Absolute Values and Change from Baseline in PR Interval Meeting Pre-defined Criteria (Phase 2 and DDI Substudy) ^[53]

End point description

PR Interval was determined by ECG measurement. Baseline was defined as the average of the triplicate measurements prior to the first dose of study drug. The safety analysis set included all enrolled participants who received at least 1 dose of PF-06463922. Here, "Overall Number of Participants Analyzed" signifies participants evaluable for this outcome measure.

End point type

Secondary

End point timeframe

From first dose of study treatment to end of treatment (maximum of 89.65 months of treatment exposure for Phase 2 and maximum of 68.69 months of treatment exposure for DDI participants)

Notes
[53] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	DDI Substudy	Phase 2
Number of subjects analysed	32	272
Units: Participants
40-<60 msec	2	19
60-<80 msec	0	9
>=80 msec	0	5

No statistical analyses for this end point

Other pre-specified: Percentage of Participants with Overall and Intracranial Objective Response (Phase 2 and DDI sub-study)

Top of page

End point title

Percentage of Participants with Overall and Intracranial Objective Response (Phase 2 and DDI sub-study) ^[54]

End point description

ITT analysis set was used for overall response assessment and included all enrolled participants with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922; participants with central nervous system (CNS) metastases in the ITT analysis set were used for intracranial response assessment. Here, "Number Analyzed" signifies participants evaluable for specified rows.

End point type

Other pre-specified

End point timeframe

From first dose of study treatment to end of treatment (maximum of 89.65 months of treatment exposure for Phase 2 and maximum of 68.69 months of treatment exposure for DDI participants)

Notes
[54] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint is reporting statistics for the arms specified

End point values	EXP-1 (Phase 2)	EXP-2 (Phase 2)	EXP-3 (Phase 2)	EXP-4 (Phase 2)	EXP-5 (Phase 2)	EXP-6 (Phase 2)	DDI Substudy
Number of subjects analysed	30	27	60	65	46	47	32
Units: Percentage of participants
number (confidence interval 95%)
OR, n=30,27,60,65,46,47,32	90.0 (73.5 to 97.9)	77.8 (57.7 to 91.4)	56.7 (43.2 to 69.4)	40.0 (28.0 to 52.9)	37.0 (23.2 to 52.5)	38.3 (24.5 to 53.6)	40.6 (23.7 to 59.4)
Intracranial OR, n=8,17,33,45,37,25,16	75.0 (34.9 to 96.8)	58.8 (32.9 to 81.6)	66.7 (48.2 to 82.0)	53.3 (37.9 to 68.3)	43.2 (27.1 to 60.5)	56.0 (34.9 to 75.6)	25.0 (7.3 to 52.4)

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Adverse event reporting additional description

The same event may appear as both an AE and a SAE. However, what is presented are distinct events. An event may be categorized as serious in one participant and as non-serious in another participant, or one participant may have experienced both a serious and non-serious event during the study.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

26.0

Reporting group title

50 mg QD (Phase 1)

Reporting group description

Reporting group title

25 mg QD (Phase 1)

Reporting group description

Reporting group title

10 mg QD (Phase 1)

Reporting group description

Reporting group title

DDI Substudy

Reporting group description

Reporting group title

35 mg BID (Phase 1)

Reporting group description

Reporting group title

75 mg BID (Phase 1)

Reporting group description

Reporting group title

100 mg BID (Phase 1)

Reporting group description

Reporting group title

Phase 2

Reporting group description

Reporting group title

Japan Lead-In Cohort (LIC)

Reporting group description

Reporting group title

150 mg QD (Phase 1)

Reporting group description

Reporting group title

100 mg QD (Phase 1)

Reporting group description

Reporting group title

75 mg QD (Phase 1)

Reporting group description

Reporting group title

200 mg QD (Phase 1)

Reporting group description

50 mg QD (Phase 1)

25 mg QD (Phase 1)

10 mg QD (Phase 1)

DDI Substudy

35 mg BID (Phase 1)

75 mg BID (Phase 1)

100 mg BID (Phase 1)

Phase 2

Japan Lead-In Cohort (LIC)

150 mg QD (Phase 1)

100 mg QD (Phase 1)

75 mg QD (Phase 1)

200 mg QD (Phase 1)

Total subjects affected by serious adverse events

subjects affected / exposed

1 / 3 (33.33%)

2 / 3 (66.67%)

3 / 3 (100.00%)

13 / 32 (40.63%)

2 / 3 (66.67%)

2 / 4 (50.00%)

135 / 275 (49.09%)

1 / 3 (33.33%)

3 / 3 (100.00%)

10 / 17 (58.82%)

6 / 12 (50.00%)

2 / 3 (66.67%)

number of deaths (all causes)

number of deaths resulting from adverse events

Neoplasms benign, malignant and unspecified (incl cysts and polyps)

Acute leukaemia

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Acute myeloid leukaemia

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Breast cancer

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Colon cancer

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pulmonary tumour thrombotic microangiopathy

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Neoplasm progression

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Vascular disorders

Embolism

subjects affected / exposed

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

5 / 275 (1.82%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 5

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Embolism venous

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 275 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Aortic dissection

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Deep vein thrombosis

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypertensive crisis

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Peripheral artery occlusion

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Superior vena cava syndrome

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

2 / 275 (0.73%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Thrombosis

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

2 / 275 (0.73%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Haemorrhage

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

General disorders and administration site conditions

Disease progression

subjects affected / exposed

0 / 3 (0.00%)

1 / 3 (33.33%)

5 / 32 (15.63%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 4 (0.00%)

29 / 275 (10.55%)

0 / 3 (0.00%)

1 / 3 (33.33%)

4 / 17 (23.53%)

1 / 12 (8.33%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 5

0 / 0

0 / 1

0 / 0

0 / 29

0 / 0

0 / 1

0 / 4

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 12

0 / 0

0 / 1

0 / 3

0 / 1

0 / 0

Pyrexia

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

9 / 275 (3.27%)

0 / 3 (0.00%)

0 / 17 (0.00%)

1 / 12 (8.33%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 10

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Asthenia

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 275 (0.00%)

0 / 3 (0.00%)

0 / 17 (0.00%)

1 / 12 (8.33%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

General physical health deterioration

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

2 / 275 (0.73%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Chest pain

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

2 / 275 (0.73%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Peripheral swelling

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pain

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

2 / 275 (0.73%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Generalised oedema

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Oedema peripheral

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Gait disturbance

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory, thoracic and mediastinal disorders

Dyspnoea

subjects affected / exposed

0 / 3 (0.00%)

1 / 3 (33.33%)

1 / 32 (3.13%)

0 / 3 (0.00%)

1 / 4 (25.00%)

8 / 275 (2.91%)

0 / 3 (0.00%)

1 / 17 (5.88%)

1 / 12 (8.33%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 1

0 / 0

0 / 1

0 / 9

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Hypoxia

subjects affected / exposed ^[1]

0 / 3 (0.00%)

1 / 3 (33.33%)

1 / 32 (3.13%)

0 / 3 (0.00%)

0 / 4 (0.00%)

2 / 275 (0.73%)

0 / 2 (0.00%)

1 / 3 (33.33%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Pleural effusion

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

4 / 275 (1.45%)

0 / 3 (0.00%)

1 / 17 (5.88%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 6

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Haemoptysis

subjects affected / exposed

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

1 / 17 (5.88%)

0 / 12 (0.00%)

1 / 3 (33.33%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Acute respiratory failure

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

3 / 275 (1.09%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

Acute pulmonary oedema

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Chronic obstructive pulmonary disease

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

2 / 275 (0.73%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Dyspnoea exertional

subjects affected / exposed

0 / 3 (0.00%)

1 / 32 (3.13%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Epistaxis

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Asthma

subjects affected / exposed ^[2]

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 47 (2.13%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonitis

subjects affected / exposed

0 / 3 (0.00%)

1 / 32 (3.13%)

0 / 3 (0.00%)

0 / 4 (0.00%)

3 / 275 (1.09%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 0

1 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

Interstitial lung disease

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Lung disorder

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

3 / 275 (1.09%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

Pleuritic pain

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pulmonary congestion

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory distress

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Pulmonary hypertension

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pulmonary embolism

subjects affected / exposed

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

1 / 32 (3.13%)

0 / 3 (0.00%)

0 / 4 (0.00%)

4 / 275 (1.45%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 4

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory failure

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

2 / 275 (0.73%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Wheezing

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 275 (0.00%)

0 / 3 (0.00%)

1 / 17 (5.88%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Asphyxia

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Peripheral bilateral pulmonary embolism

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Psychiatric disorders

Mental status changes

subjects affected / exposed

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

4 / 275 (1.45%)

0 / 3 (0.00%)

1 / 3 (33.33%)

1 / 17 (5.88%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 4

0 / 0

1 / 1

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Confusional state

subjects affected / exposed

0 / 3 (0.00%)

2 / 32 (6.25%)

0 / 3 (0.00%)

0 / 4 (0.00%)

3 / 275 (1.09%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 0

1 / 3

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Delirium

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

2 / 275 (0.73%)

0 / 3 (0.00%)

1 / 17 (5.88%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Hallucination

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 275 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Assisted suicide

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Impulse-control disorder

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Schizophreniform disorder

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Investigations

Aspartate aminotransferase increased

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

1 / 4 (25.00%)

2 / 275 (0.73%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Lipase increased

subjects affected / exposed

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 275 (0.00%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Alanine aminotransferase increased

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

2 / 275 (0.73%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Blood cholesterol increased

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Ejection fraction decreased

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blood creatine phosphokinase increased

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

SARS-CoV-2 test positive

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Injury, poisoning and procedural complications

Subdural haematoma

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 275 (0.00%)

0 / 3 (0.00%)

1 / 17 (5.88%)

0 / 12 (0.00%)

1 / 3 (33.33%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Fall

subjects affected / exposed

0 / 3 (0.00%)

1 / 32 (3.13%)

0 / 3 (0.00%)

0 / 4 (0.00%)

6 / 275 (2.18%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

1 / 3 (33.33%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 7

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Femoral neck fracture

subjects affected / exposed ^[3]

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

2 / 47 (4.26%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Hip fracture

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pelvic fracture

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Humerus fracture

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Post procedural haemorrhage

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Road traffic accident

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Rib fracture

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Toxicity to various agents

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Ankle fracture

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Thoracic vertebral fracture

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Traumatic intracranial haemorrhage

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 275 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Tendon rupture

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Radiation necrosis

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

2 / 275 (0.73%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac disorders

Cardiac arrest

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

1 / 3 (33.33%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

Pericardial effusion

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 4 (0.00%)

5 / 275 (1.82%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

1 / 3 (33.33%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 5

0 / 0

0 / 2

deaths causally related to treatment / all

0 / 0

Atrial fibrillation

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

2 / 275 (0.73%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Atrioventricular block complete

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Myocardial infarction

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Supraventricular tachycardia

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Sinus node dysfunction

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Atrial flutter

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Acute myocardial infarction

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Coronary artery disease

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nervous system disorders

Headache

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

1 / 4 (25.00%)

2 / 275 (0.73%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 3

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Haemorrhage intracranial

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

2 / 275 (0.73%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Presyncope

subjects affected / exposed ^[4]

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 4 (0.00%)

1 / 47 (2.13%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cerebrovascular accident

subjects affected / exposed

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

2 / 275 (0.73%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Seizure

subjects affected / exposed

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

1 / 4 (25.00%)

2 / 275 (0.73%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 2

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Brain oedema

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

2 / 275 (0.73%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Cognitive disorder

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

2 / 275 (0.73%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Hydrocephalus

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

2 / 275 (0.73%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

Partial seizures

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Ischaemic stroke

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Lacunar stroke

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Peripheral sensory neuropathy

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Syncope

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vagus nerve disorder

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Neurological symptom

subjects affected / exposed

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 275 (0.00%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Brainstem compression

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Aphasia

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cerebral infarction

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Dysarthria

subjects affected / exposed

0 / 3 (0.00%)

1 / 32 (3.13%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 275 (0.00%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hemiparesis

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Metabolic encephalopathy

subjects affected / exposed

0 / 3 (0.00%)

1 / 32 (3.13%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 275 (0.00%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nervous system disorder

alternative assessment type: Systematic

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Tremor

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blood and lymphatic system disorders

Thrombocytopenia

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Ear and labyrinth disorders

Vertigo

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

2 / 275 (0.73%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

Eye disorders

Eye pain

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

1 / 4 (25.00%)

0 / 275 (0.00%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cataract

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 275 (0.00%)

0 / 3 (0.00%)

0 / 17 (0.00%)

1 / 12 (8.33%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blepharitis

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorders

Abdominal pain

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 4 (0.00%)

0 / 275 (0.00%)

0 / 3 (0.00%)

0 / 17 (0.00%)

1 / 12 (8.33%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Ileus

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

1 / 4 (25.00%)

0 / 275 (0.00%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Large intestinal obstruction

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 275 (0.00%)

0 / 3 (0.00%)

0 / 17 (0.00%)

1 / 12 (8.33%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Intestinal perforation

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 275 (0.00%)

0 / 3 (0.00%)

0 / 17 (0.00%)

1 / 12 (8.33%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Abdominal pain upper

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Abdominal wall haematoma

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastric volvulus

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastritis

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Glossitis

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Intestinal obstruction

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nausea

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pancreatitis

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vomiting

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

3 / 275 (1.09%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

Terminal ileitis

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

1 / 4 (25.00%)

0 / 275 (0.00%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Dysphagia

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Small intestinal obstruction

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

2 / 275 (0.73%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 5

0 / 0

deaths causally related to treatment / all

0 / 0

Diarrhoea

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

2 / 275 (0.73%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Hepatobiliary disorders

Biloma

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 275 (0.00%)

0 / 3 (0.00%)

1 / 17 (5.88%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Jaundice

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Bile duct stenosis

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cholangitis

subjects affected / exposed

0 / 3 (0.00%)

1 / 32 (3.13%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 275 (0.00%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cholecystocholangitis

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Skin and subcutaneous tissue disorders

Dermatomyositis

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 275 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Renal and urinary disorders

Acute kidney injury

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Neurogenic bladder

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Renal cyst haemorrhage

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Renal failure

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Musculoskeletal and connective tissue disorders

Back pain

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Intervertebral disc protrusion

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Spinal pain

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Musculoskeletal chest pain

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Muscular weakness

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Arthralgia

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Infections and infestations

Influenza

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

2 / 275 (0.73%)

0 / 3 (0.00%)

1 / 17 (5.88%)

1 / 12 (8.33%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Lower respiratory tract infection

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

1 / 4 (25.00%)

2 / 275 (0.73%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 4

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonia

subjects affected / exposed

0 / 3 (0.00%)

1 / 32 (3.13%)

0 / 3 (0.00%)

0 / 4 (0.00%)

19 / 275 (6.91%)

0 / 3 (0.00%)

2 / 3 (66.67%)

2 / 17 (11.76%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

2 / 33

0 / 0

0 / 2

0 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Respiratory tract infection

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

4 / 275 (1.45%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

1 / 3 (33.33%)

occurrences causally related to treatment / all

0 / 0

0 / 4

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Bronchitis

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

1 / 17 (5.88%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pyelonephritis

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 275 (0.00%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

1 / 3 (33.33%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Urinary tract infection

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

4 / 275 (1.45%)

0 / 3 (0.00%)

1 / 17 (5.88%)

0 / 12 (0.00%)

1 / 3 (33.33%)

occurrences causally related to treatment / all

0 / 0

0 / 5

0 / 0

0 / 2

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Diverticulitis

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Sepsis

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

2 / 275 (0.73%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Lung abscess

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Erysipelas

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

3 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

Septic shock

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Upper respiratory tract infection

subjects affected / exposed

0 / 3 (0.00%)

1 / 32 (3.13%)

0 / 3 (0.00%)

0 / 4 (0.00%)

2 / 275 (0.73%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Vestibular neuronitis

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cellulitis

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

3 / 275 (1.09%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

1 / 3 (33.33%)

occurrences causally related to treatment / all

0 / 0

0 / 4

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Pneumonia aspiration

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

1 / 17 (5.88%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Escherichia bacteraemia

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

COVID-19

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Infection

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Skin infection

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Infectious pleural effusion

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Viral upper respiratory tract infection

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Urethritis

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastroenteritis

subjects affected / exposed

0 / 3 (0.00%)

1 / 32 (3.13%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 275 (0.00%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Metabolism and nutrition disorders

Decreased appetite

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

1 / 4 (25.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypercalcaemia

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 275 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hyperuricaemia

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 275 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypertriglyceridaemia

subjects affected / exposed

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hyponatraemia

subjects affected / exposed

0 / 3 (0.00%)

1 / 32 (3.13%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 275 (0.00%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Dehydration

alternative assessment type: Systematic

subjects affected / exposed ^[5]

0 / 3 (0.00%)

0 / 32 (0.00%)

0 / 3 (0.00%)

1 / 275 (0.36%)

0 / 3 (0.00%)

0 / 17 (0.00%)

0 / 12 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Notes
[1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Data is valid
[2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Data is valid
[3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Data is valid
[4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Data is valid
[5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed to this adverse event. These numbers are expected to be equal.
Justification: Data is valid

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	50 mg QD (Phase 1)	25 mg QD (Phase 1)	10 mg QD (Phase 1)	DDI Substudy	35 mg BID (Phase 1)	75 mg BID (Phase 1)	100 mg BID (Phase 1)	Phase 2	Japan Lead-In Cohort (LIC)	150 mg QD (Phase 1)	100 mg QD (Phase 1)	75 mg QD (Phase 1)	200 mg QD (Phase 1)
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	32 / 32 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	4 / 4 (100.00%)	273 / 275 (99.27%)	3 / 3 (100.00%)	3 / 3 (100.00%)	17 / 17 (100.00%)	12 / 12 (100.00%)	3 / 3 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Melanocytic naevus
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Tumour pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 275 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	1	0	0	0	0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 32 (6.25%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 4 (0.00%)	35 / 275 (12.73%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 17 (5.88%)	2 / 12 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	10	1	1	0	82	2	1	3	3	0
Deep vein thrombosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	1	0	0	0	0	0	0
Haematoma
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Hypotension
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	1	0	0	0
Hot flush
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0	0	1	0	0
Haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Shock
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Raynaud's phenomenon
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Flushing
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	1 / 3 (33.33%)	8 / 32 (25.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	40 / 275 (14.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 17 (23.53%)	4 / 12 (33.33%)	1 / 3 (33.33%)
occurrences all number	2	0	1	18	1	0	0	82	0	0	7	8	2
Mucosal inflammation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0	0	0	0	0
Gait disturbance
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 32 (3.13%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	14 / 275 (5.09%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	1 / 12 (8.33%)	1 / 3 (33.33%)
occurrences all number	2	2	1	1	0	0	0	25	0	0	1	1	1
Fatigue
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	4 / 32 (12.50%)	0 / 3 (0.00%)	1 / 3 (33.33%)	3 / 4 (75.00%)	50 / 275 (18.18%)	0 / 3 (0.00%)	2 / 3 (66.67%)	5 / 17 (29.41%)	5 / 12 (41.67%)	1 / 3 (33.33%)
occurrences all number	0	1	1	5	0	1	5	90	0	4	8	6	3
Face oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	2 / 12 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	2	0
Chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	30 / 275 (10.91%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	2	0	1	0	42	0	0	2	0	0
Oedema
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 32 (3.13%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	25 / 275 (9.09%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	2 / 12 (16.67%)	2 / 3 (66.67%)
occurrences all number	1	1	0	1	0	1	1	34	0	0	0	3	2
Oedema peripheral
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	3 / 3 (100.00%)	14 / 32 (43.75%)	0 / 3 (0.00%)	2 / 3 (66.67%)	3 / 4 (75.00%)	127 / 275 (46.18%)	1 / 3 (33.33%)	3 / 3 (100.00%)	10 / 17 (58.82%)	4 / 12 (33.33%)	1 / 3 (33.33%)
occurrences all number	1	1	3	31	0	3	7	238	1	7	17	7	1
Pyrexia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 32 (9.38%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	49 / 275 (17.82%)	0 / 3 (0.00%)	1 / 3 (33.33%)	3 / 17 (17.65%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	1	0	0	4	0	0	1	70	0	1	3	1	0
Pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	15 / 275 (5.45%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	1	2	0	0	0	19	0	0	1	1	0
Peripheral swelling
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	4 / 32 (12.50%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	21 / 275 (7.64%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	1 / 3 (33.33%)
occurrences all number	0	0	1	4	0	0	0	26	0	0	0	1	1
Axillary pain
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0
Catheter site extravasation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Chills
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Chest discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Disease progression
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Generalised oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	1	0	0	0
Non-cardiac chest pain
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0
Performance status decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	2	0	0
Swelling
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	3 / 32 (9.38%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	5 / 275 (1.82%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	4	0	0	0	5	0	0	0	0	0
Swelling face
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	1	0	0
Seasonal allergy
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	1
Social circumstances
Menopause
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Reproductive system and breast disorders
Menstruation irregular
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Vaginal haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Dysmenorrhoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Breast pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Erectile dysfunction
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	1 / 3 (33.33%)	2 / 3 (66.67%)	1 / 3 (33.33%)	7 / 32 (21.88%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 4 (50.00%)	68 / 275 (24.73%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 17 (11.76%)	2 / 12 (16.67%)	1 / 3 (33.33%)
occurrences all number	1	2	1	9	1	0	4	134	0	0	2	3	1
Dysphonia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	13 / 275 (4.73%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	2 / 12 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	1	2	0	0	1	15	0	0	0	2	0
Dyspnoea
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	10 / 32 (31.25%)	3 / 3 (100.00%)	1 / 3 (33.33%)	2 / 4 (50.00%)	82 / 275 (29.82%)	1 / 3 (33.33%)	0 / 3 (0.00%)	4 / 17 (23.53%)	3 / 12 (25.00%)	0 / 3 (0.00%)
occurrences all number	1	1	1	16	4	4	5	116	1	0	0	3	0
Dyspnoea exertional
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	15 / 275 (5.45%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	2 / 12 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	1	0	2	0	0	4	25	0	0	1	2	0
Epistaxis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	1	0	0
Haemoptysis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	2 / 3 (66.67%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0
Hypoxia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Pleural effusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 32 (3.13%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 4 (0.00%)	15 / 275 (5.45%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	1	1	0	16	0	0	0	0	0
Wheezing
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	1	0	0	0	0	0	0	0	0
Acute respiratory failure
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Bronchitis chronic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Laryngeal inflammation
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0
Nasal congestion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Oropharyngeal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 17 (11.76%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	2	0	0
Pulmonary hypertension
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	0	0	0	0
Pulmonary embolism
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Productive cough
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 32 (3.13%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	15 / 275 (5.45%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	21	0	1	0	0	0
Pleuritic pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0	0	2	0	0
Pulmonary oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Respiratory tract congestion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Rhinorrhoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Sinus congestion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Rales
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0
Sleep apnoea syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Rhinitis allergic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Lung disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Snoring
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Psychiatric disorders
Affect lability
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	3 / 12 (25.00%)	2 / 3 (66.67%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	5	2
Anxiety
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 32 (3.13%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 4 (25.00%)	21 / 275 (7.64%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	2 / 12 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	2	0	1	25	0	0	0	2	0
Insomnia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 32 (9.38%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	30 / 275 (10.91%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	5	0	0	0	40	0	1	0	1	0
Irritability
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	16 / 275 (5.82%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 17 (11.76%)	2 / 12 (16.67%)	1 / 3 (33.33%)
occurrences all number	0	0	0	2	0	0	0	21	0	0	2	2	2
Abnormal dreams
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 17 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	1
Mental status changes
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	1	0	0
Hallucination
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0	0	0
Depressed mood
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	1 / 12 (8.33%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	1	1	1
Confusional state
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	11 / 275 (4.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 17 (11.76%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	2	0	1	0	13	0	1	2	0	0
Bradyphrenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	1	0
Agitation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 32 (6.25%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	4 / 275 (1.45%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	2	2	0	0	5	0	0	0	0	0
Nightmare
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Sleep disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Reading disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Depression
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	16 / 275 (5.82%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	2	0	0	0	24	0	0	0	0	0
Hallucination, auditory
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 32 (9.38%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	5 / 275 (1.82%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	4	0	0	0	7	2	0	0	0	0
Mental disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Attention deficit hyperactivity disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Mania
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 275 (0.36%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	3	0	0	0	1	0	0	0	0	0
Investigations
Blood cholesterol increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	17 / 32 (53.13%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	97 / 275 (35.27%)	3 / 3 (100.00%)	1 / 3 (33.33%)	4 / 17 (23.53%)	6 / 12 (50.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	60	0	0	3	566	24	1	13	9	0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	14 / 275 (5.09%)	2 / 3 (66.67%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	5	0	1	0	44	22	0	7	0	0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	44 / 275 (16.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	4 / 17 (23.53%)	3 / 12 (25.00%)	2 / 3 (66.67%)
occurrences all number	1	1	0	6	0	0	8	109	1	0	9	6	3
Amylase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	3 / 32 (9.38%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	35 / 275 (12.73%)	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 17 (29.41%)	1 / 12 (8.33%)	1 / 3 (33.33%)
occurrences all number	0	0	3	35	0	0	2	119	0	0	18	3	1
Alanine aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 32 (3.13%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	42 / 275 (15.27%)	2 / 3 (66.67%)	0 / 3 (0.00%)	4 / 17 (23.53%)	3 / 12 (25.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	4	0	0	5	97	2	0	8	5	0
Weight increased
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	9 / 32 (28.13%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 4 (50.00%)	77 / 275 (28.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	4 / 17 (23.53%)	4 / 12 (33.33%)	1 / 3 (33.33%)
occurrences all number	1	1	0	20	0	2	3	175	2	1	7	9	1
Lipase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	39 / 275 (14.18%)	1 / 3 (33.33%)	0 / 3 (0.00%)	5 / 17 (29.41%)	3 / 12 (25.00%)	1 / 3 (33.33%)
occurrences all number	0	0	2	2	0	0	2	123	5	0	30	6	3
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	19 / 275 (6.91%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	2	0	0	0	1	28	0	1	0	0	0
Blood triglycerides increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	4 / 32 (12.50%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	17 / 275 (6.18%)	0 / 3 (0.00%)	1 / 3 (33.33%)	4 / 17 (23.53%)	2 / 12 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	1	0	12	0	0	6	38	0	1	10	3	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0	0	0	1	1	0
Blood creatinine increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	1 / 17 (5.88%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	2	2	3	0
Blood phosphorus decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Candida test positive
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Ejection fraction decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	2	0	0	2	0	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 4 (50.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	12	0	0	0	1	3	0
Glucose urine present
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
International normalised ratio increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	0	0
Transaminases increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Weight decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Liver function test increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Electrocardiogram PR prolongation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Amino acid level increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Blood glucose increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Haemoglobin decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	0	0
Platelet count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	10 / 275 (3.64%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	3	0	0	0	10	0	0	1	0	0
SARS-CoV-2 test positive
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Lipids increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	1	0	0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 32 (15.63%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	17 / 275 (6.18%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	8	0	0	0	35	2	0	1	0	0
Contusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	1	0
Ligament sprain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Joint dislocation
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Incision site pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Limb injury
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Toxicity to various agents
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Road traffic accident
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Skin abrasion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Skin laceration
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	1	0	0
Fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Spinal fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0	0	0	0	0
Cardiac disorders
Tachycardia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	11 / 275 (4.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	2	0	0	0	12	0	0	0	0	0
Atrial fibrillation
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 32 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0	0	0	0	0	0	0	0
Ventricular dysfunction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Sinus tachycardia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Angina pectoris
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Nervous system disorders
Disturbance in attention
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 32 (9.38%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	13 / 275 (4.73%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	1 / 3 (33.33%)
occurrences all number	0	0	0	3	0	0	0	28	0	0	0	1	1
Cognitive disorder
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 32 (3.13%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	23 / 275 (8.36%)	0 / 3 (0.00%)	2 / 3 (66.67%)	1 / 17 (5.88%)	2 / 12 (16.67%)	1 / 3 (33.33%)
occurrences all number	0	1	1	1	0	0	1	31	0	2	1	2	5
Aphasia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	2 / 32 (6.25%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	9 / 275 (3.27%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	2	2	0	1	0	9	0	0	0	0	1
Amnesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 32 (3.13%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	24 / 275 (8.73%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	1	0	1	0	41	0	0	1	0	2
Dizziness
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	6 / 32 (18.75%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 4 (50.00%)	51 / 275 (18.55%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 17 (11.76%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	2	1	9	0	1	2	90	1	0	2	1	0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 32 (3.13%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	25 / 275 (9.09%)	2 / 3 (66.67%)	0 / 3 (0.00%)	1 / 17 (5.88%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	36	2	0	1	1	0
Paraesthesia
subjects affected / exposed	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	8 / 32 (25.00%)	2 / 3 (66.67%)	1 / 3 (33.33%)	2 / 4 (50.00%)	44 / 275 (16.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 17 (23.53%)	1 / 12 (8.33%)	1 / 3 (33.33%)
occurrences all number	0	2	0	15	2	1	4	72	0	0	5	4	1
Neuropathy peripheral
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 3 (66.67%)	3 / 32 (9.38%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 4 (0.00%)	42 / 275 (15.27%)	0 / 3 (0.00%)	1 / 3 (33.33%)	3 / 17 (17.65%)	4 / 12 (33.33%)	2 / 3 (66.67%)
occurrences all number	1	0	2	4	0	2	0	51	0	3	3	6	6
Memory impairment
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	3 / 32 (9.38%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	36 / 275 (13.09%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 17 (17.65%)	2 / 12 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	1	0	3	0	0	2	85	0	0	3	4	0
Headache
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	4 / 32 (12.50%)	1 / 3 (33.33%)	1 / 3 (33.33%)	2 / 4 (50.00%)	57 / 275 (20.73%)	1 / 3 (33.33%)	1 / 3 (33.33%)	2 / 17 (11.76%)	4 / 12 (33.33%)	1 / 3 (33.33%)
occurrences all number	0	0	1	9	1	2	3	98	1	1	6	5	1
Dysgeusia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 32 (9.38%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	11 / 275 (4.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	2 / 12 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	3	0	0	1	11	0	0	0	2	0
Presyncope
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	1	0	0	0	1	0	0
Slow speech
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 17 (17.65%)	1 / 12 (8.33%)	1 / 3 (33.33%)
occurrences all number	2	0	0	0	0	0	0	0	0	0	4	1	1
Formication
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Dysarthria
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 275 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	1 / 3 (33.33%)
occurrences all number	0	4	0	0	0	1	0	0	1	0	0	1	1
Dysaesthesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Carpal tunnel syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	1	1	0
Balance disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	7 / 275 (2.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	3	0	0	1	12	0	0	1	0	1
Ataxia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Hemiparesis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 275 (0.73%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	2	0	0	0	2	0	1	0	0	0
Neurotoxicity
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	5	0	0
Neuralgia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	4 / 275 (1.45%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	2	0	0	0	9	0	0	0	0	0
Nervous system disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Migraine
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Mental impairment
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Hypoaesthesia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	3 / 12 (25.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0	0	0	1	3	0
Partial seizures
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Psychomotor hyperactivity
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Peroneal nerve palsy
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Seizure
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	1
Tremor
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 275 (0.73%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	5	0	0	0	2	0	0	0	1	0
Speech disorder
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	2 / 12 (16.67%)	1 / 3 (33.33%)
occurrences all number	0	1	0	0	0	1	0	0	0	0	1	2	1
Sensory disturbance
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Brachial plexopathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Bradykinesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Facial paralysis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Sciatica
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Motor dysfunction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	0	0
Hyperaesthesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Sleep deficit
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Syncope
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0	0	1	0	0
Fine motor skill dysfunction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0	0	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	8 / 32 (25.00%)	1 / 3 (33.33%)	2 / 3 (66.67%)	2 / 4 (50.00%)	46 / 275 (16.73%)	0 / 3 (0.00%)	3 / 3 (100.00%)	7 / 17 (41.18%)	3 / 12 (25.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	17	1	4	2	101	0	5	22	4	1
Thrombocytopenia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 17 (11.76%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0	0	0	2	1	0
Thrombocytosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Neutropenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	8	0	0
Leukocytosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	3 / 275 (1.09%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	2 / 12 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	2	0	0	0	3	0	0	0	2	0
Iron deficiency anaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Haemorrhagic diathesis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Febrile neutropenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 32 (9.38%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	25 / 275 (9.09%)	1 / 3 (33.33%)	1 / 3 (33.33%)	3 / 17 (17.65%)	3 / 12 (25.00%)	0 / 3 (0.00%)
occurrences all number	3	0	0	4	0	0	3	37	1	1	4	4	0
Vertigo positional
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Vertigo
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	1 / 12 (8.33%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	1	1
Hypoacusis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	2 / 12 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	3	0
Ear discomfort
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Deafness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Tympanic membrane perforation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	3	0
Ear pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Eye disorders
Visual impairment
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	15 / 275 (5.45%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 17 (0.00%)	1 / 12 (8.33%)	1 / 3 (33.33%)
occurrences all number	0	1	0	3	0	0	0	23	0	3	0	1	1
Vision blurred
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 32 (3.13%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	16 / 275 (5.82%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 17 (11.76%)	1 / 12 (8.33%)	1 / 3 (33.33%)
occurrences all number	0	0	1	1	0	0	0	20	0	0	2	1	2
Dry eye
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Diplopia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Conjunctival oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Astigmatism
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Asthenopia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Presbyopia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Retinal vein occlusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Visual acuity reduced
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	2 / 12 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	1	2	0
Photopsia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	1	0	0
Photophobia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Retinal detachment
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	22 / 275 (8.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 17 (11.76%)	2 / 12 (16.67%)	1 / 3 (33.33%)
occurrences all number	0	0	0	3	0	0	4	32	0	0	3	2	1
Abdominal distension
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	7 / 32 (21.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	20 / 275 (7.27%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	9	0	0	0	24	0	0	1	0	0
Vomiting
subjects affected / exposed	1 / 3 (33.33%)	2 / 3 (66.67%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	43 / 275 (15.64%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 17 (17.65%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	1	2	0	3	0	0	6	59	0	0	5	1	0
Nausea
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	3 / 32 (9.38%)	0 / 3 (0.00%)	1 / 3 (33.33%)	3 / 4 (75.00%)	59 / 275 (21.45%)	1 / 3 (33.33%)	0 / 3 (0.00%)	4 / 17 (23.53%)	3 / 12 (25.00%)	1 / 3 (33.33%)
occurrences all number	0	1	1	3	0	1	5	83	1	0	5	3	1
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	20 / 275 (7.27%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 17 (17.65%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	2	0	1	0	22	0	0	4	1	0
Dysphagia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 32 (9.38%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	17 / 275 (6.18%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	2 / 12 (16.67%)	1 / 3 (33.33%)
occurrences all number	0	0	0	4	0	0	0	17	0	0	0	2	1
Dyspepsia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Diarrhoea
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 32 (15.63%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 4 (75.00%)	69 / 275 (25.09%)	0 / 3 (0.00%)	1 / 3 (33.33%)	4 / 17 (23.53%)	3 / 12 (25.00%)	2 / 3 (66.67%)
occurrences all number	1	0	0	6	0	0	5	122	0	1	5	7	4
Constipation
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	8 / 32 (25.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 4 (0.00%)	50 / 275 (18.18%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 17 (23.53%)	3 / 12 (25.00%)	2 / 3 (66.67%)
occurrences all number	0	1	0	13	1	2	0	76	0	0	5	3	2
Abdominal discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	4 / 275 (1.45%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	2	0	1	0	7	0	1	0	0	0
Abdominal pain upper
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	3 / 32 (9.38%)	1 / 3 (33.33%)	1 / 3 (33.33%)	2 / 4 (50.00%)	15 / 275 (5.45%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	1	4	1	1	2	22	0	0	0	0	0
Faeces discoloured
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0
Gastrointestinal disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Intestinal obstruction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Swollen tongue
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Ascites
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Dry mouth
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	3 / 32 (9.38%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	12 / 275 (4.36%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	3	0	0	0	12	0	0	1	0	0
Stomatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 32 (3.13%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	14 / 275 (5.09%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	19	0	0	0	0	0
Colitis ulcerative
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Dental caries
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	10 / 32 (31.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	2	0	0	2	0
Diarrhoea haemorrhagic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Food poisoning
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Terminal ileitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Pancreatic disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Oesophagitis
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	1	0
Tooth impacted
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Flatulence
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 32 (12.50%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	9 / 275 (3.27%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	4	0	0	0	10	0	0	0	0	0
Hepatobiliary disorders
Hypertransaminasaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Hepatic cytolysis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 32 (9.38%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	18 / 275 (6.55%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 17 (5.88%)	1 / 12 (8.33%)	1 / 3 (33.33%)
occurrences all number	0	0	0	3	0	0	1	20	1	0	1	1	2
Dry skin
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 275 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 17 (11.76%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	1	1	0	1	0	2	0	0
Rash
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	3 / 32 (9.38%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	33 / 275 (12.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	3 / 12 (25.00%)	0 / 3 (0.00%)
occurrences all number	0	1	1	5	0	0	0	49	0	0	1	4	0
Pruritus
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	3 / 32 (9.38%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	11 / 275 (4.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	3	0	0	0	14	0	0	0	0	0
Hyperhidrosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 32 (3.13%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	19 / 275 (6.91%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	2 / 12 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	20	0	0	0	2	0
Dermatitis acneiform
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Dermatitis contact
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Dermatomyositis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Night sweats
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Photosensitivity reaction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	1 / 12 (8.33%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	1	1
Rash erythematous
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Rash maculo-papular
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	3	0	0
Rash pruritic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Rosacea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Seborrhoeic dermatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Skin lesion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Erythema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Dermatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Eczema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Rash papular
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	0	0
Lipohypertrophy
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Hand dermatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Renal and urinary disorders
Haematuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	14 / 275 (5.09%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 17 (11.76%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	20	0	0	2	1	0
Pollakiuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	1	0	0
Micturition urgency
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	1	0	0
Hydronephrosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Chronic kidney disease
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Proteinuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	1	0	0
Urinary incontinence
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	1	1	0	0
Dysuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Renal colic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Endocrine disorders
Cushingoid
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	0	0
Hyperparathyroidism
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Hypothyroidism
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	6 / 32 (18.75%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	84 / 275 (30.55%)	1 / 3 (33.33%)	0 / 3 (0.00%)	6 / 17 (35.29%)	3 / 12 (25.00%)	1 / 3 (33.33%)
occurrences all number	0	1	3	9	0	1	1	138	1	0	12	4	1
Back pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	6 / 32 (18.75%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 4 (50.00%)	45 / 275 (16.36%)	1 / 3 (33.33%)	0 / 3 (0.00%)	6 / 17 (35.29%)	2 / 12 (16.67%)	2 / 3 (66.67%)
occurrences all number	0	1	0	7	0	3	2	63	1	0	11	2	4
Bone pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 32 (12.50%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	8 / 275 (2.91%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	4	0	0	0	8	0	0	1	1	0
Joint swelling
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	1	0	0
Muscle spasms
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 32 (3.13%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	19 / 275 (6.91%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	1	1	22	0	0	0	0	0
Muscular weakness
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	18 / 275 (6.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	1	1	2	0	0	0	22	0	0	1	1	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	11 / 275 (4.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 17 (11.76%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	2	0	0	0	12	0	0	2	0	0
Musculoskeletal pain
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	7 / 275 (2.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 17 (23.53%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	2	0	0	0	9	0	0	5	0	0
Myalgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 32 (15.63%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	38 / 275 (13.82%)	2 / 3 (66.67%)	0 / 3 (0.00%)	2 / 17 (11.76%)	2 / 12 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	7	0	1	1	50	3	0	2	3	0
Pain in extremity
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 32 (15.63%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	50 / 275 (18.18%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 17 (11.76%)	2 / 12 (16.67%)	1 / 3 (33.33%)
occurrences all number	0	0	0	8	0	4	0	64	0	1	2	2	1
Arthritis
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	1	0
Bone lesion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Flank pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 17 (17.65%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	4	0	0
Limb discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Musculoskeletal discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Neck pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 32 (9.38%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	8 / 275 (2.91%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 17 (17.65%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	3	0	0	0	9	0	0	3	1	0
Osteoarthritis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Osteoporosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Pain in jaw
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 17 (11.76%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	0	0
Plantar fasciitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 17 (11.76%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	0	0
Torticollis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Musculoskeletal stiffness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Joint lock
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Synovial cyst
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Sacral pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Osteonecrosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Trismus
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Spinal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	3 / 275 (1.09%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	2	0	0	0	3	0	0	0	0	0
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 32 (3.13%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	20 / 275 (7.27%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 17 (11.76%)	2 / 12 (16.67%)	1 / 3 (33.33%)
occurrences all number	0	0	0	1	0	4	4	30	0	1	6	2	1
Influenza
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	17 / 275 (6.18%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	24	0	0	1	0	1
Pneumonia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 32 (12.50%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	27 / 275 (9.82%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	4	0	0	1	37	1	1	0	0	0
Rhinitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 32 (3.13%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	16 / 275 (5.82%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	2	26	0	0	0	2	0
Upper respiratory tract infection
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	38 / 275 (13.82%)	0 / 3 (0.00%)	1 / 3 (33.33%)	4 / 17 (23.53%)	3 / 12 (25.00%)	2 / 3 (66.67%)
occurrences all number	2	1	0	4	0	0	0	61	0	1	8	12	3
Sinusitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	2	0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Bacterial infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	0	0
Candida infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0
Cellulitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	1
Chronic sinusitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Clostridium difficile colitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Enteritis infectious
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0
Gastroenteritis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Enterococcal bacteraemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Helicobacter infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Lower respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1	0
Laryngitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 17 (17.65%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	3	0	0
Herpes virus infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	0	0	0
Nasopharyngitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 32 (3.13%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	24 / 275 (8.73%)	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	1	31	3	0	0	0	0
Oral candidiasis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 275 (0.73%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	2	0	0	0	2	0	0	1	0	0
Periodontitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Pharyngitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	2	0	1	0	0
Respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 17 (17.65%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	4	1	0
Soft tissue infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0
Tooth abscess
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Urinary tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 32 (12.50%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	20 / 275 (7.27%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 17 (23.53%)	1 / 12 (8.33%)	2 / 3 (66.67%)
occurrences all number	0	0	0	4	0	0	1	28	0	0	8	2	3
Viral rhinitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0
Conjunctivitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Herpes zoster
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Cystitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	1	0	0
Ear infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Enterocolitis infectious
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	0	0
Infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	2 / 12 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	2	0
Paronychia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	1 / 12 (8.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	2	0
Pyelonephritis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0
Tooth infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	1	0	0
Viral infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	1 / 12 (8.33%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	3	1
Metabolism and nutrition disorders
Hyperglycaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	3 / 32 (9.38%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	26 / 275 (9.45%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	5	0	6	0	0	0	76	0	0	12	0	0
Hypercholesterolaemia
subjects affected / exposed	1 / 3 (33.33%)	2 / 3 (66.67%)	1 / 3 (33.33%)	15 / 32 (46.88%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 4 (25.00%)	153 / 275 (55.64%)	0 / 3 (0.00%)	2 / 3 (66.67%)	12 / 17 (70.59%)	7 / 12 (58.33%)	3 / 3 (100.00%)
occurrences all number	2	6	1	91	1	17	8	789	0	4	68	38	21
Decreased appetite
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	18 / 275 (6.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	2	0	0	3	20	0	0	1	0	0
Hypophosphataemia
subjects affected / exposed	0 / 3 (0.00%)	2 / 3 (66.67%)	1 / 3 (33.33%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	19 / 275 (6.91%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 17 (0.00%)	0 / 12 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	5	1	0	0	0	0	43	0	4	0	0	4
Hypomagnesaemia
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 32 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	17 / 275 (6.18%)	0 / 3 (0.00%)	3 / 3 (100.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	2	0	0	1	0	0	27	0	5	0	0	0
Hypokalaemia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 32 (9.38%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	18 / 275 (6.55%)	0 / 3 (0.00%)	2 / 3 (66.67%)	1 / 17 (5.88%)	0 / 12 (0.00%)	1 / 3 (33.33%)
occurrences all number	1	0	0	4	1	0	0	30	0	7	1	0	16
Hyperuricaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 32 (3.13%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	19 / 275 (6.91%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	1	1	24	1	1	0	0	0
Hypertriglyceridaemia
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	23 / 32 (71.88%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	179 / 275 (65.09%)	3 / 3 (100.00%)	1 / 3 (33.33%)	7 / 17 (41.18%)	5 / 12 (41.67%)	2 / 3 (66.67%)
occurrences all number	4	9	0	137	0	3	11	1273	33	1	74	10	11
Hyperlipidaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	0	0
Dehydration
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 17 (5.88%)	1 / 12 (8.33%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	1	1	1
Hypercalcaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0
Fluid retention
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 32 (6.25%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	7 / 275 (2.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	2 / 12 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	3	1	0	0	8	0	0	0	2	0
Hypocalcaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	4	0	0	0
Hypoalbuminaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	16 / 275 (5.82%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	2	0	0	0	26	0	0	0	0	0
Increased appetite
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Hyperkalaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 17 (5.88%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0
Cell death
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 32 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 275 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	4	0	0	0	0	0	0
Gout
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 275 (0.36%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	3	0	0	0	2	0	0	0	0	0
Hyponatraemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 32 (6.25%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	10 / 275 (3.64%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 17 (0.00%)	0 / 12 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	3	0	0	0	14	0	0	0	0	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

17 Sep 2013

Added left ventricular ejection fraction (LVEF) evaluation, exclusion criterion about LVEF, secondary efficacy measures, specific DLT definition and dose modification in case of toxicity.

28 Mar 2014

Updated Schedule of Activities; revised inclusion and exclusion criteria; updated DLT definition and clarified intra-subject dose escalation.

29 Oct 2014

Added lipid testing, a food effect substudy, neurological assessment, BID dosing, Japanese LIC; revised inclusion and exclusion criteria.

22 Jul 2015

Revised inclusion and exclusion criteria; removed midazolam, food effect and some other assessments from Phase 2; added cognition, mood and suicidal ideation and behavior assessment in Phase 2.

11 Mar 2016

Excluded subjects with PR interval >220 msec, or 2nd or 3rd degree atrioventricular block within 3 months prior to study entry; added dose modification for subjects with PR interval prolongation.

15 Jul 2016

Added Drug Drug Interaction, Holter Monitoring; updated dose modification for those with 1st, 2nd degree or complete heart block; deleted restriction for taking proton pump inhibitors with study drug.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

Participant with ALK/ROS1positive NSCLC were enrolled in EXP-1 to EXP-6 cohort,received 100mg dose.Primary safety population=participant had atleast 1dose of lorlatinib.Sample size N=275 provided more valuable information than single expansion cohort

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials

Clinical Trial Results: Phase 1/2 Study of PF-06463922 (an ALK/ROS1 Tyrosine Kinase Inhibitor) in Patients With Advanced Non-Small Cell Lung Cancer Harboring Specific Molecular Alterations

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Participants with Cycle 1 Dose-Limiting Toxicities (DLTs) in Phase 1

Primary: Number of Participants with Cycle 1 Dose-Limiting Toxicities (DLTs) in Phase 1

Primary: Percentage of Participants with Overall and Intracranial Objective Response (Phase 2)

Primary: Percentage of Participants with Overall and Intracranial Objective Response (Phase 2)

Secondary: Percentage of Participants With Overall and Intracranial Objective Response (Phase 1)

Secondary: Percentage of Participants With Overall and Intracranial Objective Response (Phase 1)

Secondary: Time to Tumor Response (TTR) and Intracranial TTR (Phase 1)

Secondary: Time to Tumor Response (TTR) and Intracranial TTR (Phase 1)

Secondary: Number of Participants With Duration of Response (DOR) and Intracranial DOR (Phase 1)

Secondary: Number of Participants With Duration of Response (DOR) and Intracranial DOR (Phase 1)

Secondary: Percentage of Participants Achieving Disease Control and Intracranial Disease Control at 12 and 24 Weeks (Phase 1)

Secondary: Percentage of Participants Achieving Disease Control and Intracranial Disease Control at 12 and 24 Weeks (Phase 1)

Secondary: Probability of First Event Being a Central Nervous System (CNS) Progression, Non CNS Progression, or Death (Phase 1)

Secondary: Probability of First Event Being a Central Nervous System (CNS) Progression, Non CNS Progression, or Death (Phase 1)

Secondary: Progression-Free Survival (PFS) (Phase 1)

Secondary: Progression-Free Survival (PFS) (Phase 1)

Secondary: Overall Survival (OS) (Phase 1)

Secondary: Overall Survival (OS) (Phase 1)

Secondary: Maximum Observed Plasma Concentration (Cmax) of PF-06463922 Following Single Oral Doses (Phase 1)

Secondary: Maximum Observed Plasma Concentration (Cmax) of PF-06463922 Following Single Oral Doses (Phase 1)

Secondary: Maximum Observed Plasma Concentration (Cmax) of PF-06463922 Following Multiple Oral Doses (Phase 1)

Secondary: Maximum Observed Plasma Concentration (Cmax) of PF-06463922 Following Multiple Oral Doses (Phase 1)

Secondary: Time for Cmax (Tmax) of PF-06463922 Following Single Oral Doses (Phase 1)

Secondary: Time for Cmax (Tmax) of PF-06463922 Following Single Oral Doses (Phase 1)

Secondary: Time for Cmax (Tmax) of PF-06463922 Following Multiple Oral Doses (Phase 1)

Secondary: Time for Cmax (Tmax) of PF-06463922 Following Multiple Oral Doses (Phase 1)

Secondary: Area under the Plasma Concentration-Time profile from Time Zero to Time Tau (AUCtau) of PF-06463922 Following Single Oral Doses (Phase 1)

Secondary: Area under the Plasma Concentration-Time profile from Time Zero to Time Tau (AUCtau) of PF-06463922 Following Single Oral Doses (Phase 1)

Secondary: Area under the Plasma Concentration-Time profile from Time Zero to Time Tau (AUCtau) of PF-06463922 Following Multiple Oral Doses (Phase 1)

Secondary: Area under the Plasma Concentration-Time profile from Time Zero to Time Tau (AUCtau) of PF-06463922 Following Multiple Oral Doses (Phase 1)

Secondary: Area under the Plasma Concentration-Time Profile from Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06463922 Following Single Oral Doses (Phase 1)

Secondary: Area under the Plasma Concentration-Time Profile from Time Zero Extrapolated to Infinite Time (AUCinf) of PF-06463922 Following Single Oral Doses (Phase 1)

Secondary: Apparent Oral Clearance (CL/F) of PF-06463922 Following Single Oral Doses (Phase 1)

Secondary: Apparent Oral Clearance (CL/F) of PF-06463922 Following Single Oral Doses (Phase 1)

Secondary: Apparent Oral Clearance (CL/F) of PF-06463922 Following Multiple Oral Doses (Phase 1)

Secondary: Apparent Oral Clearance (CL/F) of PF-06463922 Following Multiple Oral Doses (Phase 1)

Secondary: Apparent Volume of Distribution (Vz/F) of PF-06463922 Following Single Oral Doses (Phase 1)

Secondary: Apparent Volume of Distribution (Vz/F) of PF-06463922 Following Single Oral Doses (Phase 1)

Secondary: Observed Accumulation Ratio (Rac) of PF-06463922 Following Multiple Oral Doses (Phase 1)

Secondary: Observed Accumulation Ratio (Rac) of PF-06463922 Following Multiple Oral Doses (Phase 1)

Secondary: Terminal Half-Life of PF-06463922 Following Single Oral Doses (Phase 1)

Secondary: Terminal Half-Life of PF-06463922 Following Single Oral Doses (Phase 1)

Secondary: Steady State Accumulation Ratio (Rss) of PF-06463922 Following Multiple Oral Doses (Phase 1)

Secondary: Steady State Accumulation Ratio (Rss) of PF-06463922 Following Multiple Oral Doses (Phase 1)

Secondary: Renal Clearance (CLr) of PF-06463922 (Phase 1)

Secondary: Renal Clearance (CLr) of PF-06463922 (Phase 1)

Secondary: Percent of PF-06463922 Recovered Unchanged in Urine up to Dosing Interval (AEtau%) (Phase 1)

Secondary: Percent of PF-06463922 Recovered Unchanged in Urine up to Dosing Interval (AEtau%) (Phase 1)

Secondary: Maximum Observed Plasma Concentration (Cmax) of Midazolam (Phase 1)

Secondary: Maximum Observed Plasma Concentration (Cmax) of Midazolam (Phase 1)

Secondary: Time for Cmax (Tmax) of Midazolam (Phase 1)

Secondary: Time for Cmax (Tmax) of Midazolam (Phase 1)

Secondary: Area under the Plasma Concentration-Time profile from Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Midazolam (Phase 1)

Secondary: Area under the Plasma Concentration-Time profile from Time Zero to the Time of the Last Quantifiable Concentration (AUClast) of Midazolam (Phase 1)

Secondary: Area under the Plasma Concentration-Time Profile from Time Zero Extrapolated to Infinite Time (AUCinf) of Midazolam (Phase 1)

Secondary: Area under the Plasma Concentration-Time Profile from Time Zero Extrapolated to Infinite Time (AUCinf) of Midazolam (Phase 1)

Secondary: Apparent Oral Clearance (CL/F) of Midazolam (Phase 1)

Secondary: Apparent Oral Clearance (CL/F) of Midazolam (Phase 1)

Secondary: Apparent Volume of Distribution (Vz/F) of Midazolam (Phase 1)

Secondary: Apparent Volume of Distribution (Vz/F) of Midazolam (Phase 1)

Secondary: Terminal Half-Life of Midazolam (Phase 1)

Secondary: Terminal Half-Life of Midazolam (Phase 1)

Secondary: Number of Participants with ALK Mutation Based on Plasma CNA Analysis (Phase 1)

Secondary: Number of Participants with ALK Mutation Based on Plasma CNA Analysis (Phase 1)

Secondary: Number of Participants with ALK Mutation Based on Tumor Tissue Analysis (Phase 1)

Secondary: Number of Participants with ALK Mutation Based on Tumor Tissue Analysis (Phase 1)

Secondary: Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-C30 (Phase 1)

Secondary: Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-C30 (Phase 1)

Secondary: Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-LC13 (Phase 1)

Secondary: Number of Participants Who Improved, Worsened or Remained Stable in EORTC QLQ-LC13 (Phase 1)

Clinical Trial Results:
Phase 1/2 Study of PF-06463922 (an ALK/ROS1 Tyrosine Kinase Inhibitor) in Patients With Advanced Non-Small Cell Lung Cancer Harboring Specific Molecular Alterations