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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

Results information
Results version number	v1(current)
This version publication date	24 Mar 2018
First version publication date	24 Mar 2018
Other versions

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

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Trial information

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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., +1 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer, Inc., +1 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

Interim

Date of interim/final analysis

22 Nov 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

15 Mar 2017

Global end of trial reached?

Main objective of the trial

The primary objective of the Phase 1 portion of the study was to assess safety and tolerability of lorlatinib as a single agent at increasing dose levels in subjects 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). The primary objective of the Phase 2 portion of the study was to evaluate overall (intra- and extra-cranial) and intra-cranial anti-tumor activity of single-agent lorlatinib at RP2D in subjects 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 subjects.

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: 23

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: 27

Country: Number of subjects enrolled

Japan: 42

Country: Number of subjects enrolled

Korea, Republic of: 4

Country: Number of subjects enrolled

Singapore: 26

Country: Number of subjects enrolled

Spain: 30

Country: Number of subjects enrolled

Switzerland: 7

Country: Number of subjects enrolled

Taiwan: 11

Country: Number of subjects enrolled

United States: 121

Worldwide total number of subjects

332

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)

270

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

A total of 334 subjects were enrolled in this study, and 2 of them (one each in Phase 1 and Phase 2) didn't receive any study treatment.

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 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. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.

Arm type

Experimental

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.

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.

50 mg QD (Phase 1)

Arm description

PF-06463922 50 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 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 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 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 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 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.

150 mg QD (Phase 1)

Arm description

PF-06463922 150 mg was orally given 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. Midazolam 2 mg was orally given QD on Day -7 and Cycle 1 Day 15.

Arm type

Experimental

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.

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.

200 mg QD (Phase 1)

Arm description

PF-06463922 200 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 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 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 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 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 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 subjects with advanced ALK-positive NSCLC with or without asymptomatic central nervous system (CNS) metastases were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for subjects 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

Subjects with advanced ALK-positive NSCLC with or without asymptomatic CNS metastases relapsing after only crizotinib therapy were given PF-06463922 100 mg orally once daily (QD) on Day -7 (only for subjects 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

Subjects 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 subjects 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 once daily (QD) on Day -7 (only for subjects 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

subjects 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 subjects 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

Subjects 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 subjects 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

Subjects 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 subjects 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 subjects 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 subjects, in order to support inclusion of Japanese subjects 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.

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)
Started	3	3	3	12	17	3	3	3	3	4	30	27	60	65	46	47	3
Received treatment	3	3	3	12	17	3	3	3	3	4	30	27	60	65	46	47	3
Completed	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Not completed	3	3	3	12	17	3	3	3	3	4	30	27	60	65	46	47	3
Adverse event, serious fatal	3	1	3	4	6	3	1	3	2	1	1	4	14	19	15	10	1
Study ongoing	-	2	-	6	8	-	2	-	1	3	29	22	43	41	29	29	2
Consent withdrawn by subject	-	-	-	1	2	-	-	-	-	-	-	1	2	5	2	7	-
Unspecified	-	-	-	-	-	-	-	-	-	-	-	-	-	-	-	1	-
Lost to follow-up	-	-	-	1	1	-	-	-	-	-	-	-	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 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)	Total
Number of subjects	3	3	3	12	17	3	3	3	3	4	30	27	60	65	46	47	3	332
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Adults (18-64 years)	1	2	3	11	16	2	3	2	2	3	22	18	48	56	39	39	3	270
From 65-84 years	2	1	0	1	1	1	0	1	1	1	8	8	12	9	7	8	0	61
85 years and over	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	1
Age Continuous
Units: years
arithmetic mean (standard deviation)	67.3 ( 11.2 )	53.7 ( 13.0 )	52.7 ( 10.0 )	48.2 ( 13.2 )	49 ( 11.1 )	55.3 ( 14.7 )	44.7 ( 4.2 )	61.3 ( 15.4 )	61.3 ( 18.1 )	50.8 ( 15.2 )	57.4 ( 12.1 )	57.1 ( 12.7 )	54 ( 11.9 )	52.2 ( 11.8 )	51.5 ( 11.2 )	52.8 ( 12.9 )	44.3 ( 6.1 )	-
Sex: Female, Male
Units: Subjects
FEMALE	2	0	1	7	11	2	2	2	3	2	13	17	38	37	25	27	2	191
MALE	1	3	2	5	6	1	1	1	0	2	17	10	22	28	21	20	1	141
Race/Ethnicity, Customized
Units: Subjects
White\|	2	2	3	7	13	2	2	1	2	3	10	13	25	32	27	25	0	169
Black\|	1	0	0	0	0	1	0	1	0	0	1	0	1	0	0	1	0	6
Asian\|	0	1	0	3	2	0	1	0	0	0	17	10	23	23	14	16	3	113
Other\|	0	0	0	0	1	0	0	0	0	0	1	2	1	3	2	3	0	13
Unspecified\|	0	0	0	2	1	0	0	1	1	1	1	2	10	7	3	2	0	31

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 intent-to-treat (ITT) subjects 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 intent-to-treat (ITT) subjects 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 intent-to-treat (ITT) subjects.

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 subjects who received at least 1 dose of PF-06463922 and completed a baseline and at least 1 post-baseline patient reported outcome (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 intent-to-treat (ITT) subjects.

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 subjects and Japan LIC. These subjects 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 sets values	ALK Positive Population (Phase 1)	ROS1 Positive Population (Phase 1)	Phase 1 ITT Population	Phase 1 PRO Evaluable Population	Phase 2 ITT Population	Phase 2 and Japan LIC PK Analysis Set
Number of subjects	41	12	53	43	274	22
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0
Adults (18-64 years)	36	8	44	36	221	21
From 65-84 years	5	4	9	7	52	1
85 years and over	0	0	0	0	1	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	51.0 ( 11.2 )	55.0 ( 18.0 )	51.9 ( 13.0 )	51.4 ( 13.2 )	53.6 ( 12.1 )	50.9 ( 9.8 )
Sex: Female, Male
Units: Subjects
FEMALE	24	7	31	24	157	13
MALE	17	5	22	19	117	9
Race/Ethnicity, Customized
Units: Subjects
White\|	32	5	37	31	132	9
Black\|	2	1	3	1	3	0
Asian\|	5	2	7	5	103	11
Other\|	0	1	1	1	11	2
Unspecified\|	2	3	5	5	25	0

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

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 intent-to-treat (ITT) subjects 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 intent-to-treat (ITT) subjects 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 intent-to-treat (ITT) subjects.

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 subjects who received at least 1 dose of PF-06463922 and completed a baseline and at least 1 post-baseline patient reported outcome (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 intent-to-treat (ITT) subjects.

Subject analysis set title

Phase 2 and Japan LIC PK Analysis Set

Subject analysis set type

Sub-group analysis

Subject analysis set description

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

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End point title

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

End point description

DLT was defined as any of the following adverse events (AEs) attributable to PF-06463922: (1) hematologic: grade 4 neutropenia for >7 days; febrile neutropenia; grade >=3 neutropenic infection; grade >=3 thrombocytopenia with bleeding; grade 4 thrombocytopenia; (2) 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 that had been confirmed by repeat testing and re-evaluation by a qualified person, and persisted after correction of reversible causes; >=20% decrease from baseline in left ventricular ejection fraction (LVEF); (3) other: failure to deliver at least 16 out of the 21 prescribed daily total doses due to toxicities attributable to study drug; failure to restart dosing after 21 days (1 cycle) delay due to toxicities attributable to study drug.

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 analyses were planned for this primary end point.
[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: All other reporting arms are not applicable to this end point.

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: subjects
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 Subjects with Overall and Intracranial Objective Response (Phase 2)

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End point title

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

End point description

Objective response (OR) refers to confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. Intracranial OR refers to confirmed CR or PR considering only lesions within brain. Results presented here were based on independent central review. The intent-to-treat (ITT) analysis set was used for overall response assessment, and included all enrolled subjects with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922; subjects with central nervous system (CNS) metastases in the ITT analysis set were used for intracranial response assessment.

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 analyses were planned for this primary end point.
[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: All other reporting arms are not applicable to this end point.

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 ^[5]	27 ^[6]	59 ^[7]	65 ^[8]	46 ^[9]	47 ^[10]
Units: percentage of subjects
number (confidence interval 95%)
Objective response\|	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 objective response\|	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)

Notes
[5] - Number of subjects analyzed for intracranial objective response is 8.
[6] - Number of subjects analyzed for intracranial objective response is 17.
[7] - Number of subjects analyzed for intracranial objective response is 32.
[8] - Number of subjects analyzed for intracranial objective response is 45.
[9] - Number of subjects analyzed for intracranial objective response is 38.
[10] - Number of subjects analyzed for intracranial objective response is 25.

No statistical analyses for this end point

Secondary: Percentage of Subjects with Overall and Intracranial Objective Response (Phase 1)

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End point title

Percentage of Subjects with Overall and Intracranial Objective Response (Phase 1)

End point description

Objective response (OR) refers to confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. Intracranial OR refers to confirmed CR or PR considering only lesions within brain. Results presented here were based on independent central review. The intent-to-treat (ITT) analysis set was used for overall response assessment, and included all enrolled subjects with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922; subjects with CNS metastases in the ITT analysis set was used for intracranial response assessment.

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 ^[11]	12 ^[12]
Units: percentage of subjects
number (confidence interval 95%)
Objective response\|	39.0 (24.2 to 55.5)	50.0 (21.1 to 78.9)
Intracranial objective response\|	41.2 (24.6 to 59.3)	50.0 (15.7 to 84.3)

Notes
[11] - Number of subjects analyzed for intracranial objective response is 34.
[12] - Number of subjects analyzed for intracranial objective response is 8.

No statistical analyses for this end point

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

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End point title

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

End point description

Time to tumor response (TTR) was defined as the time from the first dose of study treatment to the first documentation of objective tumor response (CR or PR). For subjects whose objective response proceeded from PR to CR, the onset of PR was taken as the onset of response. TTR was only calculated for the subgroup of subjects with a confirmed objective tumor response. Intracranial TTR was only calculated for subjects with confirmed intracranial objective response. Results presented here were based on independent central review.

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	16 ^[13]	6 ^[14]
Units: months
median (full range (min-max))
TTR\|	1.4 (1.2 to 15.2)	1.4 (1.2 to 2.8)
Intracranial TTR\|	1.4 (1.2 to 20.1)	1.4 (1.1 to 2.8)

Notes
[13] - Number of subjects analyzed for intracranial TTR is 14.
[14] - Number of subjects analyzed for intracranial TTR is 4.

No statistical analyses for this end point

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

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End point title

Duration of Response (DOR) and Intracranial DOR (Phase 1)

End point description

Duration of Response (DOR) was defined as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of disease progression or to death due to any cause, whichever occurred first. DOR was only calculated for the subgroup of subjects with a confirmed objective tumor response. Intracranial DOR was only calculated for subjects with confirmed intracranial objective response. Results presented here were based on independent central review. "99999" represents "not applicable" or "non evaluable" data.

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	16 ^[15]	6 ^[16]
Units: months
median (confidence interval 95%)
DOR\|	14.06 (4.17 to 99999)	99999 (9.69 to 99999)
Intra-cranial DOR\|	99999 (14.06 to 99999)	99999 (99999 to 99999)

Notes
[15] - Number of subjects analyzed for intracranial DOR is 14.
[16] - Number of subjects analyzed for intracranial DOR is 4.

No statistical analyses for this end point

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

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End point title

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

End point description

Tumor response was evaluated according to RECIST version 1.1, and disease control was defined as confirmed complete response (CR), confirmed partial response (PR), or stable disease (SD). Results presented here were based on independent central review. The intent-to-treat (ITT) analysis set was used for overall response assessment, and included all enrolled subjects with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922; subjects with CNS metastases in the ITT analysis set was used for intracranial response assessment.

End point type

Secondary

End point timeframe

12 weeks

End point values	ALK Positive Population (Phase 1)	ROS1 Positive Population (Phase 1)
Number of subjects analysed	41 ^[17]	12 ^[18]
Units: percentage of subjects
number (confidence interval 95%)
Disease control rate\|	53.7 (37.4 to 69.3)	58.3 (27.7 to 84.8)
Intra-cranial disease control rate\|	50.0 (32.4 to 67.6)	37.5 (8.5 to 75.5)

Notes
[17] - Number of subjects analyzed for intracranial disease control rate is 34.
[18] - Number of subjects analyzed for intracranial disease control rate is 8.

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)

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End point title

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

End point description

The probability of the 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. Subjects not known to have any of the Competing Events were censored on the date they were last assessed for disease status for PFS. Subjects 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. The results are based on independent central review.

End point type

Secondary

End point timeframe

3 years

End point values	Phase 1 ITT Population
Number of subjects analysed	53
Units: not applicable
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)

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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. Results presented here were based on independent central review. PFS analysis set included all subjects with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922. "99999" represents "not applicable" or "non evaluable" data.

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 ^[19]	12 ^[20]
Units: months
median (confidence interval 95%)	5.3 (2.5 to 11.8)	10.1 (1.6 to 99999)

Notes
[19] - Number of subjects with objective progression or death is 29; others were censored.
[20] - Number of subjects with objective progression or death is 7; others were censored.

No statistical analyses for this end point

Secondary: Overall Survival (OS) (Phase 1)

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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 subjects still alive at the time of analysis, the OS time was censored on the last date the subjects were known to be alive. Estimates of OS and its 95% confidence interval were determined using Kaplan-Meier method. ITT population was used for OS analysis, and it included all enrolled subjects with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922. "99999" represents "not applicable" or "non evaluable" data.

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 ^[21]	12 ^[22]
Units: months
median (confidence interval 95%)	22.3 (11.4 to 99999)	99999 (4.7 to 99999)

Notes
[21] - Number of deaths is 21; others were censored.
[22] - Number of deaths is 5; others were censored.

No statistical analyses for this end point

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

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End point title

Maximum Observed Plasma Concentration (Cmax) of PF-06463922 Following Single Oral Doses (Phase 1) ^[23]

End point description

Maximum observed plasma concentration (Cmax) of PF-06463922 was observed directly from data. PK concentration analysis set for PF-06463922 included all subjects treated who had at least 1 concentration of PF-06463922. "99999" represents "not applicable" or "non evaluable" data.

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cylce 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
[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: All other reporting arms are not applicable to this end point.

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: 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)

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End point title

Maximum Observed Plasma Concentration (Cmax) of PF-06463922 Following Multiple Oral Doses (Phase 1) ^[24]

End point description

Maximum Observed Plasma Concentration (Cmax) of PF-06463922 was observed directly from data. PK concentration analysis set for PF-06463922 included all subjects treated who had at least 1 concentration of PF-06463922. "99999" represents "not applicable" or "non evaluable" data.

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
[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: All other reporting arms are not applicable to this end point.

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)

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End point title

Time for Cmax (Tmax) of PF-06463922 Following Single Oral Doses (Phase 1) ^[25]

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 subjects 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

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: All other reporting arms are not applicable to this end point.

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)

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End point title

Time for Cmax (Tmax) of PF-06463922 Following Multiple Oral Doses (Phase 1) ^[26]

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
[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: All other reporting arms are not applicable to this end point.

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)

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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) ^[27]

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 subjects 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 "not applicable" or "non evaluable" data.

End point type

Secondary

End point timeframe

Pre-dose, 0.5, 1, 2, 3, 4, 6, 8, 9 and 24 hours post-dose on Cylce 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
[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: All other reporting arms are not applicable to this end point.

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)

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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) ^[28]

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
[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: All other reporting arms are not applicable to this end point.

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)

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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) ^[29]

End point description

AUCinf was calculated as AUClast + (Clast*/kel), where AUClast was the area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration, Clast* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel was the rate constant for terminal phase. PK parameter analysis set for PF-06463922 included all enrolled subjects 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 "not applicable" or "non evaluable" data.

End point type

Secondary

End point timeframe

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: All other reporting arms are not applicable to this end point.

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)

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End point title

Apparent Oral Clearance (CL/F) of PF-06463922 Following Single Oral Doses (Phase 1) ^[30]

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 subjects 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 "not applicable" or "non evaluable" data.

End point type

Secondary

End point timeframe

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: All other reporting arms are not applicable to this end point.

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)

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End point title

Apparent Oral Clearance (CL/F) of PF-06463922 Following Multiple Oral Doses (Phase 1) ^[31]

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
[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: All other reporting arms are not applicable to this end point.

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)

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End point title

Apparent Volume of Distribution (Vz/F) of PF-06463922 Following Single Oral Doses (Phase 1) ^[32]

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 subjects 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 "not applicable" or "non evaluable" data.

End point type

Secondary

End point timeframe

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: All other reporting arms are not applicable to this end point.

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)

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End point title

Observed Accumulation Ratio (Rac) of PF-06463922 Following Multiple Oral Doses (Phase 1) ^[33]

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 subjects 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 "not applicable" or "non evaluable" data.

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
[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: All other reporting arms are not applicable to this end point.

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)

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End point title

Terminal Half-Life of PF-06463922 Following Single Oral Doses (Phase 1) ^[34]

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 subjects 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 "not applicable" or "non evaluable" data.

End point type

Secondary

End point timeframe

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: All other reporting arms are not applicable to this end point.

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)

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End point title

Steady State Accumulation Ratio (Rss) of PF-06463922 Following Multiple Oral Doses (Phase 1) ^[35]

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 (12 and 24 hours for BID and QD dosing regimen, respectively), 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 subjects 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 "not applicable" or "non evaluable" data.

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
[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: All other reporting arms are not applicable to this end point.

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)

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End point title

Renal Clearance (CLr) of PF-06463922 (Phase 1) ^[36]

End point description

Renal clearance was calculated as Aetau/AUCtau, where Aetau was the cumulative amount of drug recovered unchanged in urine up to dosing interval tau (24 hours for QD dosing regimen), and AUCtau was the area under the plasma concentration-time profile from time 0 to time tau (24 hours for QD dosing regimen). PK parameter analysis set for PF-06463922 included all enrolled subjects 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. This end point is only applicable to 100 mg QD group.

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
[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: All other reporting arms are not applicable to this end point.

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)

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End point title

Percent of PF-06463922 Recovered Unchanged in Urine up to Dosing Interval (AEtau%) (Phase 1) ^[37]

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 subjects 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. This end point is only applicable to 100 mg QD group.

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
[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: All other reporting arms are not applicable to this end point.

End point values	100 mg QD (Phase 1)
Number of subjects analysed	3
Units: percentage
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)

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End point title

Maximum Observed Plasma Concentration (Cmax) of Midazolam (Phase 1) ^[38]

End point description

Cmax of midazolam was observed directly from data. Only subjects 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 concentration analysis set for midazolam included all subjects treated with midazolam who had at least 1 concentration of midazolam.

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
[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: All other reporting arms are not applicable to this end point.

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)

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End point title

Time for Cmax (Tmax) of Midazolam (Phase 1) ^[39]

End point description

Tmax of midazolam was observed directly from data as time of first occurrence. Only subjects 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 included all subjects 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
[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: All other reporting arms are not applicable to this end point.

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)

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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) ^[40]

End point description

Area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration (AUClast) of midazolam was determined using linear/log trapezoidal method. Only subjects 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 included all subjects 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
[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: All other reporting arms are not applicable to this end point.

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)

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End point title

Area under the Plasma Concentration-Time Profile from Time Zero Extrapolated to Infinite Time (AUCinf) of Midazolam (Phase 1) ^[41]

End point description

AUCinf was calculated as AUClast + (Clast*/kel), where AUClast was the area under the plasma concentration-time profile from time 0 to the time of the last quantifiable concentration, Clast* was the predicted plasma concentration at the last quantifiable time point estimated from the log-linear regression analysis, and kel was the rate constant for terminal phase. Only subjects 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 included all subjects who received at least 1 dose of midazolam and for which at least 1 midazolam PK parameter of interest was available. "99999" represents "not applicable" or "non evaluable" data.

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
[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: All other reporting arms are not applicable to this end point.

End point values	25 mg QD (Phase 1)	150 mg QD (Phase 1)
Number of subjects analysed	3	3 ^[42]
Units: ng*hr/mL
geometric mean (geometric coefficient of variation)
Day -7\|	54.53 ( 43 )	99999 ( 99999 )
Cycle 1 Day 15\|	21.32 ( 18 )	16.09 ( 29 )

Notes
[42] - Number of subjects contributing to Day -7 data is 2.

No statistical analyses for this end point

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

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End point title

Apparent Oral Clearance (CL/F) of Midazolam (Phase 1) ^[43]

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. Only subjects 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 included all subjects who received at least 1 dose of midazolam and for which at least 1 midazolam PK parameter of interest was available. "99999" represents "not applicable" or "non evaluable" data.

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
[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: All other reporting arms are not applicable to this end point.

End point values	25 mg QD (Phase 1)	150 mg QD (Phase 1)
Number of subjects analysed	3	3 ^[44]
Units: L/hr
geometric mean (geometric coefficient of variation)
Day -7\|	36.68 ( 43 )	99999 ( 99999 )
Cycle 1 Day 15\|	93.86 ( 18 )	124.2 ( 29 )

Notes
[44] - Number of subjects contributing to Day -7 data is 2.

No statistical analyses for this end point

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

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End point title

Apparent Volume of Distribution (Vz/F) of Midazolam (Phase 1) ^[45]

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. Only subjects 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 included all subjects who received at least 1 dose of midazolam and for which at least 1 midazolam PK parameter of interest was available. "99999" represents "not applicable" or "non evaluable" data.

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
[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: All other reporting arms are not applicable to this end point.

End point values	25 mg QD (Phase 1)	150 mg QD (Phase 1)
Number of subjects analysed	3	3 ^[46]
Units: liter
geometric mean (geometric coefficient of variation)
Day -7\|	229.0 ( 7 )	99999 ( 99999 )
Cycle 1 Day 15\|	404.4 ( 51 )	702.2 ( 100 )

Notes
[46] - Number of subjects contributing to Day -7 data is 2.

No statistical analyses for this end point

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

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End point title

Terminal Half-Life of Midazolam (Phase 1) ^[47]

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. Only subjects 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 included all subjects who received at least 1 dose of midazolam and for which at least 1 midazolam PK parameter of interest was available. "99999" represents "not applicable" or "non evaluable" data.

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
[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: All other reporting arms are not applicable to this end point.

End point values	25 mg QD (Phase 1)	150 mg QD (Phase 1)
Number of subjects analysed	3	3 ^[48]
Units: hr
arithmetic mean (standard deviation)
Day -7\|	4.620 ( 1.9328 )	5.120 ( 99999 )
Cycle 1 Day 15\|	3.343 ( 2.0358 )	5.257 ( 5.0639 )

Notes
[48] - Number of subjects contributing to Day -7 data is 2.

No statistical analyses for this end point

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

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End point title

Number of Subjects 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 subjects with one or more ALK mutations is presented. CNA peripheral blood analysis set included all subjects of the ITT analysis set who had at least 1 molecular biomarker assayed.

End point type

Secondary

End point timeframe

Screening

End point values	ALK Positive Population (Phase 1)
Number of subjects analysed	39
Units: subjects	14

No statistical analyses for this end point

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

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End point title

Number of Subjects 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 subjects with one or more ALK mutations is presented. Tumor Tissue analysis set included all subjects 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

End point values	ALK Positive Population (Phase 1)
Number of subjects analysed	30
Units: subjects	7

No statistical analyses for this end point

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

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End point title

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

End point description

European Organisation for Research and Treatment of Cancer Core Quality of Life Questionaires (EORTC QLQ)-C30 (v3.0) consists of 30 questions for 5 functional domains (physical, role, emotional, cognitive, social), global quality of life (QoL), disease/treatment related symptoms (fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea), and the perceived financial impact of disease. Each scale was transformed to a range of 0 to 100 using EORTC algorithm. For global QoL and functional scales, higher score means better performance, improvement was an increase of at least 10 points, worsening was a decrease of at least 10 points. For symptom scales, higher score means worse symptoms, improvement was a decrease of at least 10 points, worsening was an increase of at least 10 points. Patient reported outcome (PRO) set included all subjects who received at least 1 dose of PF-06463922, completed a baseline and at least 1 post-baseline assessment.

End point type

Secondary

End point timeframe

3 years

End point values	Phase 1 PRO Evaluable Population
Number of subjects analysed	43
Units: subjects
Improved in global QoL\|	20
Stable in global QoL\|	13
Worsened in global QoL\|	10
Improved in physical functioning\|	6
Stable in physical functioning\|	30
Worsened in physical functioning\|	7
Improved in role functioning\|	15
Stable in role functioning\|	16
Worsened in role functioning\|	12
Improved in emotional functioning\|	15
Stable in emotional functioning\|	20
Worsened in emotional functioning\|	8
Improved in cognitive functioning\|	8
Stable in cognitive functioning\|	21
Worsened in cognitive functioning\|	14
Improved in social functioning\|	13
Stable in social functioning\|	18
Worsened in social functioning\|	12
Improved in fatigue\|	18
Stable in fatigue\|	19
Worsened in fatigue\|	6
Improved in nausea and vomiting\|	10
Stable in nausea and vomiting\|	32
worsened in nausea and vomiting\|	1
Improved in pain\|	18
Stable in pain\|	15
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\|	11
Stable in constipation\|	27
Worsened in constipation\|	5
Improved in diarrhea\|	9
Stable in diarrhea\|	29
Worsened in diarrhea\|	5
Improved in financial difficulties\|	7
Stable in financial difficulties\|	21
Worsened in financial difficulties\|	15

No statistical analyses for this end point

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

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End point title

Number of Subjects 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. Patient reported outcome (PRO) set included all subjects who received at least 1 dose of PF-06463922, completed a baseline and at least 1 post-baseline assessment.

End point type

Secondary

End point timeframe

3 years

End point values	Phase 1 PRO Evaluable Population
Number of subjects analysed	43 ^[49]
Units: subjects
Improved in dyspnea\|	10
Stable in dyspnea\|	22
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\|	19
Worsened in peripheral neuropathy\|	18
Improved in alopecia\|	3
Stable in alopecia\|	30
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\|	28
Worsened in arm or shoulder pain\|	5
Improved in pain in other parts\|	19
Stable in pain in other parts\|	14
Worsened in pain in other parts\|	10

Notes
[49] - Number of subjects analyzed for alopecia is 42.

No statistical analyses for this end point

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

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End point title

Change from Baseline in Mini Mental State Examination (MMSE) Score (Phase 1) ^[50]

End point description

In Phase 1, the MMSE was collected to assess mental status. The MMSE is a 30 item questionnaire that tests 5 areas of cognitive function: orientation, registration, attention and calculation, recall and language. The maximum score is 30. A score of 23 or lower is indicative of cognitive impairment. The MMSE was removed under Amendment 6 of the study protocol, and not required for Phase 2, as the tool was not considered meaningful for assessment of cognitive function. MMSE assessment evaluable analysis set included all subjects who received at least 1 dose of PF-06463922 and completed a baseline and at least 1 post-baseline assessment. "99999" represents "not applicable" or "non evaluable data".

End point type

Secondary

End point timeframe

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: All other reporting arms are not applicable to this end point.

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 ^[51]	3 ^[52]	3 ^[53]	9 ^[54]	16 ^[55]	3 ^[56]	2 ^[57]	2 ^[58]	3 ^[59]	4 ^[60]
Units: units on a score
arithmetic mean (standard deviation)
Cycle 1 Day 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\|	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\|	2.0 ( 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\|	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\|	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\|	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\|	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\|	-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\|	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\|	-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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	99999 ( 99999 )	1.0 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )	99999 ( 99999 )
End of treatment\|	-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 )

Notes
[51] - Not all subjects had evaluable data at each time point.
[52] - Not all subjects had evaluable data at each time point.
[53] - Not all subjects had evaluable data at each time point.
[54] - Not all subjects had evaluable data at each time point.
[55] - Not all subjects had evaluable data at each time point.
[56] - Not all subjects had evaluable data at each time point.
[57] - Not all subjects had evaluable data at each time point.
[58] - Not all subjects had evaluable data at each time point.
[59] - Not all subjects had evaluable data at each time point.
[60] - Not all subjects had evaluable data at each time point.

No statistical analyses for this end point

Secondary: Time to Tumor Response (TTR) and Intracranial TTR (Phase 2)

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End point title

Time to Tumor Response (TTR) and Intracranial TTR (Phase 2) ^[61]

End point description

End point type

Secondary

End point timeframe

3 years

Notes
[61] - 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: All other reporting arms are not applicable to this end point.

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	27 ^[62]	20 ^[63]	30 ^[64]	27 ^[65]	16 ^[66]	17 ^[67]
Units: months
median (full range (min-max))
TTR\|	1.4 (1.2 to 5.4)	1.4 (1.2 to 11.0)	1.4 (1.1 to 5.7)	2.6 (1.2 to 9.9)	1.4 (1.2 to 4.0)	1.4 (1.3 to 4.2)
Intracranial TTR\|	2.1 (1.2 to 2.8)	1.4 (1.2 to 1.5)	1.4 (1.1 to 5.7)	1.5 (1.2 to 6.2)	1.4 (1.2 to 3.3)	1.4 (1.2 to 5.5)

Notes
[62] - Number of subjects analyzed for intracranial TTR is 6.
[63] - Number of subjects analyzed for intracranial TTR is 10.
[64] - Number of subjects analyzed for intracranial TTR is 20.
[65] - Number of subjects analyzed for intracranial TTR is 25.
[66] - Number of subjects analyzed for intracranial TTR is 15.
[67] - Number of subjects analyzed for intracranial TTR is 14.

No statistical analyses for this end point

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

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End point title

Duration of Response (DOR) and Intracranial DOR (Phase 2) ^[68]

End point description

Duration of Response (DOR) was defined as the time from the first documentation of objective tumor response (CR or PR) to the first documentation of disease progression or to death due to any cause, whichever occurred first. DOR was only calculated for the subgroup of subjects with a confirmed objective tumor response. Intracranial DOR was only calculated for subjects with confirmed intracranial objective response. Results presented here were based on independent central review. "99999" and "-99999" represent "not applicable" or "non evaluable" data.

End point type

Secondary

End point timeframe

3 years

Notes
[68] - 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: All other reporting arms are not applicable to this end point.

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	27 ^[69]	20 ^[70]	30 ^[71]	27 ^[72]	16 ^[73]	17 ^[74]
Units: months
median (confidence interval 95%)
DOR\|	99999 (10.02 to 99999)	99999 (99999 to 99999)	99999 (6.80 to 99999)	6.93 (5.22 to 99999)	99999 (4.17 to 99999)	13.83 (11.10 to 99999)
Intra-cranial DOR\|	9.15 (8.28 to 10.02)	99999 (99999 to 99999)	99999 (8.38 to 99999)	14.52 (-99999 to 99999)	8.31 (6.93 to 99999)	99999 (4.99 to 99999)

Notes
[69] - Number of subjects analyzed for intracranial DOR is 6.
[70] - Number of subjects analyzed for intracranial DOR is 10.
[71] - Number of subjects analyzed for intracranial DOR is 20.
[72] - Number of subjects analyzed for intracranial DOR is 25.
[73] - Number of subjects analyzed for intracranial DOR is 15.
[74] - Number of subjects analyzed for intracranial DOR is 14.

No statistical analyses for this end point

Secondary: Percentage of Subjects Achieving Disease Control and Intracranial Disease Control at 12 Weeks (Phase 2)

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End point title

Percentage of Subjects Achieving Disease Control and Intracranial Disease Control at 12 Weeks (Phase 2) ^[75]

End point description

Tumor response was evaluated according to RECIST version 1.1, and disease control was defined as confirmed complete response (CR), confirmed partial response (PR), or stable disease (SD). Intracranial assessment was only performed for subjects with CNS metastases. Results presented here were based on independent central review.

End point type

Secondary

End point timeframe

12 weeks

Notes
[75] - 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: All other reporting arms are not applicable to this end point.

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 ^[76]	27 ^[77]	59 ^[78]	65 ^[79]	46 ^[80]	47 ^[81]
Units: percentage of subjects
number (confidence interval 95%)
Disease control rate\|	93.3 (77.9 to 99.2)	85.2 (66.3 to 95.8)	67.8 (54.4 to 79.4)	63.1 (50.2 to 74.7)	52.2 (36.9 to 67.1)	63.8 (48.5 to 77.3)
Intra-cranial disease control rate\|	87.5 (47.3 to 99.7)	94.1 (71.3 to 99.9)	75.0 (56.6 to 88.5)	77.8 (62.9 to 88.8)	68.4 (51.3 to 82.5)	72.0 (50.6 to 87.9)

Notes
[76] - Number of subjects analyzed for intracranial disease control is 8.
[77] - Number of subjects analyzed for intracranial disease control is 17.
[78] - Number of subjects analyzed for intracranial disease control is 32.
[79] - Number of subjects analyzed for intracranial disease control is 45.
[80] - Number of subjects analyzed for intracranial disease control is 38.
[81] - Number of subjects analyzed for intracranial disease control is 25.

No statistical analyses for this end point

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

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End point title

Time to Progression (TTP) on the Last Prior Therapy (Phase 2) ^[82]

End point description

TTP on the last prior therapy was defined as time from the first dose date of the last prior treatment regimen to the date of progression.

End point type

Secondary

End point timeframe

3 years

Notes
[82] - 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: All other reporting arms are not applicable to this end point.

End point values	EXP-2 (Phase 2)	EXP-3 (Phase 2)	EXP-4 (Phase 2)	EXP-5 (Phase 2)
Number of subjects analysed	27	59	65	46
Units: months
median (confidence interval 95%)
Prior systemic therapy before PF-06463922\|	11.5 (7.2 to 19.6)	12.8 (9.2 to 16.9)	10.2 (7.6 to 14.9)	3.7 (2.1 to 6.4)
Prior ALK+/ROS1+ TKI treatment\|	11.5 (7.2 to 19.6)	12.9 (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 30.7)	8.5 (5.0 to 12.6)	5.0 (3.1 to 10.8)	5.6 (4.7 to 11.2)

No statistical analyses for this end point

Secondary: Time to Tumor Progression (Phase 2)

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End point title

Time to Tumor Progression (Phase 2) ^[83]

End point description

Time to progression (TTP) was defined as the time from the first dose of study treatment to the first documentation of objective disease progression. Intracranial TTP was defined as the time from the first dose of study treatment to the date of the first documentation of objective progression of intracranial disease, based on either new brain metastases or progression of existing brain metastases. Results presented here were based on independent central review. ITT analysis set was used for TTP determination and included all enrolled subjects with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922; ITT subjects with CNS metastases were analyzed for intracranial TTP. "99999" represents "not applicable" or "non evaluable" data.

End point type

Secondary

End point timeframe

3 years

Notes
[83] - 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: All other reporting arms are not applicable to this end point.

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 ^[84]	27 ^[85]	59 ^[86]	65 ^[87]	46 ^[88]	47 ^[89]
Units: months
median (confidence interval 95%)
TTP\|	99999 (11.4 to 99999)	99999 (99999 to 99999)	9.0 (5.5 to 99999)	8.4 (5.6 to 13.7)	7.1 (4.1 to 12.5)	12.5 (8.2 to 99999)
Intracranial\|	11.4 (9.6 to 11.4)	99999 (99999 to 99999)	99999 (6.9 to 99999)	15.7 (11.0 to 15.7)	99999 (8.3 to 99999)	99999 (99999 to 99999)

Notes
[84] - Number of subjects analyzed for intracranial TTP is 8.
[85] - Number of subjects analyzed for intracranial TTP is 17.
[86] - Number of subjects analyzed for intracranial TTP is 32.
[87] - Number of subjects analyzed for intracranial TTP is 45.
[88] - Number of subjects analyzed for intracranial TTP is 38.
[89] - Number of subjects analyzed for intracranial TTP is 25.

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)

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End point title

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

End point description

End point type

Secondary

End point timeframe

3 years

End point values	Phase 2 ITT Population
Number of subjects analysed	274
Units: not applicable
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)

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End point title

Progression-Free Survival (PFS) (Phase 2) ^[90]

End point description

End point type

Secondary

End point timeframe

3 years

Notes
[90] - 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: All other reporting arms are not applicable to this end point.

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 ^[91]	27 ^[92]	59 ^[93]	65 ^[94]	46 ^[95]	47 ^[96]
Units: months
median (confidence interval 95%)	99999 (11.4 to 99999)	99999 (99999 to 99999)	8.2 (5.5 to 99999)	7.3 (5.4 to 11.0)	5.6 (4.0 to 12.5)	9.6 (4.7 to 99999)

Notes
[91] - Number of subjects with objective progression or death is 7; others were censored.
[92] - Number of subjects with objective progression or death is 8; others were censored.
[93] - Number of subjects with objective progression or death is 30; others were censored.
[94] - Number of subjects with objective progression or death is 36; others were censored.
[95] - Number of subjects with objective progression or death is 26; others were censored.
[96] - Number of subjects with objective progression or death is 21; others were censored.

No statistical analyses for this end point

Secondary: Overall Survival (Phase 2)

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End point title

Overall Survival (Phase 2) ^[97]

End point description

OS was defined as the time from first dose to the date of death due to any cause. For subjects still alive at the time of analysis, the OS time was censored on the last date the subjects were known to be alive. Estimates of OS and its 95% confidence interval were determined using Kaplan-Meier method. ITT set was used for OS analysis, and it included all enrolled subjects with documented ALK or ROS1 rearrangement who received at least 1 dose of PF-06463922. "99999" represents "not applicable" or "non evaluable" data.

End point type

Secondary

End point timeframe

3 years

Notes
[97] - 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: All other reporting arms are not applicable to this end point.

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 ^[98]	27 ^[99]	59 ^[100]	65 ^[101]	46 ^[102]	47 ^[103]
Units: months
median (confidence interval 95%)	99999 (99999 to 99999)	99999 (12.1 to 99999)	99999 (14.4 to 99999)	99999 (14.7 to 99999)	99999 (9.7 to 99999)	99999 (99999 to 99999)

Notes
[98] - Number of death is 1; others were censored.
[99] - Number of death is 4; others were censored.
[100] - Number of death is 14; others were censored.
[101] - Number of death is 20; others were censored.
[102] - Number of death is 15; others were censored.
[103] - Number of death is 10; others were censored.

No statistical analyses for this end point

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

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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 concentration analysis set of PF-06463922 included all subjects treated who had at least 1 concentration of PF-06463922.

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 ^[104]
Units: ng/mL
geometric mean (geometric coefficient of variation)
Day -7\|	695.2 ( 40 )
Cycle 1 Day 15\|	576.5 ( 42 )

Notes
[104] - Number of subjects contributing to Day -7 data is 19.

No statistical analyses for this end point

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

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End point title

Time for Cmax (Tmax) 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 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 ^[105]
Units: hours
median (full range (min-max))
Day -7\|	1.15 (0.50 to 4.02)
Cycle 1 Day 15\|	1.96 (0.50 to 22.7)

Notes
[105] - Number of subjects contributing to Day -7 data is 19.

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)

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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)

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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 subjects 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, 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 ^[106]
Units: ng*hour/mL
geometric mean (geometric coefficient of variation)
Day -7\|	5308 ( 36 )
Cycle 1 Day 15\|	5650 ( 39 )

Notes
[106] - Number of subjects contributing to Day -7 data is 19.

No statistical analyses for this end point

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

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End point title

Apparent Oral Clearance (CL/F) 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 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 ^[107]
Units: liter/hour
geometric mean (geometric coefficient of variation)
Day -7\|	11.01 ( 35 )
Cycle 1 Day 15\|	17.70 ( 39 )

Notes
[107] - Number of subjects contributing to Day -7 data is 16.

No statistical analyses for this end point

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

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End point title

Apparent Volume of Distribution (Vz/F) 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: liters
geometric mean (geometric coefficient of variation)	351.5 ( 37 )

No statistical analyses for this end point

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

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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 subjects 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, 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)

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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 subjects 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, 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)

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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 subjects 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, 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 Subjects with ALK Mutation Based on Plasma CNA Analysis (Phase 2)

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End point title

Number of Subjects with ALK Mutation Based on Plasma CNA Analysis (Phase 2) ^[108]

End point description

Plasma CNA samples were analyzed for ALK kinase domain mutations by Next Generation Sequencing (NGS). Number of subjects with one or more ALK mutations is presented. CNA peripheral blood analysis set included all subjects of the ITT analysis set who had at least 1 molecular biomarker assayed.

End point type

Secondary

End point timeframe

Screening

Notes
[108] - 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: All other reporting arms are not applicable to this end point.

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	58	61	45
Units: subjects	1	6	8	17	14

No statistical analyses for this end point

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

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End point title

Number of Subjects with ALK Mutation Based on Tumor Tissue Analysis (Phase 2) ^[109]

End point description

End point type

Secondary

End point timeframe

Screening

Notes
[109] - 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: All other reporting arms are not applicable to this end point.

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	26	26	52	48	33
Units: subjects	0	7	8	11	13

No statistical analyses for this end point

Secondary: Number of Subjects Who Improved, Worsened or Remained Stable in EORTC QLQ-C30 (Phase 2)

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End point title

Number of Subjects Who Improved, Worsened or Remained Stable in EORTC QLQ-C30 (Phase 2) ^[110]

End point description

End point type

Secondary

End point timeframe

3 years

Notes
[110] - 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: All other reporting arms are not applicable to this end point.

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	26	55	60	43	40 ^[111]
Units: subjects
Improved in global QoL\|	17	11	18	25	18	20
Stable in global QoL\|	10	13	26	22	17	13
Worsened in global QoL\|	3	2	11	13	8	7
Improved in physical functioning\|	10	7	14	23	8	11
Stable in physical functioning\|	14	19	37	27	25	24
Worsened in physical functioning\|	6	0	4	10	10	5
Improved in role functioning\|	12	8	18	25	16	17
Stable in role functioning\|	11	15	31	19	16	19
Worsened in role functioning\|	7	3	6	16	11	3
Improved in emotional functioning\|	12	12	18	21	18	17
Stable in emotional functioning\|	14	14	29	32	20	20
Worsened in emotional functioning\|	4	0	8	7	5	3
Improved in cognitive functioning\|	10	3	11	13	13	12
Stable in cognitive functioning\|	12	15	31	35	16	22
Worsened in cognitive functioning\|	8	8	13	12	14	6
Improved in social functioning\|	14	7	18	22	12	13
Stable in social functioning\|	13	17	32	28	23	22
Worsened in social functioning\|	3	2	5	10	8	5
Improved in fatigue\|	17	14	22	29	26	17
Stable in fatigue\|	9	11	25	22	11	19
Worsened in fatigue\|	4	1	8	9	6	4
Improved in nausea and vomiting\|	8	4	11	16	14	10
Stable in nausea and vomiting\|	22	22	43	38	28	28
Worsened in nausea and vomiting\|	0	0	1	6	1	2
Improved in pain\|	14	9	19	23	18	21
Stable in pain\|	11	15	27	26	20	12
Worsened in pain\|	5	2	9	11	5	7
Improved in dyspnea\|	15	9	10	21	14	13
Stable in dyspnea\|	11	14	34	22	21	19
Worsened in dyspnea\|	4	3	11	17	8	8
Improved in insomnia\|	19	8	19	28	22	19
Stable in insomnia\|	10	14	28	23	14	18
Worsened in insomnia\|	1	4	8	9	7	3
Improved in appetite loss\|	14	4	17	29	22	20
Stable in appetite loss\|	16	22	37	26	21	20
Worsened in appetite loss\|	0	0	1	5	0	0
Improved in constipation\|	10	6	9	15	11	13
Stable in constipation\|	13	18	36	33	28	23
Worsened in constipation\|	7	2	10	12	4	4
Improved in diarrhea\|	5	3	8	9	11	8
Stable in diarrhea\|	19	22	42	40	26	28
Worsened in diarrhea\|	6	1	5	11	6	4
Improved in financial difficulties\|	10	6	11	13	11	10
Stable in financial difficulties\|	18	18	33	38	22	26
Worsened in financial difficulties\|	2	2	11	9	10	4

Notes
[111] - Number of subjects analyzed for role functioning is 39.

No statistical analyses for this end point

Secondary: Number of Subjects Who Improved, Worsened or Remained Stable in EORTC QLQ-LC13 (Phase 2)

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End point title

Number of Subjects Who Improved, Worsened or Remained Stable in EORTC QLQ-LC13 (Phase 2) ^[112]

End point description

End point type

Secondary

End point timeframe

3 years

Notes
[112] - 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: All other reporting arms are not applicable to this end point.

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	26	55 ^[113]	60	42	41
Units: subjects
Improved in dyspnea\|	11	5	11	20	12	13
Stable in dyspnea\|	16	19	36	26	22	22
Worsened in dyspnea\|	3	2	8	14	8	6
Improved in coughing\|	18	9	22	27	18	17
Stable in coughing\|	9	14	26	27	15	17
Worsened in coughing\|	3	3	7	6	9	7
Improved in hemoptysis\|	4	0	7	5	5	4
Stable in hemoptysis\|	24	26	47	53	34	36
Worsened in hemoptysis\|	2	0	1	2	3	1
Improved in sore mouth\|	0	2	4	10	2	5
Stable in sore mouth\|	24	21	45	39	32	28
Worsened in sore mouth\|	6	3	6	11	8	8
Improved in dysphagia\|	3	1	5	7	4	5
Stable in dysphagia\|	24	25	44	47	33	30
Worsened in dysphagia\|	3	0	6	6	5	6
Improved in peripheral neuropathy\|	2	4	9	5	6	8
Stable in peripheral neuropathy\|	10	13	25	32	23	19
Worsened in peripheral neuropathy\|	18	9	21	23	13	14
Improved in alopecia\|	1	1	2	10	8	9
Stable in alopecia\|	19	22	41	38	27	26
Worsened in alopecia\|	10	3	12	12	7	6
Improved in chest pain\|	11	5	14	18	14	14
Stable in chest pain\|	15	19	36	33	25	22
Worsened in chest pain\|	4	2	4	9	3	5
Improved in arm or shoulder pain\|	9	4	13	14	12	12
Stable in arm or shoulder pain\|	16	18	33	37	21	21
Worsened in arm or shoulder pain\|	5	4	9	9	9	8
Improved in pain in other parts\|	10	5	18	19	14	17
Stable in pain in other parts\|	14	12	23	25	11	17
Worsened in pain in other parts\|	6	9	14	16	16	7

Notes
[113] - Number of subjects analyzed for chest pain is 54.

No statistical analyses for this end point

Secondary: Number of Subjects with Treatment-Emergent Adverse Events (Phase 1 and Phase 2)

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End point title

Number of Subjects with Treatment-Emergent Adverse Events (Phase 1 and Phase 2) ^[114]

End point description

AE was any untoward medical occurrence in a clinical investigation subject administered a product or medical device, regardless of the causal relationship to study treatment. Treatment-emergent AEs (TEAEs) were AEs which occurred for the first time during the effective duration of treatment or AEs that increased in severity during treatment. Serious AEs (SAEs) were 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. AEs included SAEs and non-serious AEs. Causality to study treatment was determined by the investigator. Severity was graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03. The safety analysis set included all enrolled subjects who received at least 1 dose of PF-06463922.

End point type

Secondary

End point timeframe

3 years

Notes
[114] - 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: All other reporting arms are not applicable to this end point.

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)	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	3	3	3	12	17	3	3	3	3	4	30	27	60	65	46	47
Units: subjects
AEs (all causality)\|	3	3	3	12	17	3	3	3	3	4	30	27	59	65	46	47
AEs (treatment-related)\|	3	3	3	11	16	3	3	1	3	4	30	27	55	61	43	45
SAEs (all causality)\|	3	1	1	4	9	3	1	2	2	2	8	5	18	24	18	16
SAEs (treatment-related)\|	1	0	0	1	1	3	0	0	0	1	3	0	5	4	5	2
Grade 1 (all causality)\|	0	0	1	1	0	0	0	0	0	0	3	0	5	3	3	0
Grade 2 (all causality)\|	0	1	2	4	5	0	1	1	1	0	12	11	20	19	11	12
Grade 3 (all causality)\|	2	0	0	5	8	0	2	1	0	1	12	12	24	28	20	26
Grade 4 (all causality)\|	0	1	0	1	1	1	0	1	1	3	3	3	3	7	4	3
Grade 5 (all causality)\|	1	1	0	1	3	2	0	0	1	0	0	1	7	8	8	6

No statistical analyses for this end point

Secondary: Number of Subjects with Laboratory Abnormalities (Phase 1 and Phase 2) – Hematology

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End point title

Number of Subjects with Laboratory Abnormalities (Phase 1 and Phase 2) – Hematology ^[115]

End point description

Hematology evaluation included hemoglobin, platelets, white blood cell, absolute neutrophils, absolute lymphocytes, absolute monocytes, absolute eosinophils and absolute basophils. The safety analysis set included all enrolled subjects who received at least 1 dose of PF-06463922.

End point type

Secondary

End point timeframe

3 years

Notes
[115] - 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: All other reporting arms are not applicable to this end point.

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)	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	3 ^[116]	3 ^[117]	3 ^[118]	12 ^[119]	17 ^[120]	3 ^[121]	3 ^[122]	3 ^[123]	3 ^[124]	4 ^[125]	30 ^[126]	27 ^[127]	60 ^[128]	64 ^[129]	45 ^[130]	47 ^[131]
Units: subjects
Anemia\|	3	3	3	8	16	3	3	3	3	4	20	14	50	48	35	32
Hemoglobin increased\|	0	0	0	0	0	0	0	0	0	0	0	0	1	3	1	1
Lymphocyte count decreased\|	2	2	2	6	4	3	3	0	0	2	9	9	21	29	18	21
Lymphocyte count increased\|	1	0	0	0	3	1	0	0	0	0	3	3	6	4	2	1
Neutrophil count decreased\|	1	0	0	4	2	0	0	0	0	1	5	2	7	6	1	5
Platelet count decreased\|	2	2	0	4	5	1	0	0	0	1	6	9	13	9	10	11
White blood cell decreased\|	2	0	0	4	2	2	1	0	0	1	6	3	6	9	5	8

Notes
[116] - Not all subjects had evaluable data for each parameter.
[117] - Not all subjects had evaluable data for each parameter.
[118] - Not all subjects had evaluable data for each parameter.
[119] - Not all subjects had evaluable data for each parameter.
[120] - Not all subjects had evaluable data for each parameter.
[121] - Not all subjects had evaluable data for each parameter.
[122] - Not all subjects had evaluable data for each parameter.
[123] - Not all subjects had evaluable data for each parameter.
[124] - Not all subjects had evaluable data for each parameter.
[125] - Not all subjects had evaluable data for each parameter.
[126] - Not all subjects had evaluable data for each parameter.
[127] - Not all subjects had evaluable data for each parameter.
[128] - Not all subjects had evaluable data for each parameter.
[129] - Not all subjects had evaluable data for each parameter.
[130] - Not all subjects had evaluable data for each parameter.
[131] - Not all subjects had evaluable data for each parameter.

No statistical analyses for this end point

Secondary: Number of Subjects with Laboratory Abnormalities (Phase 1 and Phase 2) – Chemistry

Top of page

End point title

Number of Subjects with Laboratory Abnormalities (Phase 1 and Phase 2) – Chemistry ^[132]

End point description

Chemistry evaluation included alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, sodium, potassium, magnesium, chloride, total calcium, total bilirubin, blood urea nitrogen (BUN) or urea, creatinine, uric acid, glucose (non-fasted), albumin, phosphorus or phosphate, serum total amylase and serum lipase. The safety analysis set included all enrolled subjects who received at least 1 dose of PF-06463922.

End point type

Secondary

End point timeframe

3 years

Notes
[132] - 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: All other reporting arms are not applicable to this end point.

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)	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	3 ^[133]	3 ^[134]	3 ^[135]	12 ^[136]	17 ^[137]	3 ^[138]	3 ^[139]	3 ^[140]	3 ^[141]	4 ^[142]	30 ^[143]	27 ^[144]	60 ^[145]	64 ^[146]	45 ^[147]	47 ^[148]
Units: subjects
ALT increased\|	2	1	1	4	7	2	2	0	0	3	11	11	23	17	12	13
Alkaline phosphatase increased\|	1	1	3	4	9	3	1	0	2	3	6	8	21	21	21	14
AST increased\|	2	2	2	3	7	2	2	0	1	3	15	12	31	27	17	17
Blood bilirubin increased\|	1	0	0	1	0	0	0	0	0	1	0	0	2	0	1	1
CPK increased\|	0	0	0	0	1	1	0	0	1	0	0	0	3	0	0	2
Creatinine increased\|	3	2	3	9	13	3	3	2	2	3	26	21	37	44	32	34
GGT increased\|	0	0	0	0	1	0	1	0	0	2	0	1	2	1	0	1
Hypercalcemia\|	0	0	0	0	1	1	0	0	0	1	4	3	4	4	3	1
Hyperglycemia\|	3	2	2	6	8	2	1	1	2	0	11	16	30	41	31	29
Hyperkalemia\|	0	1	2	2	6	1	1	1	1	2	8	7	14	11	5	5
Hypermagnesemia\|	2	0	0	1	2	0	0	0	0	0	2	1	2	2	1	3
Hypernatremia\|	0	1	0	0	4	2	0	0	0	1	3	1	2	4	2	4
Hypoalbuminemia\|	2	1	3	4	6	3	1	1	3	1	16	15	34	42	29	27
Hypocalcemia\|	1	0	1	3	3	2	1	0	0	1	2	4	11	9	3	9
Hypoglycemia\|	0	0	1	3	4	0	1	0	1	0	1	2	8	7	5	3
Hypokalemia\|	0	0	2	3	3	3	1	1	0	2	6	1	9	9	6	13
Hypomagnesemia\|	0	1	2	4	1	3	0	1	1	3	4	8	20	17	13	11
Hyponatremia\|	2	1	1	1	4	1	1	0	2	2	8	6	10	19	9	6
Hypophosphatemia\|	1	2	0	3	3	2	1	1	2	1	3	6	17	14	7	14
Lipase increased\|	3	1	0	8	6	0	1	0	2	2	9	5	11	15	14	16
Serum amylase increased\|	3	0	0	2	5	0	1	0	0	2	9	5	14	18	10	13

Notes
[133] - Not all subjects had evaluable data for each parameter.
[134] - Not all subjects had evaluable data for each parameter.
[135] - Not all subjects had evaluable data for each parameter.
[136] - Not all subjects had evaluable data for each parameter.
[137] - Not all subjects had evaluable data for each parameter.
[138] - Not all subjects had evaluable data for each parameter.
[139] - Not all subjects had evaluable data for each parameter.
[140] - Not all subjects had evaluable data for each parameter.
[141] - Not all subjects had evaluable data for each parameter.
[142] - Not all subjects had evaluable data for each parameter.
[143] - Not all subjects had evaluable data for each parameter.
[144] - Not all subjects had evaluable data for each parameter.
[145] - Not all subjects had evaluable data for each parameter.
[146] - Not all subjects had evaluable data for each parameter.
[147] - Not all subjects had evaluable data for each parameter.
[148] - Not all subjects had evaluable data for each parameter.

No statistical analyses for this end point

Secondary: Number of Subjects with Laboratory Abnormalities (Phase 1 and Phase 2) – Coagulation, Lipids and Urinalysis

Top of page

End point title

Number of Subjects with Laboratory Abnormalities (Phase 1 and Phase 2) – Coagulation, Lipids and Urinalysis ^[149]

End point description

Coagulation evaluation included activated partial thromboplastin time, international normalized ratio (INR), and prothrombin time. Lipid evaluation included total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL) and triglycerides. Urinalysis included urine protein and urine blood. The safety analysis set included all enrolled subjects who received at least 1 dose of PF-06463922.

End point type

Secondary

End point timeframe

3 years

Notes
[149] - 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: All other reporting arms are not applicable to this end point.

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)	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	3 ^[150]	3 ^[151]	3 ^[152]	12 ^[153]	17 ^[154]	3 ^[155]	3 ^[156]	3 ^[157]	3 ^[158]	4 ^[159]	30 ^[160]	27 ^[161]	60 ^[162]	65 ^[163]	46 ^[164]	47 ^[165]
Units: subjects
Activated partial thromboplastin time prolonged\|	1	0	1	3	2	0	0	0	0	0	1	0	1	0	1	4
Cholesterol high\|	2	2	2	10	16	2	3	3	2	3	30	26	57	64	45	44
Hypertriglyceridemia\|	0	2	2	10	16	2	3	2	1	3	30	25	56	60	45	42
INR increased\|	2	0	1	2	2	1	0	0	0	0	0	0	1	4	0	6
Proteinuria\|	2	0	0	0	4	3	0	0	1	0	1	0	2	2	2	4
Prothrombin time\|	2	0	1	3	3	1	0	0	1	1	0	1	4	4	2	5

Notes
[150] - Not all subjects had evaluable data for each parameter.
[151] - Not all subjects had evaluable data for each parameter.
[152] - Not all subjects had evaluable data for each parameter.
[153] - Not all subjects had evaluable data for each parameter.
[154] - Not all subjects had evaluable data for each parameter.
[155] - Not all subjects had evaluable data for each parameter.
[156] - Not all subjects had evaluable data for each parameter.
[157] - Not all subjects had evaluable data for each parameter.
[158] - Not all subjects had evaluable data for each parameter.
[159] - Not all subjects had evaluable data for each parameter.
[160] - Not all subjects had evaluable data for each parameter.
[161] - Not all subjects had evaluable data for each parameter.
[162] - Not all subjects had evaluable data for each parameter.
[163] - Not all subjects had evaluable data for each parameter.
[164] - Not all subjects had evaluable data for each parameter.
[165] - Not all subjects had evaluable data for each parameter.

No statistical analyses for this end point

Secondary: Number of Subjects with Vital Signs Data Meeting Pre-defined Criteria (Phase 1 and Phase 2)

Top of page

End point title

Number of Subjects with Vital Signs Data Meeting Pre-defined Criteria (Phase 1 and Phase 2) ^[166]

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 subjects who received at least 1 dose of PF-06463922.

End point type

Secondary

End point timeframe

3 years

Notes
[166] - 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: All other reporting arms are not applicable to this end point.

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)	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	3	3	3	12	17	3	3	3	3	4	30	26	60	65	45	46
Units: subjects
Sitting pulse rate <50 bpm\|	0	1	0	0	0	0	0	0	0	0	0	0	3	1	0	2
Sitting pulse rate >120 bpm\|	0	0	1	1	2	2	0	0	0	0	0	0	4	8	3	2
Increase in weight: 10% to <20%\|	1	1	0	6	6	2	2	0	1	0	9	12	14	18	15	12
Increase in weight: >=20%\|	0	1	1	1	4	1	0	0	0	1	8	1	4	9	3	8
Increase in sitting SBP >=40 mmHg\|	0	0	0	0	1	2	0	0	0	0	5	3	4	5	5	3
Increase in sitting SBP >=60 mmHg\|	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0
Increase in sitting DBP >=20 mmHg\|	0	2	0	0	7	3	1	0	0	0	9	9	16	12	10	11
Increase in sitting DBP >=40 mmHg\|	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	2
Increase in sitting pulse rate >=30 bpm\|	0	1	0	1	3	1	0	0	0	1	0	2	10	15	12	13
Decrease in weight >=10%\|	0	0	0	0	0	0	0	0	0	1	1	0	6	4	1	1
Decrease in SBP >=40 mmHg\|	0	0	0	3	2	1	0	0	0	0	0	1	2	1	1	3
Decrease in SBP >=60 mmHg\|	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Decrease in DBP >=20 mmHg\|	2	1	0	4	3	2	2	0	1	2	5	3	12	8	5	6
Decrease in DBP >=40 mmHg\|	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Decrease in sitting pulse rate >=30 bpm\|	0	0	1	2	0	1	0	1	1	1	7	2	4	5	3	5

No statistical analyses for this end point

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

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End point title

Number of Subjects with Maximum Decrease from Baseline Greater than or Equal to 20 Percent in Left Ventricular Ejection Fraction (LVEF) (Phase 1 and Phase 2) ^[167]

End point description

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

End point type

Secondary

End point timeframe

3 years

Notes
[167] - 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: All other reporting arms are not applicable to this end point.

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)	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	3	3	3	12	17	3	3	3	3	4	30	27	60	65	46	47
Units: subjects	1	0	1	3	4	2	1	0	0	2	3	1	9	11	3	4

No statistical analyses for this end point

Secondary: Number of Subjects with Absolute Values and Change from Baseline in QTcF Meeting Pre-defined Criteria (Phase 1 and Phase 2)

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End point title

Number of Subjects with Absolute Values and Change from Baseline in QTcF Meeting Pre-defined Criteria (Phase 1 and Phase 2) ^[168]

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 subjects who received at least 1 dose of PF-06463922.

End point type

Secondary

End point timeframe

3 years

Notes
[168] - 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: All other reporting arms are not applicable to this end point.

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)	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	3	3	3	12	17	3	3	3	3	4	30	27	60	65	46	47
Units: subjects
QTcF: 450 to <480 ms\|	1	0	0	2	1	1	0	2	0	0	4	7	11	9	13	8
QTcF: 480 to <500 ms\|	1	0	0	0	0	0	0	0	0	1	1	1	3	0	1	1
QTcF: >=500 ms\|	0	0	0	0	0	0	0	0	0	0	0	0	0	1	1	0
QTcF Increase: 30 to <60 ms\|	0	0	1	3	3	0	0	1	0	0	8	8	17	20	7	11
QTcF: >=60 ms\|	0	0	0	0	0	0	0	0	0	1	0	0	0	1	3	1

No statistical analyses for this end point

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

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End point title

Number of Subjects with Suicidal Ideation and Suicidal Behavior (Phase 2) ^[169]

End point description

The Columbia Suicide Severity Rating Scale (C-SSRS) was used to analyze subjects' 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. The analysis set included all enrolled subjects who received study treatment, had a baseline test assessment and at least 1 on-study test assessment.

End point type

Secondary

End point timeframe

3 years

Notes
[169] - 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: All other reporting arms are not applicable to this end point.

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: subjects
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) ^[170]

End point description

The Beck Depression Inventory (BDI)-II is a 21-item self-report scale, with each item rated by subjects on a 4-point scale (ranging from 0-3). The 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. The analysis set included all enrolled subjects who received study treatment, had a baseline test assessment and at least 1 on-study test assessment. "99999" represents "not applicable" or "non evaluable" data.

End point type

Secondary

End point timeframe

3 years

Notes
[170] - 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: All other reporting arms are not applicable to this end point.

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 ^[171]	24 ^[172]	53 ^[173]	41 ^[174]	28 ^[175]	26 ^[176]
Units: units on score
least squares mean (confidence interval 95%)
Cycle 2 Day 1\|	-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\|	-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\|	-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\|	-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\|	-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\|	-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\|	-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\|	-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\|	-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\|	-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\|	-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\|	-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\|	-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\|	-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\|	-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\|	-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)

Notes
[171] - Not all subjects had evaluable data at each time point.
[172] - Not all subjects had evaluable data at each time point.
[173] - Not all subjects had evaluable data at each time point.
[174] - Not all subjects had evaluable data at each time point.
[175] - Not all subjects had evaluable data at each time point.
[176] - Not all subjects had evaluable data at each time point.

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) ^[177]

End point description

The Detection Test is a measure of psychomotor function and uses a well validated simple reaction time paradigm with playing card stimuli. In this test, the playing cards all depict the same joker. The subject is asked to press the Yes key as soon as the card in the center of the screen turns face up. The speed and accuracy of each response are recorded and mean of the log10 transformed reaction times for correct responses is calculated. Lower scores indicate better performance. The analysis set included all enrolled subjects who received study treatment, had a baseline test assessment and at least 1 on-study test assessment. "99999" represents "not applicable" or "non evaluable" data.

End point type

Secondary

End point timeframe

3 years

Notes
[177] - 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: All other reporting arms are not applicable to this end point.

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 ^[178]	26 ^[179]	50 ^[180]	46 ^[181]	38 ^[182]	29 ^[183]
Units: units on a score
least squares mean (confidence interval 95%)
Cycle 2 Day 1\|	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\|	-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\|	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\|	-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\|	-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\|	-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\|	-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\|	-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\|	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\|	-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\|	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\|	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\|	-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\|	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\|	-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)

Notes
[178] - Not all subjects had evaluable data at each time point.
[179] - Not all subjects had evaluable data at each time point.
[180] - Not all subjects had evaluable data at each time point.
[181] - Not all subjects had evaluable data at each time point.
[182] - Not all subjects had evaluable data at each time point.
[183] - Not all subjects had evaluable data at each time point.

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) ^[184]

End point description

The Identification Test is a measure of visual attention and uses a well validated choice reaction time paradigm with playing card stimuli. In this task, the playing cards are all either red or black jokers. The subject is asked whether the card displayed in the center of the screen is red. The patient responds by pressing the Yes key when the joker card is red and No when it is black. The speed and accuracy of each response are recorded and mean of the log10 transformed reaction times for correct responses is calculated. Lower scores indicate better performance. The analysis set included all enrolled subjects who received study treatment, had a baseline test assessment and at least 1 on-study test assessment. "99999" represents "not applicable" or "non evaluable" data.

End point type

Secondary

End point timeframe

3 years

Notes
[184] - 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: All other reporting arms are not applicable to this end point.

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 ^[185]	26 ^[186]	50 ^[187]	46 ^[188]	38 ^[189]	29 ^[190]
Units: units on a score
least squares mean (confidence interval 95%)
Cycle 2 Day 1\|	-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\|	-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\|	-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\|	-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\|	-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\|	-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\|	-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\|	-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\|	-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\|	-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\|	-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\|	-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\|	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\|	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\|	-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)

Notes
[185] - Not all subjects had evaluable data at each time point.
[186] - Not all subjects had evaluable data at each time point.
[187] - Not all subjects had evaluable data at each time point.
[188] - Not all subjects had evaluable data at each time point.
[189] - Not all subjects had evaluable data at each time point.
[190] - Not all subjects had evaluable data at each time point.

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) ^[191]

End point description

The One Back Test is a measure of working memory and uses a well validated n back paradigm with playing card stimuli. In this task, the playing cards are identical to those found in a standard deck of 52 playing cards (without the joker cards). The patient is asked whether the card displayed in the center of the screen is the same as the card presented immediately previously. The patient responds by pressing the Yes or No key. Because no card has been presented yet on the first trial, a correct first response is always No. The speed and accuracy of each response are recorded and mean of the log10 transformed reaction times for correct responses is calculated. Lower scores indicate better performance. The analysis set included all enrolled subjects who received study treatment, had a baseline test assessment and at least 1 on-study test assessment. "99999" represents "not applicable" or "non evaluable" data.

End point type

Secondary

End point timeframe

3 years

Notes
[191] - 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: All other reporting arms are not applicable to this end point.

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 ^[192]	26 ^[193]	50 ^[194]	46 ^[195]	38 ^[196]	29 ^[197]
Units: units on a score
least squares mean (confidence interval 95%)
Cycle 2 Day 1\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	-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\|	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\|	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\|	-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)

Notes
[192] - Not all subjects had evaluable data at each time point.
[193] - Not all subjects had evaluable data at each time point.
[194] - Not all subjects had evaluable data at each time point.
[195] - Not all subjects had evaluable data at each time point.
[196] - Not all subjects had evaluable data at each time point.
[197] - Not all subjects had evaluable data at each time point.

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) ^[198]

End point description

The International Shopping List Test is a measure of verbal learning and uses a well validated list learning paradigm. Total number of correct responses remembering the word list on 3 consecutive trials at a single assessment was recorded. Higher scores indicate better performance. The analysis set included all enrolled subjects who received study treatment, had a baseline test assessment and at least 1 on-study test assessment. "99999" represents "not applicable" or "non evaluable" data.

End point type

Secondary

End point timeframe

3 years

Notes
[198] - 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: All other reporting arms are not applicable to this end point.

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 ^[199]	26 ^[200]	50 ^[201]	46 ^[202]	38 ^[203]	29 ^[204]
Units: units on a score
least squares mean (confidence interval 95%)
Cycle 2 Day 1\|	-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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	-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\|	-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\|	-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\|	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)

Notes
[199] - Not all subjects had evaluable data at each time point.
[200] - Not all subjects had evaluable data at each time point.
[201] - Not all subjects had evaluable data at each time point.
[202] - Not all subjects had evaluable data at each time point.
[203] - Not all subjects had evaluable data at each time point.
[204] - Not all subjects had evaluable data at each time point.

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) ^[205]

End point description

The International Shopping List Test-Delayed Recall is a measure of memory and uses a well validated list learning paradigm. Total number of correct responses made in remembering the word list after a delay was recorded. Higher scores indicate better performance. The analysis set included all enrolled subjects who received study treatment, had a baseline test assessment and at least 1 on-study test assessment. "99999" represents "not applicable" or "non evaluable" data.

End point type

Secondary

End point timeframe

3 years

Notes
[205] - 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: All other reporting arms are not applicable to this end point.

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 ^[206]	26 ^[207]	50 ^[208]	46 ^[209]	38 ^[210]	29 ^[211]
Units: units on a score
least squares mean (confidence interval 95%)
Cycle 2 Day 1\|	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\|	-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\|	-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\|	-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\|	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\|	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\|	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\|	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\|	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\|	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\|	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\|	-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\|	-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\|	-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\|	-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)

Notes
[206] - Not all subjects had evaluable data at each time point.
[207] - Not all subjects had evaluable data at each time point.
[208] - Not all subjects had evaluable data at each time point.
[209] - Not all subjects had evaluable data at each time point.
[210] - Not all subjects had evaluable data at each time point.
[211] - Not all subjects had evaluable data at each time point.

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

3 years

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 subject and as non-serious in another subject, or one subject may have experienced both a serious and non-serious event during the study.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

20.0

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

EXP-1 (Phase 2)

Reporting group description

Reporting group title

100 mg BID (Phase 1)

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

Few Japanese participants were given PF-06463922 100 mg orally twice daily (BID) 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.

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)

EXP-1 (Phase 2)

100 mg BID (Phase 1)

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)

Total subjects affected by serious adverse events

subjects affected / exposed

3 / 3 (100.00%)

1 / 3 (33.33%)

4 / 12 (33.33%)

9 / 17 (52.94%)

3 / 3 (100.00%)

1 / 3 (33.33%)

2 / 3 (66.67%)

8 / 30 (26.67%)

2 / 4 (50.00%)

5 / 27 (18.52%)

18 / 60 (30.00%)

24 / 65 (36.92%)

18 / 46 (39.13%)

16 / 47 (34.04%)

0 / 3 (0.00%)

number of deaths (all causes)

number of deaths resulting from adverse events

Vascular disorders

Embolism

subjects affected / exposed

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

1 / 65 (1.54%)

1 / 46 (2.17%)

0 / 47 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

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 / 12 (0.00%)

0 / 17 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

1 / 47 (2.13%)

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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

1 / 65 (1.54%)

0 / 46 (0.00%)

0 / 47 (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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

1 / 65 (1.54%)

0 / 46 (0.00%)

0 / 47 (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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

1 / 65 (1.54%)

0 / 46 (0.00%)

0 / 47 (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

Superior vena cava syndrome

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

2 / 65 (3.08%)

0 / 46 (0.00%)

0 / 47 (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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

2 / 46 (4.35%)

0 / 47 (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

General disorders and administration site conditions

Disease progression

subjects affected / exposed

1 / 3 (33.33%)

0 / 3 (0.00%)

1 / 12 (8.33%)

3 / 17 (17.65%)

1 / 3 (33.33%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

6 / 60 (10.00%)

6 / 65 (9.23%)

5 / 46 (10.87%)

5 / 47 (10.64%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 3

0 / 1

0 / 0

0 / 1

0 / 0

0 / 6

0 / 5

0 / 0

deaths causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 3

0 / 1

0 / 0

0 / 1

0 / 0

0 / 2

0 / 4

0 / 1

0 / 4

0 / 0

Pyrexia

subjects affected / exposed

0 / 3 (0.00%)

1 / 12 (8.33%)

0 / 17 (0.00%)

0 / 3 (0.00%)

3 / 30 (10.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

1 / 60 (1.67%)

1 / 65 (1.54%)

0 / 46 (0.00%)

1 / 47 (2.13%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 3

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Asthenia

subjects affected / exposed

0 / 3 (0.00%)

1 / 12 (8.33%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Chest pain

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

1 / 60 (1.67%)

0 / 65 (0.00%)

1 / 46 (2.17%)

0 / 47 (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

Fatigue

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

1 / 30 (3.33%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

General physical health deterioration

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

1 / 46 (2.17%)

0 / 47 (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

Generalised oedema

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

1 / 60 (1.67%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Pain

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

1 / 46 (2.17%)

0 / 47 (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 swelling

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

1 / 60 (1.67%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 12 (0.00%)

1 / 17 (5.88%)

0 / 3 (0.00%)

1 / 30 (3.33%)

1 / 4 (25.00%)

0 / 27 (0.00%)

1 / 60 (1.67%)

3 / 65 (4.62%)

1 / 46 (2.17%)

0 / 47 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 3

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 3

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

Hypoxia

subjects affected / exposed

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

1 / 65 (1.54%)

0 / 46 (0.00%)

0 / 47 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

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 / 12 (0.00%)

1 / 17 (5.88%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

1 / 60 (1.67%)

1 / 65 (1.54%)

0 / 46 (0.00%)

0 / 47 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Haemoptysis

subjects affected / exposed

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 12 (0.00%)

1 / 17 (5.88%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Acute pulmonary oedema

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

1 / 60 (1.67%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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 respiratory failure

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

1 / 60 (1.67%)

1 / 65 (1.54%)

0 / 46 (0.00%)

0 / 47 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Asthma

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

1 / 30 (3.33%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Chronic obstructive pulmonary disease

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

1 / 60 (1.67%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Dyspnoea exertional

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

1 / 60 (1.67%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Epistaxis

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

1 / 30 (3.33%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Interstitial lung disease

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

1 / 46 (2.17%)

0 / 47 (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

Lung disorder

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

1 / 65 (1.54%)

0 / 46 (0.00%)

0 / 47 (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

Pleuritic pain

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

1 / 46 (2.17%)

0 / 47 (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

Pneumonitis

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

2 / 65 (3.08%)

0 / 46 (0.00%)

0 / 47 (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

Pulmonary congestion

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

1 / 60 (1.67%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

2 / 65 (3.08%)

1 / 46 (2.17%)

0 / 47 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pulmonary hypertension

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

1 / 27 (3.70%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

1 / 27 (3.70%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Respiratory failure

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

1 / 60 (1.67%)

1 / 65 (1.54%)

0 / 46 (0.00%)

0 / 47 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Psychiatric disorders

Confusional state

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

1 / 30 (3.33%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Mental status changes

subjects affected / exposed

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 12 (0.00%)

1 / 17 (5.88%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

1 / 65 (1.54%)

1 / 46 (2.17%)

1 / 47 (2.13%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

1 / 1

0 / 0

0 / 1

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Delirium

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

1 / 17 (5.88%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Hallucination

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Investigations

Aspartate aminotransferase increased

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

1 / 30 (3.33%)

1 / 4 (25.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

1 / 65 (1.54%)

0 / 46 (0.00%)

0 / 47 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Lipase increased

subjects affected / exposed

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Alanine aminotransferase increased

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

1 / 30 (3.33%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

1 / 65 (1.54%)

0 / 46 (0.00%)

0 / 47 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blood cholesterol increased

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

1 / 60 (1.67%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Blood creatine phosphokinase increased

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

1 / 60 (1.67%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Ejection fraction decreased

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

1 / 47 (2.13%)

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 / 12 (0.00%)

1 / 17 (5.88%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Fall

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

1 / 65 (1.54%)

0 / 46 (0.00%)

0 / 47 (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

Femoral neck fracture

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

1 / 60 (1.67%)

1 / 65 (1.54%)

0 / 46 (0.00%)

0 / 47 (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

Hip fracture

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

1 / 65 (1.54%)

0 / 46 (0.00%)

0 / 47 (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

Humerus fracture

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

1 / 47 (2.13%)

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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

1 / 65 (1.54%)

0 / 46 (0.00%)

0 / 47 (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

Post procedural haemorrhage

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

1 / 46 (2.17%)

0 / 47 (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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

1 / 47 (2.13%)

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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

1 / 27 (3.70%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

1 / 65 (1.54%)

0 / 46 (0.00%)

0 / 47 (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

Cardiac disorders

Cardiac arrest

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

1 / 47 (2.13%)

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

Pericardial effusion

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

1 / 30 (3.33%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

1 / 65 (1.54%)

1 / 46 (2.17%)

0 / 47 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Atrial fibrillation

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

2 / 65 (3.08%)

0 / 46 (0.00%)

0 / 47 (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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

1 / 47 (2.13%)

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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

1 / 47 (2.13%)

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

Sinus node dysfunction

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

1 / 65 (1.54%)

0 / 46 (0.00%)

0 / 47 (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

Supraventricular tachycardia

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

1 / 65 (1.54%)

0 / 46 (0.00%)

0 / 47 (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 disorders

Haemorrhage intracranial

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

1 / 46 (2.17%)

0 / 47 (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

Headache

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

1 / 4 (25.00%)

0 / 27 (0.00%)

1 / 60 (1.67%)

1 / 65 (1.54%)

0 / 46 (0.00%)

0 / 47 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 3

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Presyncope

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

1 / 47 (2.13%)

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

Cerebrovascular accident

subjects affected / exposed

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Seizure

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 30 (0.00%)

1 / 4 (25.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Brain compression

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

1 / 47 (2.13%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Brain oedema

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

1 / 46 (2.17%)

0 / 47 (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

Cognitive disorder

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

1 / 60 (1.67%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Hydrocephalus

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

1 / 65 (1.54%)

0 / 46 (0.00%)

0 / 47 (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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

1 / 47 (2.13%)

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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

1 / 65 (1.54%)

0 / 46 (0.00%)

0 / 47 (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

Partial seizures

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

1 / 47 (2.13%)

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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

1 / 46 (2.17%)

0 / 47 (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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

1 / 60 (1.67%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

1 / 65 (1.54%)

0 / 46 (0.00%)

0 / 47 (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

Ear and labyrinth disorders

Vertigo

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

1 / 30 (3.33%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

1 / 65 (1.54%)

0 / 46 (0.00%)

0 / 47 (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

Eye disorders

Cataract

subjects affected / exposed

0 / 3 (0.00%)

1 / 12 (8.33%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Eye pain

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

1 / 4 (25.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Blepharitis

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

1 / 65 (1.54%)

0 / 46 (0.00%)

0 / 47 (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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Crohn's disease

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

1 / 4 (25.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Ileus

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

1 / 4 (25.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Intestinal perforation

subjects affected / exposed

0 / 3 (0.00%)

1 / 12 (8.33%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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%)

1 / 12 (8.33%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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 pain upper

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

1 / 46 (2.17%)

0 / 47 (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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

1 / 47 (2.13%)

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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

1 / 30 (3.33%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

1 / 46 (2.17%)

0 / 47 (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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

1 / 30 (3.33%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

1 / 30 (3.33%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

1 / 30 (3.33%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

1 / 65 (1.54%)

0 / 46 (0.00%)

0 / 47 (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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

2 / 65 (3.08%)

0 / 46 (0.00%)

0 / 47 (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 / 12 (0.00%)

1 / 17 (5.88%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

1 / 60 (1.67%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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 and subcutaneous tissue disorders

Dermatomyositis

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Musculoskeletal and connective tissue disorders

Back pain

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

1 / 65 (1.54%)

1 / 46 (2.17%)

0 / 47 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Intervertebral disc protrusion

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

1 / 27 (3.70%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

1 / 60 (1.67%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Infections and infestations

Influenza

subjects affected / exposed

0 / 3 (0.00%)

1 / 12 (8.33%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

1 / 60 (1.67%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Lower respiratory tract infection

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

1 / 30 (3.33%)

1 / 4 (25.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Lung infection

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

1 / 27 (3.70%)

0 / 60 (0.00%)

0 / 65 (0.00%)

1 / 46 (2.17%)

0 / 47 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Pneumonia

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

1 / 30 (3.33%)

0 / 4 (0.00%)

1 / 27 (3.70%)

0 / 60 (0.00%)

3 / 65 (4.62%)

0 / 46 (0.00%)

0 / 47 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

2 / 2

0 / 0

0 / 1

0 / 0

0 / 6

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory tract infection

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

1 / 30 (3.33%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Bronchitis

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

1 / 17 (5.88%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Pyelonephritis

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Urinary tract infection

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

1 / 17 (5.88%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Diverticulitis

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

1 / 65 (1.54%)

0 / 46 (0.00%)

0 / 47 (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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

1 / 60 (1.67%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Lung abscess

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

1 / 60 (1.67%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

1 / 60 (1.67%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Septic shock

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

1 / 60 (1.67%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

1 / 60 (1.67%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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

Vestibular neuronitis

subjects affected / exposed

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

1 / 65 (1.54%)

0 / 46 (0.00%)

0 / 47 (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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

1 / 4 (25.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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 / 12 (0.00%)

0 / 17 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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 / 12 (0.00%)

0 / 17 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

0 / 46 (0.00%)

0 / 47 (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 / 12 (0.00%)

0 / 17 (0.00%)

0 / 3 (0.00%)

0 / 30 (0.00%)

0 / 4 (0.00%)

0 / 27 (0.00%)

0 / 60 (0.00%)

0 / 65 (0.00%)

1 / 46 (2.17%)

0 / 47 (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

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

Non-serious adverse events	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)	EXP-1 (Phase 2)	100 mg BID (Phase 1)	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)
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	12 / 12 (100.00%)	17 / 17 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	30 / 30 (100.00%)	4 / 4 (100.00%)	27 / 27 (100.00%)	59 / 60 (98.33%)	65 / 65 (100.00%)	45 / 46 (97.83%)	47 / 47 (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 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Tumour pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Vascular disorders
Hypertension
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	1 / 17 (5.88%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 30 (6.67%)	0 / 4 (0.00%)	1 / 27 (3.70%)	2 / 60 (3.33%)	8 / 65 (12.31%)	4 / 46 (8.70%)	3 / 47 (6.38%)	0 / 3 (0.00%)
occurrences all number	0	0	0	3	1	1	0	1	0	2	0	1	6	17	11	6	0
Deep vein thrombosis
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	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 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0
Haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Hot flush
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 30 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	1	0	0	0	0	0	0
Hypotension
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Shock
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 3 (66.67%)	3 / 12 (25.00%)	3 / 17 (17.65%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 30 (10.00%)	0 / 4 (0.00%)	2 / 27 (7.41%)	8 / 60 (13.33%)	6 / 65 (9.23%)	5 / 46 (10.87%)	2 / 47 (4.26%)	0 / 3 (0.00%)
occurrences all number	1	0	2	7	3	0	2	0	0	3	0	3	10	12	7	2	0
Chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)	2 / 60 (3.33%)	6 / 65 (9.23%)	5 / 46 (10.87%)	2 / 47 (4.26%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0	0	0	2	2	6	6	2	0
Face oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 30 (6.67%)	0 / 4 (0.00%)	0 / 27 (0.00%)	2 / 60 (3.33%)	1 / 65 (1.54%)	1 / 46 (2.17%)	1 / 47 (2.13%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	2	0	0	2	1	1	1	0
Fatigue
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	4 / 12 (33.33%)	4 / 17 (23.53%)	2 / 3 (66.67%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	8 / 30 (26.67%)	3 / 4 (75.00%)	4 / 27 (14.81%)	3 / 60 (5.00%)	11 / 65 (16.92%)	4 / 46 (8.70%)	7 / 47 (14.89%)	0 / 3 (0.00%)
occurrences all number	1	1	0	4	5	4	2	0	1	11	5	7	4	22	4	9	0
Gait disturbance
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 12 (8.33%)	1 / 17 (5.88%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	5 / 65 (7.69%)	3 / 46 (6.52%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	2	2	1	1	0	1	0	0	0	0	0	0	5	5	0	0
Mucosal inflammation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	3 / 30 (10.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	1 / 60 (1.67%)	2 / 65 (3.08%)	1 / 46 (2.17%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	2	3	0	0	1	2	1	0	0
Oedema
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	2 / 12 (16.67%)	0 / 17 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 30 (13.33%)	1 / 4 (25.00%)	1 / 27 (3.70%)	4 / 60 (6.67%)	6 / 65 (9.23%)	4 / 46 (8.70%)	3 / 47 (6.38%)	0 / 3 (0.00%)
occurrences all number	0	1	1	3	0	0	2	0	0	6	1	6	4	7	4	3	0
Oedema peripheral
subjects affected / exposed	3 / 3 (100.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	3 / 12 (25.00%)	9 / 17 (52.94%)	3 / 3 (100.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 3 (66.67%)	12 / 30 (40.00%)	3 / 4 (75.00%)	12 / 27 (44.44%)	29 / 60 (48.33%)	21 / 65 (32.31%)	15 / 46 (32.61%)	24 / 47 (51.06%)	1 / 3 (33.33%)
occurrences all number	3	1	1	4	16	7	1	0	3	17	7	18	43	37	24	30	1
Pain
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 30 (6.67%)	0 / 4 (0.00%)	0 / 27 (0.00%)	1 / 60 (1.67%)	4 / 65 (6.15%)	2 / 46 (4.35%)	2 / 47 (4.26%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	2	0	0	1	8	2	2	0
Peripheral swelling
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 17 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	2 / 27 (7.41%)	1 / 60 (1.67%)	7 / 65 (10.77%)	4 / 46 (8.70%)	3 / 47 (6.38%)	0 / 3 (0.00%)
occurrences all number	1	0	0	4	0	0	1	0	0	0	0	2	1	12	5	3	0
Pyrexia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	3 / 17 (17.65%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 30 (6.67%)	0 / 4 (0.00%)	1 / 27 (3.70%)	5 / 60 (8.33%)	7 / 65 (10.77%)	1 / 46 (2.17%)	5 / 47 (10.64%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	3	1	0	0	0	4	0	2	6	7	1	5	0
Axillary pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	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 / 12 (0.00%)	0 / 17 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Chest discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0
Chills
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Disease progression
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Generalised oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Non-cardiac chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Performance status decreased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Swelling
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	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 / 12 (0.00%)	0 / 17 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	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 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Vaginal haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	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%)	1 / 12 (8.33%)	1 / 17 (5.88%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	9 / 30 (30.00%)	2 / 4 (50.00%)	3 / 27 (11.11%)	7 / 60 (11.67%)	11 / 65 (16.92%)	8 / 46 (17.39%)	9 / 47 (19.15%)	0 / 3 (0.00%)
occurrences all number	1	2	1	1	1	0	1	0	0	13	2	5	10	14	12	12	0
Dysphonia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 30 (3.33%)	1 / 4 (25.00%)	0 / 27 (0.00%)	4 / 60 (6.67%)	2 / 65 (3.08%)	2 / 46 (4.35%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	1	0	4	2	2	0	0
Dyspnoea
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 12 (0.00%)	3 / 17 (17.65%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	1 / 3 (33.33%)	7 / 30 (23.33%)	2 / 4 (50.00%)	3 / 27 (11.11%)	14 / 60 (23.33%)	13 / 65 (20.00%)	9 / 46 (19.57%)	14 / 47 (29.79%)	1 / 3 (33.33%)
occurrences all number	1	1	1	0	3	0	0	3	3	8	5	3	16	14	11	20	1
Dyspnoea exertional
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 30 (3.33%)	0 / 4 (0.00%)	1 / 27 (3.70%)	3 / 60 (5.00%)	6 / 65 (9.23%)	3 / 46 (6.52%)	1 / 47 (2.13%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0	0	0	0	1	0	1	6	8	5	2	0
Epistaxis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	2 / 27 (7.41%)	3 / 60 (5.00%)	3 / 65 (4.62%)	0 / 46 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	1	0	1	0	0	0	2	3	4	0	1	0
Haemoptysis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 30 (6.67%)	0 / 4 (0.00%)	0 / 27 (0.00%)	2 / 60 (3.33%)	5 / 65 (7.69%)	1 / 46 (2.17%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	3	0	0	2	6	1	0	0
Hypoxia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	1 / 65 (1.54%)	5 / 46 (10.87%)	1 / 47 (2.13%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	1	10	2	0
Pleural effusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 30 (3.33%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	5 / 65 (7.69%)	1 / 46 (2.17%)	4 / 47 (8.51%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	1	0	0	0	5	1	4	0
Wheezing
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 30 (3.33%)	0 / 4 (0.00%)	0 / 27 (0.00%)	1 / 60 (1.67%)	2 / 65 (3.08%)	3 / 46 (6.52%)	2 / 47 (4.26%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	1	0	1	0	0	1	2	3	2	0
Acute respiratory failure
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Bronchitis chronic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Laryngeal inflammation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	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%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Oropharyngeal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	1	0	0	0	0	0	0
Pleuritic pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	1	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%)	0 / 12 (0.00%)	0 / 17 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Pulmonary embolism
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Pulmonary hypertension
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	0	0	0	0	0	0
Pulmonary oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0
Rales
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	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 / 12 (0.00%)	0 / 17 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Rhinorrhoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	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 / 12 (0.00%)	0 / 17 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Psychiatric disorders
Affect lability
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	2 / 60 (3.33%)	2 / 65 (3.08%)	0 / 46 (0.00%)	3 / 47 (6.38%)	0 / 3 (0.00%)
occurrences all number	1	0	0	5	0	0	1	0	0	0	0	0	4	3	0	3	0
Anxiety
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 30 (0.00%)	1 / 4 (25.00%)	2 / 27 (7.41%)	1 / 60 (1.67%)	7 / 65 (10.77%)	1 / 46 (2.17%)	4 / 47 (8.51%)	0 / 3 (0.00%)
occurrences all number	0	0	0	2	0	0	0	2	0	0	1	2	1	7	1	6	0
Insomnia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 17 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 30 (13.33%)	0 / 4 (0.00%)	3 / 27 (11.11%)	5 / 60 (8.33%)	3 / 65 (4.62%)	3 / 46 (6.52%)	4 / 47 (8.51%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0	0	5	0	3	6	3	3	4	0
Irritability
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	2 / 17 (11.76%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 30 (10.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)	3 / 60 (5.00%)	2 / 65 (3.08%)	6 / 46 (13.04%)	1 / 47 (2.13%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	2	0	2	0	0	3	0	1	4	2	6	1	0
Abnormal dreams
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0	0	0	0	0	0	0	0	0
Agitation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	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 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Bradyphrenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Confusional state
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	2 / 17 (11.76%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	2	1	0	0	1	0	0	0	0	0	0	0	0
Depressed mood
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	1	0	0	0	0	0	0	0	0
Hallucination
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0	0	0	0	0	0	0	0	0
Mental status changes
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Nightmare
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	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 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Sleep disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0
Depression
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 30 (3.33%)	0 / 4 (0.00%)	2 / 27 (7.41%)	6 / 60 (10.00%)	1 / 65 (1.54%)	1 / 46 (2.17%)	1 / 47 (2.13%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	5	7	1	1	1	0
Mood swings
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 30 (6.67%)	0 / 4 (0.00%)	1 / 27 (3.70%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0	1	0	0	0	0	0
Hallucination, auditory
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	2 / 17 (11.76%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 30 (16.67%)	1 / 4 (25.00%)	1 / 27 (3.70%)	6 / 60 (10.00%)	5 / 65 (7.69%)	5 / 46 (10.87%)	7 / 47 (14.89%)	2 / 3 (66.67%)
occurrences all number	0	0	0	4	3	0	0	0	0	6	5	1	12	13	7	7	2
Amylase increased
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	4 / 17 (23.53%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 30 (3.33%)	0 / 4 (0.00%)	0 / 27 (0.00%)	4 / 60 (6.67%)	7 / 65 (10.77%)	2 / 46 (4.35%)	7 / 47 (14.89%)	0 / 3 (0.00%)
occurrences all number	3	0	0	3	11	0	1	0	0	2	0	0	5	17	3	11	0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	2 / 12 (16.67%)	2 / 17 (11.76%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	7 / 30 (23.33%)	1 / 4 (25.00%)	1 / 27 (3.70%)	7 / 60 (11.67%)	7 / 65 (10.77%)	6 / 46 (13.04%)	4 / 47 (8.51%)	1 / 3 (33.33%)
occurrences all number	0	1	1	5	3	0	2	0	0	9	7	1	11	9	8	4	1
Blood cholesterol increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	6 / 12 (50.00%)	3 / 17 (17.65%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	13 / 30 (43.33%)	1 / 4 (25.00%)	13 / 27 (48.15%)	18 / 60 (30.00%)	17 / 65 (26.15%)	16 / 46 (34.78%)	18 / 47 (38.30%)	3 / 3 (100.00%)
occurrences all number	0	0	0	9	8	1	0	0	0	41	3	55	67	44	42	49	10
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 30 (3.33%)	0 / 4 (0.00%)	1 / 27 (3.70%)	5 / 60 (8.33%)	0 / 65 (0.00%)	0 / 46 (0.00%)	2 / 47 (4.26%)	2 / 3 (66.67%)
occurrences all number	0	0	0	0	4	0	0	0	1	3	0	1	10	0	0	2	16
Blood triglycerides increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 12 (16.67%)	3 / 17 (17.65%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 30 (6.67%)	1 / 4 (25.00%)	2 / 27 (7.41%)	4 / 60 (6.67%)	3 / 65 (4.62%)	3 / 46 (6.52%)	3 / 47 (6.38%)	0 / 3 (0.00%)
occurrences all number	0	2	0	3	8	1	0	0	0	2	6	4	8	3	4	8	0
Electrocardiogram QT prolonged
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	1 / 4 (25.00%)	1 / 27 (3.70%)	3 / 60 (5.00%)	4 / 65 (6.15%)	9 / 46 (19.57%)	2 / 47 (4.26%)	0 / 3 (0.00%)
occurrences all number	2	0	0	0	0	1	0	0	0	0	1	2	7	4	10	2	0
Lipase increased
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	5 / 17 (29.41%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 30 (10.00%)	1 / 4 (25.00%)	4 / 27 (14.81%)	1 / 60 (1.67%)	7 / 65 (10.77%)	5 / 46 (10.87%)	6 / 47 (12.77%)	1 / 3 (33.33%)
occurrences all number	2	0	0	5	20	0	1	0	0	5	2	6	1	14	6	12	4
Weight increased
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	3 / 12 (25.00%)	3 / 17 (17.65%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 30 (13.33%)	2 / 4 (50.00%)	4 / 27 (14.81%)	11 / 60 (18.33%)	18 / 65 (27.69%)	10 / 46 (21.74%)	10 / 47 (21.28%)	1 / 3 (33.33%)
occurrences all number	0	1	1	7	5	1	1	0	0	11	3	6	18	23	12	17	2
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	1	0	1	1	0	0	0	0	0	0	0	0	0	0	0	0
Blood creatinine increased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 17 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	3	0	2	0	0	0	0	0	0	0	0	0	0	0
Blood phosphorus decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	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 / 12 (0.00%)	0 / 17 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Ejection fraction decreased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	2	0	0	0	0	2	0	0	0	0	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 30 (0.00%)	2 / 4 (50.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	3	0	0	0	1	0	0	12	0	0	0	0	0	0
Glucose urine present
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
International normalised ratio increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0	0	0	0	0	0	0	0	0
Lipids increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	1	0	0	0	0	0	0
Liver function test increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Transaminases increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Weight decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Electrocardiogram PR prolongation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	5 / 65 (7.69%)	2 / 46 (4.35%)	2 / 47 (4.26%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	11	5	3	0
Contusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	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 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0
Joint dislocation
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Laceration
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Ligament sprain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	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 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	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 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Procedural pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	1 / 65 (1.54%)	0 / 46 (0.00%)	3 / 47 (6.38%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	4	0
Cardiac disorders
Tachycardia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)	0 / 60 (0.00%)	5 / 65 (7.69%)	2 / 46 (4.35%)	3 / 47 (6.38%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	1	0	6	2	3	0
Atrial fibrillation
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0
Ventricular dysfunction
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Pericardial effusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 30 (6.67%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	3 / 46 (6.52%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0	0	0	0	4	0	0
Nervous system disorders
Amnesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	6 / 60 (10.00%)	6 / 65 (9.23%)	2 / 46 (4.35%)	2 / 47 (4.26%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	1	0	0	0	6	10	4	2	0
Aphasia
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 30 (0.00%)	0 / 4 (0.00%)	2 / 27 (7.41%)	0 / 60 (0.00%)	2 / 65 (3.08%)	2 / 46 (4.35%)	1 / 47 (2.13%)	0 / 3 (0.00%)
occurrences all number	2	0	0	0	0	0	1	0	1	0	0	2	0	2	2	1	0
Cognitive disorder
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 17 (0.00%)	2 / 3 (66.67%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 30 (3.33%)	1 / 4 (25.00%)	1 / 27 (3.70%)	5 / 60 (8.33%)	6 / 65 (9.23%)	2 / 46 (4.35%)	3 / 47 (6.38%)	0 / 3 (0.00%)
occurrences all number	1	1	0	2	0	2	3	0	0	1	1	3	5	7	2	6	0
Disturbance in attention
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 17 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	1 / 60 (1.67%)	2 / 65 (3.08%)	1 / 46 (2.17%)	3 / 47 (6.38%)	0 / 3 (0.00%)
occurrences all number	0	0	0	2	0	0	1	0	0	0	0	0	1	13	1	3	0
Dizziness
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 12 (8.33%)	2 / 17 (11.76%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	6 / 30 (20.00%)	1 / 4 (25.00%)	4 / 27 (14.81%)	5 / 60 (8.33%)	9 / 65 (13.85%)	7 / 46 (15.22%)	11 / 47 (23.40%)	0 / 3 (0.00%)
occurrences all number	1	2	0	1	2	0	0	0	0	12	1	12	5	12	8	20	0
Dysgeusia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 30 (6.67%)	1 / 4 (25.00%)	0 / 27 (0.00%)	1 / 60 (1.67%)	6 / 65 (9.23%)	2 / 46 (4.35%)	1 / 47 (2.13%)	0 / 3 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0	2	1	0	1	6	2	1	0
Headache
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)	1 / 17 (5.88%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	5 / 30 (16.67%)	2 / 4 (50.00%)	6 / 27 (22.22%)	8 / 60 (13.33%)	11 / 65 (16.92%)	10 / 46 (21.74%)	2 / 47 (4.26%)	1 / 3 (33.33%)
occurrences all number	1	0	0	3	2	1	1	1	1	8	3	7	10	15	11	2	1
Memory impairment
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 12 (8.33%)	2 / 17 (11.76%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 30 (6.67%)	1 / 4 (25.00%)	3 / 27 (11.11%)	4 / 60 (6.67%)	6 / 65 (9.23%)	2 / 46 (4.35%)	7 / 47 (14.89%)	0 / 3 (0.00%)
occurrences all number	0	1	0	1	2	0	0	0	0	2	2	3	5	12	2	16	0
Neuropathy peripheral
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	1 / 3 (33.33%)	5 / 12 (41.67%)	2 / 17 (11.76%)	1 / 3 (33.33%)	2 / 3 (66.67%)	0 / 3 (0.00%)	1 / 3 (33.33%)	5 / 30 (16.67%)	0 / 4 (0.00%)	3 / 27 (11.11%)	6 / 60 (10.00%)	7 / 65 (10.77%)	5 / 46 (10.87%)	5 / 47 (10.64%)	0 / 3 (0.00%)
occurrences all number	2	0	1	7	2	3	4	0	1	6	0	4	7	7	5	8	0
Paraesthesia
subjects affected / exposed	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	1 / 12 (8.33%)	2 / 17 (11.76%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	3 / 30 (10.00%)	2 / 4 (50.00%)	4 / 27 (14.81%)	11 / 60 (18.33%)	9 / 65 (13.85%)	5 / 46 (10.87%)	5 / 47 (10.64%)	0 / 3 (0.00%)
occurrences all number	0	2	0	4	2	0	1	1	1	5	4	7	13	9	6	6	0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 30 (10.00%)	0 / 4 (0.00%)	3 / 27 (11.11%)	7 / 60 (11.67%)	3 / 65 (4.62%)	4 / 46 (8.70%)	2 / 47 (4.26%)	2 / 3 (66.67%)
occurrences all number	0	0	0	1	1	0	0	0	0	3	0	4	14	3	4	2	2
Presyncope
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)	1 / 60 (1.67%)	0 / 65 (0.00%)	0 / 46 (0.00%)	3 / 47 (6.38%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	1	0	1	0	0	3	0
Slow speech
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 12 (8.33%)	3 / 17 (17.65%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	5 / 60 (8.33%)	2 / 65 (3.08%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	2	1	4	0	1	0	0	0	0	0	9	2	0	0	0
Ataxia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0
Balance disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0
Carpal tunnel syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	1	0	0	0	0	0	0	0	0
Dysaesthesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Dysarthria
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	4	0	1	0	0	0	0	1	0	0	0	0	0	0	0	1
Formication
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0
Hemiparesis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Hypoaesthesia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	3 / 12 (25.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	3	1	0	0	0	1	0	0	0	0	0	0	0	0
Mental impairment
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0
Migraine
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Nervous system disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Neuralgia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Neurotoxicity
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	5	0	0	0	0	0	0	0	0	0	0	0	0
Partial seizures
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Peroneal nerve palsy
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Psychomotor hyperactivity
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	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 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Sensory disturbance
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Speech disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	1 / 17 (5.88%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	2	1	0	1	0	1	0	0	0	0	0	0	0	0
Tremor
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	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%)	2 / 12 (16.67%)	6 / 17 (35.29%)	3 / 3 (100.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	2 / 3 (66.67%)	5 / 30 (16.67%)	2 / 4 (50.00%)	1 / 27 (3.70%)	3 / 60 (5.00%)	12 / 65 (18.46%)	7 / 46 (15.22%)	3 / 47 (6.38%)	0 / 3 (0.00%)
occurrences all number	0	0	0	3	14	5	1	1	4	9	2	1	3	18	8	8	0
Thrombocytopenia
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 12 (8.33%)	2 / 17 (11.76%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)	1 / 60 (1.67%)	1 / 65 (1.54%)	0 / 46 (0.00%)	3 / 47 (6.38%)	0 / 3 (0.00%)
occurrences all number	1	1	0	1	2	0	0	0	0	0	0	1	1	1	0	8	0
Febrile neutropenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0
Haemorrhagic diathesis
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Iron deficiency anaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Leukocytosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0	0	0	0	0	0	0	0	0
Neutropenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0	0	0	0	0	0	0	0	0
Thrombocytosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	3 / 12 (25.00%)	3 / 17 (17.65%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 30 (6.67%)	1 / 4 (25.00%)	2 / 27 (7.41%)	3 / 60 (5.00%)	7 / 65 (10.77%)	4 / 46 (8.70%)	1 / 47 (2.13%)	0 / 3 (0.00%)
occurrences all number	0	0	3	4	3	1	0	0	0	2	1	8	3	10	4	1	0
Ear discomfort
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Hypoacusis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	2	1	0	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%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Vertigo positional
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Eye disorders
Vision blurred
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	2 / 17 (11.76%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 30 (10.00%)	0 / 4 (0.00%)	2 / 27 (7.41%)	0 / 60 (0.00%)	3 / 65 (4.62%)	3 / 46 (6.52%)	2 / 47 (4.26%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	2	0	1	0	0	3	0	2	0	3	3	2	0
Visual impairment
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 17 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)	1 / 60 (1.67%)	3 / 65 (4.62%)	3 / 46 (6.52%)	2 / 47 (4.26%)	0 / 3 (0.00%)
occurrences all number	0	1	0	1	0	3	1	0	0	0	0	1	1	3	3	4	0
Asthenopia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0
Astigmatism
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Conjunctival oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	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%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Dry eye
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Photophobia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0
Photopsia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	1
Presbyopia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Retinal vein occlusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0
Visual acuity reduced
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	1	0	0	0	1	0	0	0	0	0	0	0	0
Eye irritation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 30 (6.67%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0	0	0	0	0	0	0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 30 (6.67%)	0 / 4 (0.00%)	1 / 27 (3.70%)	0 / 60 (0.00%)	4 / 65 (6.15%)	3 / 46 (6.52%)	5 / 47 (10.64%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	1	0	0	0	0	2	0	1	0	4	6	5	0
Abdominal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	1 / 17 (5.88%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	1 / 4 (25.00%)	1 / 27 (3.70%)	2 / 60 (3.33%)	4 / 65 (6.15%)	3 / 46 (6.52%)	1 / 47 (2.13%)	0 / 3 (0.00%)
occurrences all number	0	0	0	2	1	0	1	0	0	0	3	1	2	4	4	1	0
Constipation
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	3 / 12 (25.00%)	3 / 17 (17.65%)	0 / 3 (0.00%)	2 / 3 (66.67%)	1 / 3 (33.33%)	1 / 3 (33.33%)	8 / 30 (26.67%)	0 / 4 (0.00%)	5 / 27 (18.52%)	8 / 60 (13.33%)	8 / 65 (12.31%)	5 / 46 (10.87%)	5 / 47 (10.64%)	0 / 3 (0.00%)
occurrences all number	0	1	0	3	4	0	2	1	1	9	0	6	10	8	5	5	0
Diarrhoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	3 / 12 (25.00%)	3 / 17 (17.65%)	1 / 3 (33.33%)	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	7 / 30 (23.33%)	3 / 4 (75.00%)	4 / 27 (14.81%)	7 / 60 (11.67%)	16 / 65 (24.62%)	8 / 46 (17.39%)	7 / 47 (14.89%)	0 / 3 (0.00%)
occurrences all number	0	0	1	6	4	1	4	0	0	13	5	6	14	22	9	7	0
Dyspepsia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 30 (3.33%)	0 / 4 (0.00%)	1 / 27 (3.70%)	2 / 60 (3.33%)	5 / 65 (7.69%)	0 / 46 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	1	0	1	2	5	0	1	0
Dysphagia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)	3 / 60 (5.00%)	4 / 65 (6.15%)	2 / 46 (4.35%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	1	3	4	2	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	2 / 17 (11.76%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 30 (3.33%)	0 / 4 (0.00%)	0 / 27 (0.00%)	4 / 60 (6.67%)	1 / 65 (1.54%)	2 / 46 (4.35%)	3 / 47 (6.38%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	2	0	0	0	0	1	0	0	4	1	4	3	0
Nausea
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 12 (16.67%)	2 / 17 (11.76%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	4 / 30 (13.33%)	2 / 4 (50.00%)	3 / 27 (11.11%)	4 / 60 (6.67%)	15 / 65 (23.08%)	7 / 46 (15.22%)	6 / 47 (12.77%)	1 / 3 (33.33%)
occurrences all number	1	1	0	2	3	0	1	0	1	4	4	4	4	16	9	8	1
Vomiting
subjects affected / exposed	0 / 3 (0.00%)	2 / 3 (66.67%)	1 / 3 (33.33%)	1 / 12 (8.33%)	3 / 17 (17.65%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 30 (13.33%)	2 / 4 (50.00%)	0 / 27 (0.00%)	5 / 60 (8.33%)	7 / 65 (10.77%)	3 / 46 (6.52%)	5 / 47 (10.64%)	0 / 3 (0.00%)
occurrences all number	0	2	1	1	4	0	0	0	0	7	6	0	5	10	3	5	0
Abdominal discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	1	0	0	0	0	0	0	0	0
Abdominal pain upper
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 30 (0.00%)	2 / 4 (50.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	1	0	0	0	0	1	1	0	2	0	0	0	0	0	0
Ascites
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0
Crohn's disease
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0
Dry mouth
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Faeces discoloured
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	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%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Intestinal obstruction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Swollen tongue
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Odynophagia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	2 / 27 (7.41%)	1 / 60 (1.67%)	0 / 65 (0.00%)	1 / 46 (2.17%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	2	1	0	1	0	0
Stomatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 30 (3.33%)	0 / 4 (0.00%)	2 / 27 (7.41%)	2 / 60 (3.33%)	2 / 65 (3.08%)	1 / 46 (2.17%)	2 / 47 (4.26%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	3	2	2	1	2	0
Toothache
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 30 (6.67%)	0 / 4 (0.00%)	0 / 27 (0.00%)	1 / 60 (1.67%)	0 / 65 (0.00%)	1 / 46 (2.17%)	1 / 47 (2.13%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0	0	1	0	1	1	0
Hepatobiliary disorders
Hepatocellular injury
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	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%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 30 (6.67%)	1 / 4 (25.00%)	2 / 27 (7.41%)	2 / 60 (3.33%)	2 / 65 (3.08%)	3 / 46 (6.52%)	2 / 47 (4.26%)	1 / 3 (33.33%)
occurrences all number	0	0	0	1	0	0	2	0	0	2	1	2	2	2	3	2	1
Dry skin
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	3 / 30 (10.00%)	1 / 4 (25.00%)	1 / 27 (3.70%)	2 / 60 (3.33%)	0 / 65 (0.00%)	0 / 46 (0.00%)	1 / 47 (2.13%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	1	0	0	0	1	3	1	1	2	0	0	1	1
Hyperhidrosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)	2 / 60 (3.33%)	5 / 65 (7.69%)	1 / 46 (2.17%)	4 / 47 (8.51%)	0 / 3 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0	0	0	1	2	5	1	4	0
Pruritus
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	1 / 65 (1.54%)	4 / 46 (8.70%)	1 / 47 (2.13%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	1	4	1	0
Rash
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	3 / 12 (25.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 30 (16.67%)	0 / 4 (0.00%)	3 / 27 (11.11%)	2 / 60 (3.33%)	7 / 65 (10.77%)	2 / 46 (4.35%)	4 / 47 (8.51%)	0 / 3 (0.00%)
occurrences all number	1	1	0	4	1	0	0	0	0	9	0	4	2	7	2	4	0
Dermatitis acneiform
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	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 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Dermatomyositis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0	0	0	0	0	0	0	0	0
Night sweats
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Photosensitivity reaction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0
Rash erythematous
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0
Rash maculo-papular
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	2	0	0	0	0	0	0	0	0	0	0	0	1
Rash pruritic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Rosacea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	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%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Skin lesion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Swelling face
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0
Erythema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	2 / 27 (7.41%)	1 / 60 (1.67%)	1 / 65 (1.54%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	2	1	1	0	0	0
Renal and urinary disorders
Haematuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	2 / 17 (11.76%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 30 (6.67%)	0 / 4 (0.00%)	0 / 27 (0.00%)	1 / 60 (1.67%)	1 / 65 (1.54%)	0 / 46 (0.00%)	2 / 47 (4.26%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0	2	0	0	1	1	0	3	0
Chronic kidney disease
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Hydronephrosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Micturition urgency
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Pollakiuria
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Proteinuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	1	1	0	0	0	0	0	0	0	0	0	0	1
Urinary incontinence
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	1	0	0	0	0	1	0	0	0	0	0	0
Endocrine disorders
Cushingoid
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0	0	0	0	0	0	0	0	0
Hyperparathyroidism
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0
Hypothyroidism
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 12 (16.67%)	4 / 17 (23.53%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	5 / 30 (16.67%)	1 / 4 (25.00%)	4 / 27 (14.81%)	9 / 60 (15.00%)	11 / 65 (16.92%)	11 / 46 (23.91%)	14 / 47 (29.79%)	0 / 3 (0.00%)
occurrences all number	2	1	0	3	5	0	1	0	1	9	1	4	12	18	13	17	0
Back pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 12 (16.67%)	6 / 17 (35.29%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 30 (6.67%)	2 / 4 (50.00%)	5 / 27 (18.52%)	2 / 60 (3.33%)	10 / 65 (15.38%)	5 / 46 (10.87%)	3 / 47 (6.38%)	1 / 3 (33.33%)
occurrences all number	0	1	0	2	7	0	4	0	1	2	2	6	2	10	5	3	1
Bone pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 30 (3.33%)	0 / 4 (0.00%)	0 / 27 (0.00%)	1 / 60 (1.67%)	0 / 65 (0.00%)	3 / 46 (6.52%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	1	0	0	0	0	1	0	0	1	0	3	0	0
Joint swelling
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)	0 / 60 (0.00%)	2 / 65 (3.08%)	0 / 46 (0.00%)	3 / 47 (6.38%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	1	0	0	0	0	0	0	3	0	3	0	3	0
Muscle spasms
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 30 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)	3 / 60 (5.00%)	1 / 65 (1.54%)	3 / 46 (6.52%)	5 / 47 (10.64%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	1	0	3	2	3	5	0
Muscular weakness
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 30 (6.67%)	0 / 4 (0.00%)	0 / 27 (0.00%)	6 / 60 (10.00%)	3 / 65 (4.62%)	1 / 46 (2.17%)	3 / 47 (6.38%)	0 / 3 (0.00%)
occurrences all number	1	1	0	1	0	0	0	0	0	2	0	0	6	5	1	3	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	3 / 60 (5.00%)	0 / 65 (0.00%)	1 / 46 (2.17%)	4 / 47 (8.51%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	3	0	1	4	0
Musculoskeletal pain
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	2 / 17 (11.76%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 30 (13.33%)	0 / 4 (0.00%)	2 / 27 (7.41%)	3 / 60 (5.00%)	3 / 65 (4.62%)	2 / 46 (4.35%)	2 / 47 (4.26%)	1 / 3 (33.33%)
occurrences all number	1	0	1	0	2	0	0	0	0	5	0	3	4	3	2	2	1
Myalgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	2 / 17 (11.76%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 30 (10.00%)	1 / 4 (25.00%)	2 / 27 (7.41%)	5 / 60 (8.33%)	6 / 65 (9.23%)	5 / 46 (10.87%)	6 / 47 (12.77%)	2 / 3 (66.67%)
occurrences all number	0	0	0	1	2	0	0	0	0	3	1	2	5	7	5	7	2
Pain in extremity
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 17 (5.88%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 30 (6.67%)	0 / 4 (0.00%)	8 / 27 (29.63%)	4 / 60 (6.67%)	6 / 65 (9.23%)	4 / 46 (8.70%)	8 / 47 (17.02%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	1	1	0	0	2	4	0	10	8	6	4	9	0
Arthritis
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Bone lesion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Flank pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	2 / 17 (11.76%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0	0	0	0	0	0	0	0	0
Limb discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Musculoskeletal discomfort
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Neck pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	2 / 17 (11.76%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	2	0	0	0	0	0	0	0	0	0	0	0	0
Osteoarthritis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Osteoporosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	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 / 12 (0.00%)	2 / 17 (11.76%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0	0	0	0	0	0	0	0	0
Plantar fasciitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Torticollis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	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 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 30 (3.33%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	3 / 65 (4.62%)	1 / 46 (2.17%)	4 / 47 (8.51%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	3	1	4	0
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	2 / 17 (11.76%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 30 (3.33%)	1 / 4 (25.00%)	2 / 27 (7.41%)	1 / 60 (1.67%)	3 / 65 (4.62%)	0 / 46 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	3	1	1	0	3	1	1	2	1	4	0	2	0
Influenza
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 30 (6.67%)	0 / 4 (0.00%)	1 / 27 (3.70%)	1 / 60 (1.67%)	3 / 65 (4.62%)	0 / 46 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	2	0	1	1	3	0	1	0
Lung infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	2 / 27 (7.41%)	3 / 60 (5.00%)	2 / 65 (3.08%)	0 / 46 (0.00%)	1 / 47 (2.13%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	2	3	2	0	1	0
Pneumonia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	1 / 4 (25.00%)	1 / 27 (3.70%)	0 / 60 (0.00%)	8 / 65 (12.31%)	1 / 46 (2.17%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	1	1	0	8	1	0	0
Rhinitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)	5 / 60 (8.33%)	2 / 65 (3.08%)	0 / 46 (0.00%)	3 / 47 (6.38%)	0 / 3 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0	0	0	1	7	3	0	3	0
Sinusitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	2 / 60 (3.33%)	0 / 65 (0.00%)	1 / 46 (2.17%)	3 / 47 (6.38%)	0 / 3 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0	0	0	0	3	0	1	3	0
Upper respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	2 / 12 (16.67%)	4 / 17 (23.53%)	1 / 3 (33.33%)	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 30 (16.67%)	0 / 4 (0.00%)	2 / 27 (7.41%)	2 / 60 (3.33%)	6 / 65 (9.23%)	1 / 46 (2.17%)	3 / 47 (6.38%)	0 / 3 (0.00%)
occurrences all number	0	0	2	6	6	1	2	0	0	6	0	2	3	7	1	3	0
Viral upper respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 30 (3.33%)	0 / 4 (0.00%)	3 / 27 (11.11%)	2 / 60 (3.33%)	2 / 65 (3.08%)	2 / 46 (4.35%)	3 / 47 (6.38%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	0	4	4	2	3	3	0
Bacterial infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0	0	0	0	0	0	0	0	0
Candida infection
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	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%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Chronic sinusitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	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 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Enteritis infectious
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Enterococcal bacteraemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Gastroenteritis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Helicobacter infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Herpes virus infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Laryngitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Lower respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	1	0	0	0	0	0	0
Nasopharyngitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0
Oral candidiasis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Periodontitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Pharyngitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	2
Respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	2 / 17 (11.76%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	3	0	0	0	0	0	0	0	0	0	0	0	0
Soft tissue infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Tooth abscess
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	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%)	1 / 12 (8.33%)	2 / 17 (11.76%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	3	0	3	0	0	0	1	0	0	0	0	0	0
Viral rhinitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	1 / 4 (25.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	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 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Herpes zoster
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 30 (13.33%)	2 / 4 (50.00%)	1 / 27 (3.70%)	0 / 60 (0.00%)	5 / 65 (7.69%)	2 / 46 (4.35%)	2 / 47 (4.26%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	4	3	1	0	5	2	2	0
Hypercholesterolaemia
subjects affected / exposed	1 / 3 (33.33%)	2 / 3 (66.67%)	1 / 3 (33.33%)	7 / 12 (58.33%)	12 / 17 (70.59%)	2 / 3 (66.67%)	3 / 3 (100.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	14 / 30 (46.67%)	1 / 4 (25.00%)	11 / 27 (40.74%)	33 / 60 (55.00%)	37 / 65 (56.92%)	25 / 46 (54.35%)	25 / 47 (53.19%)	0 / 3 (0.00%)
occurrences all number	1	6	2	25	38	4	18	1	5	61	5	39	126	102	62	60	0
Hyperglycaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 30 (10.00%)	0 / 4 (0.00%)	1 / 27 (3.70%)	2 / 60 (3.33%)	3 / 65 (4.62%)	6 / 46 (13.04%)	5 / 47 (10.64%)	3 / 3 (100.00%)
occurrences all number	0	5	0	0	6	0	0	0	0	7	0	1	7	9	23	8	11
Hyperlipidaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	2 / 17 (11.76%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 30 (6.67%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	2 / 46 (4.35%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	4	0	0	0	0	2	0	0	0	0	2	0	0
Hypertriglyceridaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	4 / 12 (33.33%)	6 / 17 (35.29%)	1 / 3 (33.33%)	2 / 3 (66.67%)	0 / 3 (0.00%)	1 / 3 (33.33%)	20 / 30 (66.67%)	1 / 4 (25.00%)	12 / 27 (44.44%)	27 / 60 (45.00%)	44 / 65 (67.69%)	29 / 46 (63.04%)	23 / 47 (48.94%)	0 / 3 (0.00%)
occurrences all number	0	9	4	9	27	1	10	0	2	106	3	34	99	135	100	78	0
Hyperuricaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 30 (6.67%)	1 / 4 (25.00%)	1 / 27 (3.70%)	2 / 60 (3.33%)	1 / 65 (1.54%)	3 / 46 (6.52%)	3 / 47 (6.38%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	2	1	1	2	1	3	3	0
Hypokalaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	1 / 17 (5.88%)	2 / 3 (66.67%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 30 (6.67%)	0 / 4 (0.00%)	0 / 27 (0.00%)	4 / 60 (6.67%)	4 / 65 (6.15%)	2 / 46 (4.35%)	3 / 47 (6.38%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	1	7	11	1	0	4	0	0	4	6	2	3	0
Hypomagnesaemia
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 17 (0.00%)	3 / 3 (100.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 30 (6.67%)	0 / 4 (0.00%)	0 / 27 (0.00%)	2 / 60 (3.33%)	1 / 65 (1.54%)	3 / 46 (6.52%)	3 / 47 (6.38%)	0 / 3 (0.00%)
occurrences all number	0	2	1	0	0	5	0	1	0	3	0	0	2	1	3	4	0
Hypophosphataemia
subjects affected / exposed	1 / 3 (33.33%)	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	2 / 27 (7.41%)	2 / 60 (3.33%)	1 / 65 (1.54%)	3 / 46 (6.52%)	3 / 47 (6.38%)	0 / 3 (0.00%)
occurrences all number	1	5	0	0	0	4	2	0	0	0	0	2	2	1	4	5	0
Dehydration
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	1	0	0	0	0	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 / 12 (16.67%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	2	0	0	0	1	0	0	0	0	0	0	0	0	0
Hypercalcaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0
Hypocalcaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	4	0	0	0	0	0	0	0	0	0	0	0
Hypocholesterolaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 17 (5.88%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Hypoalbuminaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 30 (10.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	3 / 60 (5.00%)	4 / 65 (6.15%)	4 / 46 (8.70%)	2 / 47 (4.26%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	5	0	0	6	5	6	2	0
Increased appetite
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 17 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 30 (0.00%)	0 / 4 (0.00%)	0 / 27 (0.00%)	0 / 60 (0.00%)	0 / 65 (0.00%)	0 / 46 (0.00%)	0 / 47 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1

More information

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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.

The study is still ongoing. This report reflects data collected up to 15 Mar 2017, and will be updated after completion of the whole study.

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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 Subjects with Cycle 1 Dose-Limiting Toxicities (DLTs) in Phase 1

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

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

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

Secondary: Percentage of Subjects with Overall and Intracranial Objective Response (Phase 1)

Secondary: Percentage of Subjects 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: Duration of Response (DOR) and Intracranial DOR (Phase 1)

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

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

Secondary: Percentage of Subjects Achieving Disease Control and Intracranial Disease Control at 12 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 Subjects with ALK Mutation Based on Plasma CNA Analysis (Phase 1)

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

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

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

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

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

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

Secondary: Number of Subjects 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