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Clinical Trial Results:
A Phase 1/2 Open-Label, Dose Escalation Study Investigating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ASP2215 in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Summary
EudraCT number	2014-002217-31
Trial protocol	DE IT FR
Global end of trial date	07 Mar 2018

Results information
Results version number	v1(current)
This version publication date	22 Mar 2019
First version publication date	22 Mar 2019
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

2215-CL-0101

ISRCTN number

US NCT number

NCT02014558

WHO universal trial number (UTN)

Sponsor organisation name

Astellas Pharma Global Development, Inc.

Sponsor organisation address

1 Astellas Way, Northbrook, United States, 60062

Public contact

Clinical Trial Disclosure, Astellas Pharma Global Development, Inc., 1 8008887704, astellas.resultsdisclosure@astellas.com

Scientific contact

Clinical Trial Disclosure, Astellas Pharma Global Development, Inc., 1 8008887704, astellas.resultsdisclosure@astellas.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

07 Mar 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

07 Mar 2018

Was the trial ended prematurely?

Main objective of the trial

The primary objectives of the study were to assess the safety and tolerability, including determination of the maximum tolerated dose (MTD) of oral gilteritinib in participants with relapsed or treatment-refractory acute myeloid leukemia (AML) and determine the pharmacokinetic parameters of gilteritinib.

Protection of trial subjects

This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.

Background therapy

Evidence for comparator

Actual start date of recruitment

09 Oct 2013

Long term follow-up planned

Yes

Long term follow-up rationale

Safety

Long term follow-up duration

3 Years

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Germany: 8

Country: Number of subjects enrolled

Italy: 12

Country: Number of subjects enrolled

United States: 245

Worldwide total number of subjects

265

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)

151

From 65 to 84 years

111

85 years and over

Subject disposition

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Recruitment details

This dose-escalation/dose-expansion study was conducted in sites in the United States, Germany and Italy. The study had 7 dose-escalation cohorts with ≥3 participants enrolled at each dose level. Following escalation to the next dose cohort, additional participants were enrolled to the dose-expansion cohorts per protocol-specified criteria.

Screening details

Participants with AML who relapsed after or were refractory to induction or salvage treatment were selected for this study. Re-enrollment into the dose-expansion cohorts was permissible for participants who discontinued treatment for reasons other than toxicity or disease progression, as long as they met the eligibility criteria.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Gilteritinib 20 mg in Escalation Phase

Arm description

Participants received a single dose of 20 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.

Arm type

Experimental

Investigational medicinal product name

Gilteritinib

Investigational medicinal product code

ASP2215

Other name

Xospata

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received gilteritinib orally once daily with water starting from day -2 and day 1 of cycle 1, for continuous 28-day cycles. Food intake was restricted to at least 2 hours before and 1 hour after dosing. Gilteritinib was supplied in tablets of 10 mg, 40 mg and 100 mg and was given according to the assigned treatment dosage.

Gilteritinib 40 mg in Escalation Phase

Arm description

Participants received a single dose of 40 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.

Arm type

Experimental

Investigational medicinal product name

Gilteritinib

Investigational medicinal product code

ASP2215

Other name

Xospata

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Gilteritinib 80 mg in Escalation Phase

Arm description

Participants received a single dose of 80 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.

Arm type

Experimental

Investigational medicinal product name

Gilteritinib

Investigational medicinal product code

ASP2215

Other name

Xospata

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Gilteritinib 120 mg in Escalation Phase

Arm description

Participants received a single dose of 120 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.

Arm type

Experimental

Investigational medicinal product name

Gilteritinib

Investigational medicinal product code

ASP2215

Other name

Xospata

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Gilteritinib 200 mg in Escalation Phase

Arm description

Participants received a single dose of 200 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.

Arm type

Experimental

Investigational medicinal product name

Gilteritinib

Investigational medicinal product code

ASP2215

Other name

Xospata

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Gilteritinib 300 mg in Escalation Phase

Arm description

Participants received a single dose of 300 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.

Arm type

Experimental

Investigational medicinal product name

Gilteritinib

Investigational medicinal product code

ASP2215

Other name

Xospata

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Gilteritinib 450 mg in Escalation Phase

Arm description

Participants received a single dose of 450 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.

Arm type

Experimental

Investigational medicinal product name

Gilteritinib

Investigational medicinal product code

ASP2215

Other name

Xospata

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Gilteritinib 20 mg in Expansion Phase

Arm description

Participants received 20 mg gilteritinib orally once daily stating on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. Starting on day 16 of cycle 1, participants also received 200 mg voriconazole orally every 12 hours through day 1 of cycle 2.

Arm type

Experimental

Investigational medicinal product name

Voriconazole

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received 200 mg voriconazole tablets daily every 12 hours starting from day 16 of cycle 1 through day 1 of cycle 2.

Investigational medicinal product name

Gilteritinib

Investigational medicinal product code

ASP2215

Other name

Xospata

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received gilteritinib orally once daily with water starting from day 1 of cycle 1, for continuous 28-day cycles. Food intake was restricted to at least 2 hours before and 1 hour after dosing. Gilteritinib was supplied in tablets of 10 mg, 40 mg and 100 mg and was given according to the assigned treatment dosage.

Gilteritinib 40 mg in Expansion Phase

Arm description

Participants received 40 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.

Arm type

Experimental

Investigational medicinal product name

Gilteritinib

Investigational medicinal product code

ASP2215

Other name

Xospata

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Gilteritinib 80 mg in Expansion Phase

Arm description

Participants received 80 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.

Arm type

Experimental

Investigational medicinal product name

Gilteritinib

Investigational medicinal product code

ASP2215

Other name

Xospata

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Gilteritinib 120 mg in Expansion Phase

Arm description

Participants received 120 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study.

Arm type

Experimental

Investigational medicinal product name

Gilteritinib

Investigational medicinal product code

ASP2215

Other name

Xospata

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Gilteritinib 200 mg in Expansion Phase

Arm description

Participants received 200 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, participants also received 500 mg cephalexin as a single oral dose.

Arm type

Experimental

Investigational medicinal product name

Gilteritinib

Investigational medicinal product code

ASP2215

Other name

Xospata

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Investigational medicinal product name

Cephalexin

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule, Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received a single oral dose of 500 mg cephalexin tablet or capsule on day -1 and day 15 of cycle 1.

Gilteritinib 300 mg in Expansion Phase

Arm description

Participants received 300 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, participants also received 2 mg midazolam as a single oral dose.

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

Participants received a single oral dose of 2 mg midazolam syrup on day -1 and day 15 of cycle 1.

Investigational medicinal product name

Gilteritinib

Investigational medicinal product code

ASP2215

Other name

Xospata

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 1	Gilteritinib 20 mg in Escalation Phase	Gilteritinib 40 mg in Escalation Phase	Gilteritinib 80 mg in Escalation Phase	Gilteritinib 120 mg in Escalation Phase	Gilteritinib 200 mg in Escalation Phase	Gilteritinib 300 mg in Escalation Phase	Gilteritinib 450 mg in Escalation Phase	Gilteritinib 20 mg in Expansion Phase	Gilteritinib 40 mg in Expansion Phase	Gilteritinib 80 mg in Expansion Phase	Gilteritinib 120 mg in Expansion Phase	Gilteritinib 200 mg in Expansion Phase	Gilteritinib 300 mg in Expansion Phase
Started	5	3	3	3	4	3	4	11	15	21	70	106	17
Treated	5	3	3	3	3	3	3	11	13	21	66	100	17
Incorrect dose taken (should be 120 mg)	0	0	0	0	0	0	0	1	0	0	0	0	0
Re-enrolled	0	0	0	0	0	0	0	0	0	0	1	4	0
Completed	0	0	0	0	0	0	0	0	0	0	0	0	0
Not completed	5	3	3	3	4	3	4	11	15	21	70	106	17
Lack of Efficacy	1	2	1	1	-	-	1	3	3	3	16	8	5
Adverse Event	-	-	-	-	1	-	-	-	2	2	5	22	3
Death	1	-	-	-	-	-	1	1	2	5	5	20	2
Lost to Follow-up	-	-	-	-	-	-	-	-	-	-	1	1	-
Progressive Disease	1	-	1	1	1	2	1	6	5	6	23	32	6
Miscellaneous	2	1	1	1	-	1	-	1	1	3	12	11	1
Never Received Drug	-	-	-	-	1	-	1	-	2	-	2	2	-
Withdrawal by Patient	-	-	-	-	1	-	-	-	-	2	6	10	-

Baseline characteristics

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Reporting group title

Gilteritinib 20 mg in Escalation Phase

Reporting group description

Reporting group title

Gilteritinib 40 mg in Escalation Phase

Reporting group description

Reporting group title

Gilteritinib 80 mg in Escalation Phase

Reporting group description

Reporting group title

Gilteritinib 120 mg in Escalation Phase

Reporting group description

Reporting group title

Gilteritinib 200 mg in Escalation Phase

Reporting group description

Reporting group title

Gilteritinib 300 mg in Escalation Phase

Reporting group description

Reporting group title

Gilteritinib 450 mg in Escalation Phase

Reporting group description

Reporting group title

Gilteritinib 20 mg in Expansion Phase

Reporting group description

Reporting group title

Gilteritinib 40 mg in Expansion Phase

Reporting group description

Reporting group title

Gilteritinib 80 mg in Expansion Phase

Reporting group description

Reporting group title

Gilteritinib 120 mg in Expansion Phase

Reporting group description

Reporting group title

Gilteritinib 200 mg in Expansion Phase

Reporting group description

Reporting group title

Gilteritinib 300 mg in Expansion Phase

Reporting group description

Reporting group values	Gilteritinib 20 mg in Escalation Phase	Gilteritinib 40 mg in Escalation Phase	Gilteritinib 80 mg in Escalation Phase	Gilteritinib 120 mg in Escalation Phase	Gilteritinib 200 mg in Escalation Phase	Gilteritinib 300 mg in Escalation Phase	Gilteritinib 450 mg in Escalation Phase	Gilteritinib 20 mg in Expansion Phase	Gilteritinib 40 mg in Expansion Phase	Gilteritinib 80 mg in Expansion Phase	Gilteritinib 120 mg in Expansion Phase	Gilteritinib 200 mg in Expansion Phase	Gilteritinib 300 mg in Expansion Phase	Total
Number of subjects	5	3	3	3	4	3	4	11	15	21	70	106	17
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	65.8 ( 6.8 )	56.7 ( 6.7 )	61.0 ( 8.7 )	61.7 ( 6.0 )	55.3 ( 17.5 )	55.3 ( 25.0 )	59.3 ( 10.0 )	62.5 ( 11.4 )	54.6 ( 18.5 )	56.3 ( 18.1 )	58.2 ( 16.9 )	59.7 ( 14.3 )	57.6 ( 15.9 )	-
Gender categorical
Units: Subjects
Male	3	2	2	2	2	2	3	3	11	9	32	53	12	136
Femaile	2	1	1	1	2	1	1	8	4	12	38	53	5	129
Race
Units: Subjects
White	5	2	3	2	1	3	4	9	11	14	61	96	13	224
Black or African American	0	0	0	1	1	0	0	1	0	4	2	5	3	17
Asian	0	1	0	0	1	0	0	0	0	0	1	4	0	7
Other	0	0	0	0	1	0	0	1	4	3	6	1	1	17
Ethnicity
Units: Subjects
Not Hispanic or Latino	5	3	2	3	4	3	4	10	13	20	65	103	17	252
Hispanic or latino	0	0	1	0	0	0	0	1	2	1	5	3	0	13
Local FLT3 Mutation Status
Units: Subjects
Negative	1	0	0	1	2	1	1	1	8	12	13	11	9	60
Positive	4	3	3	2	2	2	3	10	7	9	57	95	8	205
Duration of Disease (AML)
The number of participants with available data for each arm are 4, 3, 2, 3, 2, 1, 3, 9, 11,17, 48, 80, 15. SD could not be calculated for the 300 mg due to sample size of 1.
Units: months
arithmetic mean (standard deviation)	19.7 ( 24.62 )	10.81 ( 8.58 )	62.46 ( 6.97 )	49.53 ( 72.17 )	9.46 ( 2.23 )	19.75 ( 99999 )	7.21 ( 4.27 )	11.79 ( 6.82 )	10.53 ( 11.22 )	16.3 ( 9.85 )	12.43 ( 11.13 )	11.04 ( 9.86 )	12.09 ( 17.76 )	-

End points

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Reporting group title

Gilteritinib 20 mg in Escalation Phase

Reporting group description

Reporting group title

Gilteritinib 40 mg in Escalation Phase

Reporting group description

Reporting group title

Gilteritinib 80 mg in Escalation Phase

Reporting group description

Reporting group title

Gilteritinib 120 mg in Escalation Phase

Reporting group description

Reporting group title

Gilteritinib 200 mg in Escalation Phase

Reporting group description

Reporting group title

Gilteritinib 300 mg in Escalation Phase

Reporting group description

Reporting group title

Gilteritinib 450 mg in Escalation Phase

Reporting group description

Reporting group title

Gilteritinib 20 mg in Expansion Phase

Reporting group description

Reporting group title

Gilteritinib 40 mg in Expansion Phase

Reporting group description

Reporting group title

Gilteritinib 80 mg in Expansion Phase

Reporting group description

Reporting group title

Gilteritinib 120 mg in Expansion Phase

Reporting group description

Reporting group title

Gilteritinib 200 mg in Expansion Phase

Reporting group description

Reporting group title

Gilteritinib 300 mg in Expansion Phase

Reporting group description

Subject analysis set title

Gilteritinib 20 mg

Subject analysis set type

Full analysis

Subject analysis set description

Participants received 20 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 20 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation. This group is used for efficacy analysis.

Subject analysis set title

Gilteritinib 40 mg

Subject analysis set type

Full analysis

Subject analysis set description

Participants received 40 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 40 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation. This group is used for efficacy analysis.

Subject analysis set title

Gilteritinib 80 mg

Subject analysis set type

Full analysis

Subject analysis set description

Participants received 80 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 80 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation. This group is used for efficacy analysis.

Subject analysis set title

Gilteritinib 120 mg

Subject analysis set type

Full analysis

Subject analysis set description

Participants received 120 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation. This group is used for efficacy analysis.

Subject analysis set title

Gilteritinib 200 mg

Subject analysis set type

Full analysis

Subject analysis set description

Participants received 200 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 200 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation. This group is used for efficacy analysis.

Subject analysis set title

Gilteritinib 300 mg

Subject analysis set type

Full analysis

Subject analysis set description

Participants received 300 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 300 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation. This group is used for efficacy analysis.

Subject analysis set title

Gilteritinib 450 mg

Subject analysis set type

Full analysis

Subject analysis set description

Participants received 450 mg gilteritinib orally once on day -2, and starting on day 1 of cycle 1, participants received 450 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation. This group is used for efficacy analysis.

Primary: Number of Participants with Dose Limiting Toxicities (DLTs)

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End point title

Number of Participants with Dose Limiting Toxicities (DLTs) ^[1]

End point description

To determine the maximum tolerated dose, safety was assessed by DLTs, defined as any grade ≥3 non-hematologic or extramedullary toxicity that occurred within 30 days starting with the first dose taken on day -2, and included the first treatment cycle in the dose escalation phase and in the first treatment cycle (28 days) in the dose expansion phase, that was considered to be possibly or probably related to study drug. Exceptions to this were the following: (1) Alopecia, anorexia or fatigue, (2) Grade 3 nausea and/or vomiting if not required tube feeding or total parenteral nutrition, or diarrhea if not required or prolonged hospitalization that was managed to grade ≤2 with standard antiemetic or antidiarrheal medications used at prescribed dose within 7 days of onset, (3) Grade 3 fever with neutropenia, with or without infection, (4) Grade 3 infection. Only evaluable participants (received at least 80% of intended dose or had DLT in cycle 1) in SAF were included in the analysis.

End point type

Primary

End point timeframe

From first dose up to end of cycle 1 (30 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: There is no statistical analysis applicable for this endpoint.

End point values	Gilteritinib 20 mg in Escalation Phase	Gilteritinib 40 mg in Escalation Phase	Gilteritinib 80 mg in Escalation Phase	Gilteritinib 120 mg in Escalation Phase	Gilteritinib 200 mg in Escalation Phase	Gilteritinib 300 mg in Escalation Phase	Gilteritinib 450 mg in Escalation Phase	Gilteritinib 20 mg in Expansion Phase	Gilteritinib 40 mg in Expansion Phase	Gilteritinib 80 mg in Expansion Phase	Gilteritinib 120 mg in Expansion Phase	Gilteritinib 200 mg in Expansion Phase	Gilteritinib 300 mg in Expansion Phase
Number of subjects analysed	3	3	3	3	3	3	3	9	11	18	62	87	13
Units: Participants
Any DLT	0	0	0	0	0	0	2	1	1	2	7	15	3
Blood and lymphatic system disorders	0	0	0	0	0	0	0	0	0	0	0	0	1
Cardiac disorders	0	0	0	0	0	0	0	0	0	0	1	0	0
Eye disorders	0	0	0	0	0	0	0	0	0	1	0	0	0
Gastrointestinal disorders	0	0	0	0	0	0	1	0	0	0	1	4	1
General disorders & administration site conditions	0	0	0	0	0	0	0	0	0	0	0	1	0
Hepatobiliary disorders	0	0	0	0	0	0	0	0	0	0	1	0	0
Infections and infestations	0	0	0	0	0	0	0	0	1	1	0	0	0
Investigations	0	0	0	0	0	0	1	0	0	0	2	6	2
Metabolism and nutrition disorders	0	0	0	0	0	0	0	0	0	0	0	2	0
Musculoskeletal and connective tissue disorders	0	0	0	0	0	0	0	0	0	0	0	1	1
Nervous system disorders	0	0	0	0	0	0	0	1	0	0	0	3	0
Renal and urinary disorders	0	0	0	0	0	0	0	0	0	0	1	0	0
Reproductive system and breast disorders	0	0	0	0	0	0	0	0	0	0	0	1	0
Respiratory, thoracic and mediastinal disorders	0	0	0	0	0	0	0	0	0	0	1	2	1
Vascular disorders	0	0	0	0	0	0	0	0	0	0	0	2	1

No statistical analyses for this end point

Primary: Number of Participants with Adverse Events (AEs)

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End point title

Number of Participants with Adverse Events (AEs) ^[2]

End point description

Safety was assessed by AEs, which included abnormalities identified during a medical test (e.g. laboratory tests, vital signs, electrocardiogram, etc) if the abnormality induced clinical signs or symptoms, needed active intervention, interruption or discontinuation of study medication or was clinically significant. A treatment-emergent AE (TEAE) was defined as an AE observed after starting administration of the study drug up to 30 days after last dose of study drug (for participants who underwent hematopoietic stem cell transplantation [HSCT]: defined as AEs observed after starting study drug until the last dose before on study HSCT plus 30 days, and AEs that began after resumption of gilteritinib and w/in 30 days after the last dose of gilteritinib). AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.03 (1-Mild, 2-Moderate, 3-Severe, 4-LifeThreatening, 5-Death). The analysis population was the SAF (reflected actual treatment).

End point type

Primary

End point timeframe

From first dose of study drug up to 30 days after last dose of study drug (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

Notes
[2] - 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: There is no statistical analysis applicable for this endpoint.

End point values	Gilteritinib 20 mg in Escalation Phase	Gilteritinib 40 mg in Escalation Phase	Gilteritinib 80 mg in Escalation Phase	Gilteritinib 120 mg in Escalation Phase	Gilteritinib 200 mg in Escalation Phase	Gilteritinib 300 mg in Escalation Phase	Gilteritinib 450 mg in Escalation Phase	Gilteritinib 20 mg in Expansion Phase	Gilteritinib 40 mg in Expansion Phase	Gilteritinib 80 mg in Expansion Phase	Gilteritinib 120 mg in Expansion Phase	Gilteritinib 200 mg in Expansion Phase	Gilteritinib 300 mg in Expansion Phase
Number of subjects analysed	5	3	3	3	3	3	3	11 ^[3]	13	21	66	100	17
Units: Participants
AEs	5	3	3	3	3	3	3	11	13	20	64	100	17
Drug-Related AEs	3	2	1	3	3	2	3	7	6	17	52	77	13
Deaths	2	2	0	1	1	1	1	3	4	11	23	49	7
Serious AEs	2	2	2	1	2	2	2	8	12	19	52	92	14
Drug-Related Serious AEs	0	0	0	1	1	0	2	2	1	10	19	36	4
AEs Leading to Discontinuation of Study Drug	2	0	1	0	1	0	1	2	5	11	12	46	6
Drug-Related AEs Leading to Discont. of Study Drug	0	0	0	0	0	0	0	1	1	4	5	10	3
Grade 3 or Higher TEAEs	3	2	2	1	2	2	3	9	13	20	59	99	14
AEs During On-Study HSCT Period	0	0	0	0	0	0	0	0	0	0	3	7	0
Serious AEs During On-Study HSCT	0	0	0	0	0	0	0	0	0	0	0	3	0

Notes
[3] - Actual number of participants treated & analyzed is 12. Need to reflect 11 due to validation error.

No statistical analyses for this end point

Primary: Area Under the Concentration-time Curve Over the 24-Hour Dosing Interval (AUC24) after Single and Multiple Doses of Gilteritinib

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End point title

Area Under the Concentration-time Curve Over the 24-Hour Dosing Interval (AUC24) after Single and Multiple Doses of Gilteritinib ^[4]

End point description

Plasma samples were used for pharmacokinetic assessments. The analysis population was the pharmacokinetics analysis set (PKAS), which consisted of the subset of the SAF for which sufficient plasma concentration data were available to facilitate derivation of at least 1 pharmacokinetic parameter and for whom the time of dosing on the day of sampling was known. N is the number of participants with available data (applies to all endpoints). Data that could not be calculated due to low number of participants with evaluable samples is denoted as "+/-99999."

End point type

Primary

End point timeframe

Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose

Notes
[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: Only gilteritinib escalation groups are applicable to this endpoint.

End point values	Gilteritinib 20 mg in Escalation Phase	Gilteritinib 40 mg in Escalation Phase	Gilteritinib 80 mg in Escalation Phase	Gilteritinib 120 mg in Escalation Phase	Gilteritinib 200 mg in Escalation Phase	Gilteritinib 300 mg in Escalation Phase	Gilteritinib 450 mg in Escalation Phase
Number of subjects analysed	5	3	3	3	3	3	3
Units: ng*h/mL
arithmetic mean (standard deviation)
Day -2 [N=5, 3, 3, 3, 3, 3, 2]	302.1 ( 207.0 )	360.0 ( 223.5 )	1216 ( 472.6 )	2480 ( 1972 )	3022 ( 843.6 )	4163 ( 3178 )	3324 ( 221.1 )
Cycle 1 day 15 [N=3, 2, 3, 3, 2, 3, 1]	1299 ( 1006 )	2482 ( 33.28 )	6958 ( 3273 )	6943 ( 3221 )	31428 ( 21412 )	31005 ( 10068 )	34768 ( 99999 )

Statistial Analysis 1

Statistical analysis description

Dose Proportionality (Single Dose / Day -2) was evaluated using the power model.

Comparison groups

Gilteritinib 450 mg in Escalation Phase v Gilteritinib 20 mg in Escalation Phase v Gilteritinib 300 mg in Escalation Phase v Gilteritinib 200 mg in Escalation Phase v Gilteritinib 120 mg in Escalation Phase v Gilteritinib 80 mg in Escalation Phase v Gilteritinib 40 mg in Escalation Phase

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Slope

Point estimate

0.99

Confidence interval

level

90%

sides

2-sided

lower limit

0.788

upper limit

1.19

Statistial Analysis 2

Statistical analysis description

Dose Proportionality (Multiple Dose / Cycle 1 Day 15) was evaluated using the power model.

Comparison groups

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Slope

Point estimate

1.22

Confidence interval

level

90%

sides

2-sided

lower limit

upper limit

1.43

Primary: Maximum Concentration (Cmax) after Single and Multiple Doses of Gilteritinib

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End point title

Maximum Concentration (Cmax) after Single and Multiple Doses of Gilteritinib ^[5]

End point description

Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS. Data that could not be calculated due to low number of participants with evaluable samples is denoted as "+/-99999."

End point type

Primary

End point timeframe

Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only gilteritinib escalation groups are applicable to this endpoint.

End point values	Gilteritinib 20 mg in Escalation Phase	Gilteritinib 40 mg in Escalation Phase	Gilteritinib 80 mg in Escalation Phase	Gilteritinib 120 mg in Escalation Phase	Gilteritinib 200 mg in Escalation Phase	Gilteritinib 300 mg in Escalation Phase	Gilteritinib 450 mg in Escalation Phase
Number of subjects analysed	5	3	3	3	3	3	3
Units: ng/mL
arithmetic mean (standard deviation)
Day -2 [N=5, 3, 3, 3, 3, 3, 3]	28.13 ( 21.49 )	24.98 ( 14.58 )	75.29 ( 25.22 )	136.7 ( 94.37 )	168.2 ( 45.34 )	204.3 ( 136.4 )	207.6 ( 51.81 )
Cycle 1 day 15 [N=4, 3, 3, 3, 2, 3, 1]	64.64 ( 48.77 )	107.6 ( 31.92 )	376.4 ( 150.5 )	374.2 ( 190.1 )	1462 ( 815.1 )	1525 ( 664.6 )	1528 ( 99999 )

Statistial Analysis 1

Statistical analysis description

Dose Proportionality (Single Dose / Day -2) was evaluated using the power model.

Comparison groups

Gilteritinib 20 mg in Escalation Phase v Gilteritinib 450 mg in Escalation Phase v Gilteritinib 200 mg in Escalation Phase v Gilteritinib 300 mg in Escalation Phase v Gilteritinib 120 mg in Escalation Phase v Gilteritinib 80 mg in Escalation Phase v Gilteritinib 40 mg in Escalation Phase

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Slope

Point estimate

0.808

Confidence interval

level

90%

sides

2-sided

lower limit

0.629

upper limit

0.988

Statistial Analysis 2

Statistical analysis description

Dose Proportionality (Multiple Dose / Cycle 1 Day 15) was evaluated using the power model.

Comparison groups

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Slope

Point estimate

1.21

Confidence interval

level

90%

sides

2-sided

lower limit

1.02

upper limit

1.41

Primary: Area Under the Concentration-time Curve from the Time of Dosing to the Last Measurable Concentration (AUClast) after Single and Multiple Doses of Gilteritinib

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End point title

Area Under the Concentration-time Curve from the Time of Dosing to the Last Measurable Concentration (AUClast) after Single and Multiple Doses of Gilteritinib ^[6] ^[7]

End point description

End point type

Primary

End point timeframe

Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose

Notes
[6] - 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: There is no statistical analysis applicable for this endpoint.
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only gilteritinib escalation groups are applicable to this endpoint.

End point values	Gilteritinib 20 mg in Escalation Phase	Gilteritinib 40 mg in Escalation Phase	Gilteritinib 80 mg in Escalation Phase	Gilteritinib 120 mg in Escalation Phase	Gilteritinib 200 mg in Escalation Phase	Gilteritinib 300 mg in Escalation Phase	Gilteritinib 450 mg in Escalation Phase
Number of subjects analysed	5	3	3	3	3	3	3
Units: ng*h/mL
arithmetic mean (standard deviation)
Day -2 [N=5, 3, 3, 3, 3, 3, 3]	303.0 ( 207.1 )	360.4 ( 224.1 )	1216 ( 472.6 )	2480 ( 1972 )	3024 ( 846.2 )	4181 ( 3189 )	2544 ( 1427 )
Cycle 1 day 15 [N=4, 3, 3, 3, 2, 3, 1]	1030 ( 984.2 )	1990 ( 1422 )	7111 ( 3525 )	6943 ( 3221 )	32248 ( 22571 )	31749 ( 10090 )	35506 ( 99999 )

No statistical analyses for this end point

Primary: Time to Observed Cmax (tmax) after Single and Multiple Doses of Gilteritinib

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End point title

Time to Observed Cmax (tmax) after Single and Multiple Doses of Gilteritinib ^[8] ^[9]

End point description

End point type

Primary

End point timeframe

Day -2 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose

Notes
[8] - 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: There is no statistical analysis applicable for this endpoint.
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only gilteritinib escalation groups are applicable to this endpoint.

End point values	Gilteritinib 20 mg in Escalation Phase	Gilteritinib 40 mg in Escalation Phase	Gilteritinib 80 mg in Escalation Phase	Gilteritinib 120 mg in Escalation Phase	Gilteritinib 200 mg in Escalation Phase	Gilteritinib 300 mg in Escalation Phase	Gilteritinib 450 mg in Escalation Phase
Number of subjects analysed	5	3	3	3	3	3	3
Units: hours
median (full range (min-max))
Day -2 [N=5, 3, 3, 3, 3, 3, 3]	2.00 (0.500 to 4.03)	5.983 (3.97 to 24.0)	4.000 (4.00 to 4.08)	2.083 (2.00 to 3.83)	5.233 (4.00 to 5.97)	6.067 (4.08 to 24.1)	5.783 (4.08 to 5.92)
Cycle 1 day 15 [N=4, 3, 3, 3, 2, 3, 1]	4.008 (4.00 to 6.00)	3.867 (0.50 to 6.00)	4.333 (4.00 to 4.42)	2.167 (1.95 to 5.75)	6.033 (6.00 to 6.07)	6.050 (4.08 to 6.07)	5.933 (-99999 to 99999)

No statistical analyses for this end point

Primary: Terminal Elimination Half-life (t1/2) After Multiple Doses of Gilteritinib

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End point title

Terminal Elimination Half-life (t1/2) After Multiple Doses of Gilteritinib ^[10] ^[11]

End point description

Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS.

End point type

Primary

End point timeframe

Cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose

Notes
[10] - 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: There is no statistical analysis applicable for this endpoint.
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only gilteritinib escalation groups are applicable to this endpoint.

End point values	Gilteritinib 20 mg in Escalation Phase	Gilteritinib 40 mg in Escalation Phase	Gilteritinib 80 mg in Escalation Phase	Gilteritinib 120 mg in Escalation Phase	Gilteritinib 200 mg in Escalation Phase	Gilteritinib 300 mg in Escalation Phase	Gilteritinib 450 mg in Escalation Phase
Number of subjects analysed	3	2	3	3	2	3	0 ^[12]
Units: hours
arithmetic mean (standard deviation)	62.14 ( 17.88 )	151.8 ( 129.2 )	86.11 ( 24.08 )	45.85 ( 18.83 )	141.9 ( 61.51 )	142.2 ( 55.04 )	( )

Notes
[12] - Data could not be calculated due to no evaluable samples.

No statistical analyses for this end point

Primary: Accumulation Ratio After Multiple Doses of Gilteritinib

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End point title

Accumulation Ratio After Multiple Doses of Gilteritinib ^[13] ^[14]

End point description

Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS.

End point type

Primary

End point timeframe

Cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose

Notes
[13] - 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: There is no statistical analysis applicable for this endpoint.
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only gilteritinib escalation groups are applicable to this endpoint.

End point values	Gilteritinib 20 mg in Escalation Phase	Gilteritinib 40 mg in Escalation Phase	Gilteritinib 80 mg in Escalation Phase	Gilteritinib 120 mg in Escalation Phase	Gilteritinib 200 mg in Escalation Phase	Gilteritinib 300 mg in Escalation Phase	Gilteritinib 450 mg in Escalation Phase
Number of subjects analysed	3	2	3	3	2	3	0 ^[15]
Units: ratio
arithmetic mean (standard deviation)	4.259 ( 1.069 )	9.640 ( 7.754 )	5.693 ( 1.442 )	3.290 ( 1.118 )	9.041 ( 3.693 )	9.057 ( 3.303 )	( )

Notes
[15] - Data could not be calculated due to no evaluable samples.

No statistical analyses for this end point

Secondary: Percentage of Participants with Complete Remission (CR) During the First 2 Cycles

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End point title

Percentage of Participants with Complete Remission (CR) During the First 2 Cycles

End point description

CR was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were in CR when they had bone marrow regenerating normal hematopoietic cells, achieved a morphologic leukemia-free state, had an absolute neutrophil count (ANC) > 1 x 10^9/L, platelet count ≥ 100 x 10^9/L, normal marrow differential with < 5% blasts, had been red blood cell (RBC) and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion), had no presence of Auer rods and no evidence of extramedullary leukemia, and blast counts in peripheral blood had been ≤ 2%. FAS. Data could not be calculated due to low number of events, and is denoted as "+/-99999."

End point type

Secondary

End point timeframe

During the first 2 cycles (56 days)

End point values	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Number of subjects analysed	16	16	24	70	100	20	3
Units: percentage of participants
number (confidence interval 95%)
FLT3 Mutation Positive [N=14, 8, 12,56, 89, 10, 2]	0 (-99999 to 99999)	0 (-99999 to 99999)	8.3 (0.2 to 38.5)	3.6 (0.4 to 12.3)	3.4 (0.7 to 9.5)	10 (0.3 to 44.5)	0 (-99999 to 99999)
FLT3 Mutation Negative [N=2, 8, 12, 14, 11, 10, 1]	50.0 (1.3 to 98.7)	0 (-99999 to 99999)	0 (-99999 to 99999)	0 (-99999 to 99999)	0 (-99999 to 99999)	0 (-99999 to 99999)	0 (-99999 to 99999)
All Participants [N=16, 16, 24, 70, 100, 20, 3]	6.3 (0.2 to 30.2)	0 (-99999 to 99999)	4.2 (0.1 to 21.1)	2.9 (0.3 to 9.9)	3.0 (0.6 to 8.5)	5.0 (0.1 to 24.9)	0 (-99999 to 99999)

No statistical analyses for this end point

Secondary: Percentage of Participants with CR During Treatment

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End point title

Percentage of Participants with CR During Treatment

End point description

End point type

Secondary

End point timeframe

Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

End point values	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Number of subjects analysed	16	16	24	70	100	20	3
Units: percentage of participants
number (confidence interval 95%)
FLT3 Mutation Positive [N=14, 8,12, 56, 89, 10, 2]	0 (-99999 to 99999)	0 (-99999 to 99999)	16.7 (2.1 to 48.4)	12.5 (5.2 to 24.1)	11.2 (5.5 to 19.7)	10.0 (0.3 to 44.5)	0 (-99999 to 99999)
FLT3 Mutation Negative [N=2, 8, 12, 14, 11, 10, 1]	50.0 (1.3 to 98.7)	0 (-99999 to 99999)	0 (-99999 to 99999)	0 (-99999 to 99999)	0 (-99999 to 99999)	0 (-99999 to 99999)	0 (-99999 to 99999)
All Participants [N=16, 16, 24, 70, 100, 20, 3]	6.3 (0.2 to 30.2)	0 (-99999 to 99999)	8.3 (1.0 to 27.0)	10.0 (4.1 to 19.5)	10.0 (4.9 to 17.6)	5.0 (0.1 to 24.9)	0 (-99999 to 99999)

No statistical analyses for this end point

Secondary: Percentage of Participants with CR with Incomplete Platelet Recovery (CRp)

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End point title

Percentage of Participants with CR with Incomplete Platelet Recovery (CRp)

End point description

CRp was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were in CRp when they achieved CR except for incomplete platelet recovery (< 100 x 10^9/L). The analysis population was the full analysis set (FAS), which consisted of all participants who were enrolled, took at least 1 dose of study drug and who had at least 1 posttreatment data point. Re-enrolled participants and participants from one site due to concerns with this site’s GCP compliance were excluded. Participants were summarized under planned reporting groups in the FAS. Data could not be calculated due to low number of events, and is denoted as "+/-99999."

End point type

Secondary

End point timeframe

Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

End point values	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Number of subjects analysed	16	16	24	70	100	20	3
Units: percentage of participants
number (confidence interval 95%)
FLT3 Mutation Positive [N=14, 8, 12,56, 89, 10, 2]	0 (-99999 to 99999)	0 (-99999 to 99999)	0 (-99999 to 99999)	3.6 (0.4 to 12.3)	9.0 (4.0 to 16.9)	10.0 (0.3 to 44.5)	0 (-99999 to 99999)
FLT3 Mutation Negative [N=2, 8, 12, 14, 11, 10, 1]	0 (-99999 to 99999)	0 (-99999 to 99999)	0 (-99999 to 99999)	0 (-99999 to 99999)	0 (-99999 to 99999)	0 (-99999 to 99999)	0 (-99999 to 99999)
All Participants [N=16, 16, 24, 70, 100, 20, 3]	0 (-99999 to 99999)	0 (-99999 to 99999)	0 (-99999 to 99999)	2.9 (0.3 to 9.9)	8.0 (3.5 to 15.2)	5.0 (0.1 to 24.9)	0 (-99999 to 99999)

No statistical analyses for this end point

Secondary: Percentage of Participants with CR with Incomplete Hematological Recovery (CRi)

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End point title

Percentage of Participants with CR with Incomplete Hematological Recovery (CRi)

End point description

CRi was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were in CRi when they fulfilled all the criteria for CR except for incomplete hematological recovery with residual neutropenia < 1 x 10^9/L with or without complete platelet recovery. RBC and platelet transfusion independence were not required. The analysis population was the FAS. Data could not be calculated due to low number of events, and is denoted as "+/-99999."

End point type

Secondary

End point timeframe

Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

End point values	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Number of subjects analysed	16	16	24	70	100	20	3
Units: percentage of participants
number (confidence interval 95%)
FLT3 Mutation Positive [N=14, 8, 12,56, 89, 10, 2]	7.1 (0.2 to 33.9)	0 (-99999 to 99999)	25.0 (5.5 to 57.2)	30.4 (18.8 to 44.1)	20.2 (12.4 to 30.1)	10.0 (0.3 to 44.5)	0 (-99999 to 99999)
FLT3 Mutation Negative [N=2, 8, 12, 14, 11, 10, 1]	0 (-99999 to 99999)	0 (-99999 to 99999)	16.7 (2.1 to 48.4)	7.1 (0.2 to 33.9)	9.1 (0.2 to 41.3)	0 (-99999 to 99999)	0 (-99999 to 99999)
All Participants [N=16, 16, 24, 70, 100, 20, 3]	6.3 (0.2 to 30.2)	0 (-99999 to 99999)	20.8 (7.1 to 42.2)	25.7 (16.0 to 37.6)	19.0 (11.8 to 28.1)	5.0 (0.1 to 24.9)	0 (-99999 to 99999)

No statistical analyses for this end point

Secondary: Percentage of Participants with Complete Remission with Partial Hematologic Recovery (CRh)

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End point title

Percentage of Participants with Complete Remission with Partial Hematologic Recovery (CRh)

End point description

CRh was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were in CRh when they could not be classified as being in CR and had bone marrow blasts < 5% and partial hematologic recovery ANC >= 0.5 x 10^9/L and platelets >= 50 x 10^9/L. There should not be evidence of extramedullary leukemia. The analysis population was the FAS. CRh was calculated only for participants who were FLT3 mutation positive. Data could not be calculated due to low number of events, and is denoted as "99999."

End point type

Secondary

End point timeframe

Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

End point values	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Number of subjects analysed	14	8	12	56	89	10	2
Units: percentage of participants
number (confidence interval 95%)	7.1 (0.2 to 33.9)	0 (-99999 to 99999)	8.3 (0.2 to 38.5)	10.7 (4.0 to 21.9)	7.9 (3.2 to 15.5)	20.0 (2.5 to 55.6)	0 (-99999 to 99999)

No statistical analyses for this end point

Secondary: Percentage of Participants with Composite CR (CRc)

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End point title

Percentage of Participants with Composite CR (CRc)

End point description

CRc was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were in CRc when they had achieved either CR, complete remission with incomplete platelet recovery (CRp, defined as had achieved CR except for incomplete platelet recovery (< 100 x 10^9/L) or complete remission with incomplete hematologic recovery (CRi, defined as had fulfilled all the criteria for CR except for incomplete hematological recovery with residual neutropenia < 1 x 10^9/L with or without complete platelet recovery; RBC platelet transfusion independence not required). The analysis population was the FAS. Data could not be calculated due to low number of events, and is denoted as "+/-99999."

End point type

Secondary

End point timeframe

Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

End point values	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Number of subjects analysed	16	16	24	70	100	20	3
Units: percentage of participants
number (confidence interval 95%)
FLT3 Mutation Positive [N=14,8, 12, 56, 89, 10, 2]	7.1 (0.2 to 33.9)	0 (-99999 to 99999)	41.7 (15.2 to 72.3)	46.4 (33.0 to 60.3)	40.4 (30.2 to 51.4)	30.0 (6.7 to 65.2)	0 (-99999 to 99999)
FLT3 Mutation Negative [N=2, 8, 12, 14, 11, 10, 1]	50.0 (1.3 to 98.7)	0 (-99999 to 99999)	16.7 (2.1 to 48.4)	7.1 (0.2 to 33.9)	9.1 (0.2 to 41.3)	0 (-99999 to 99999)	0 (-99999 to 99999)
All Participants [N=16, 16, 24, 70, 100, 20, 3]	12.5 (1.6 to 38.3)	0 (-99999 to 99999)	29.2 (12.6 to 51.1)	38.6 (27.2 to 51.0)	37.0 (27.6 to 47.2)	15.0 (3.2 to 37.9)	0 (-99999 to 99999)

No statistical analyses for this end point

Secondary: Percentage of Participants with Partial Remission (PR)

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End point title

Percentage of Participants with Partial Remission (PR)

End point description

PR was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). Participants were classified as being in PR when they had bone marrow regenerating normal hematopoietic cells with evidence of peripheral recovery with no (or only a few regenerating) circulating blasts and with a decrease of at least 50% in the percentage of blasts in the bone marrow aspirate with the total marrow blasts between 5% and 25%. A value of less or equal than 5% blasts was also considered a PR if Auer rods were present. There should be no evidence of extramedullary leukemia. The analysis population was the FAS. Data could not be calculated due to low number of events, and is denoted as "+/-99999."

End point type

Secondary

End point timeframe

Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

End point values	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Number of subjects analysed	16	16	24	70	100	20	3
Units: percentage of participants
number (confidence interval 95%)
FLT3 Mutation Positive [N=14,8, 12, 56, 89, 10, 2]	7.1 (0.2 to 33.9)	37.5 (8.5 to 75.5)	25.0 (5.5 to 57.2)	7.1 (2.0 to 17.3)	7.9 (3.2 to 15.5)	30.0 (6.7 to 65.2)	50.0 (1.3 to 98.7)
FLT3 Mutation Negative [N=2, 8, 12, 14, 11, 10, 1]	0 (-99999 to 99999)	0 (-99999 to 99999)	0 (-99999 to 99999)	7.1 (0.2 to 33.9)	9.1 (0.2 to 41.3)	0 (-99999 to 99999)	0 (-99999 to 99999)
All Participants [N=16, 16, 24, 70, 100, 20, 3]	6.3 (0.2 to 30.2)	18.8 (4.0 to 45.6)	12.5 (2.7 to 32.4)	7.1 (2.4 to 15.9)	8.0 (3.5 to 15.2)	15.0 (3.2 to 37.9)	33.3 (0.8 to 90.6)

No statistical analyses for this end point

Secondary: Percentage of Participants with Best Response

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End point title

Percentage of Participants with Best Response

End point description

Best response was defined according to modified Cheson criteria (2003), using centrally evaluated myeloblast counts from bone marrow aspirate/biopsy assessments and centrally evaluated hematology results; if neither central bone marrow aspirate nor biopsy was available, myeloblast was imputed with locally evaluated bone marrow aspirate/biopsy assessments (derived response). BR was defined as the best measured response for all visits (in the order of CR, CRp, CRi, and PR) post-treatment. Participants who achieved the best response of CR, CRp, CRi or PR were classified as responders. Participants who did not achieve at least PR were considered as non-responders. The analysis population was the FAS. Data could not be calculated due to low number of events, and is denoted as "+/-99999."

End point type

Secondary

End point timeframe

Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

End point values	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Number of subjects analysed	16	16	24	70	100	20	3
Units: percentage of participants
number (confidence interval 95%)
FLT3 Mutation Positive [N=14,8, 12, 56, 89, 10, 2]	14.3 (1.8 to 42.8)	37.5 (8.5 to 75.5)	66.7 (34.9 to 90.1)	53.6 (39.7 to 67.0)	48.3 (37.6 to 59.2)	60.0 (26.2 to 87.8)	50.0 (1.3 to 98.7)
FLT3 Mutation Negative [N=2, 8, 12, 14, 11, 10, 1]	50.0 (1.3 to 98.7)	0 (-99999 to 99999)	16.7 (2.1 to 48.4)	14.3 (1.8 to 42.8)	18.2 (2.3 to 51.8)	0 (-99999 to 99999)	0 (-99999 to 99999)
All Participants [N=16, 16, 24, 70, 100, 20, 3]	18.8 (4.0 to 45.6)	18.8 (4.0 to 45.6)	41.7 (22.1 to 63.4)	45.7 (33.7 to 58.1)	45.0 (35.0 to 55.3)	30.0 (11.9 to 54.3)	33.3 (0.8 to 90.6)

No statistical analyses for this end point

Secondary: Percentage of Participants with Complete Remission and Complete Remission with Partial Hematologic Recovery (CR/CRh)

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End point title

Percentage of Participants with Complete Remission and Complete Remission with Partial Hematologic Recovery (CR/CRh)

End point description

Participants with CR/CRh were defined as participants who achieved either CR or CRh. Participants with CR had bone marrow regenerating normal hematopoietic cells, achieved a morphologic leukemia-free state, had an ANC > 1 x 10^9/L, platelet count ≥ 100 x 10^9/L, and normal marrow differential with < 5% blasts, had been RBC and platelet transfusion independent (defined as 1 week without RBC transfusion and 1 week without platelet transfusion). Also, there had been no presence of Auer rods, no evidence of extramedullary leukemia, and blast counts in peripheral blood had been ≤ 2%. Participants with CRh could not be in CR and had bone marrow blasts < 5%, partial hematologic recovery ANC >= 0.5 x 10^9/L and platelets >= 50 x 10^9/L and should not have evidence of extramedullary leukemia. The analysis population was the FAS. CR/CRh was calculated only for participants who were FLT3 mutation positive. Data could not be calculated due to low number of events, and is denoted as "+/-99999."

End point type

Secondary

End point timeframe

Up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

End point values	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Number of subjects analysed	14	8	12	56	89	10	2
Units: percentage of participants
number (confidence interval 95%)	7.1 (0.2 to 33.9)	0 (-99999 to 99999)	25.0 (5.5 to 57.2)	23.2 (13.0 to 36.4)	19.1 (11.5 to 28.8)	30.0 (6.7 to 65.2)	0 (-99999 to 99999)

No statistical analyses for this end point

Secondary: Duration of CR (DCR)

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End point title

Duration of CR (DCR)

End point description

DCR was defined as the time from the date of first CR until the date of documented relapse for participants who achieved CR. Participants who died without report of relapse were considered non-events and censored at their last relapse-free disease assessment date. Other participants who did not relapse on study were considered non-events and censored at the last relapse-free disease assessment date. The analysis population was the FAS. Only participants who achieved CR were included in the analysis. Data could not be calculated due to low number of events, and is denoted as "+/-99999." DCR was calculated using Kaplan-Meier method and therefore data are estimated.

End point type

Secondary

End point timeframe

From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

End point values	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Number of subjects analysed	1	0 ^[16]	2	7	10	1	0 ^[17]
Units: days
median (confidence interval 95%)
FLT3 Mutation Positive [N=0, 0, 2, 7, 10, 1, 0]	99999 (99999 to 99999)	( to )	99999 (99999 to 99999)	99999 (86.0 to 99999)	419.0 (64.0 to 99999)	99999 (99999 to 99999)	( to )
FLT3 Mutation Negative [N=1, 0, 0, 0, 0, 0, 0]	99999 (99999 to 99999)	( to )	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	( to )
All Participants [N=1, 0, 2, 7, 10, 1, 0]	99999 (99999 to 99999)	( to )	99999 (99999 to 99999)	99999 (86.0 to 99999)	419.0 (64.0 to 99999)	99999 (99999 to 99999)	( to )

Notes
[16] - Data could not be calculated due to low number of events.
[17] - Data could not be calculated due to low number of events.

No statistical analyses for this end point

Secondary: Duration of CRp (DCRp)

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End point title

Duration of CRp (DCRp)

End point description

DCRp was defined as the time from the date of first CRp until the date of documented relapse for participants who achieved CRp. Participants who died without report of relapse were considered non-events and censored at their last relapse-free disease assessment date. Other participants who did not relapse on study were considered non-events and censored at the last relapse-free disease assessment date. The analysis population was the FAS. Only participants who achieved CRp were included in the analysis. Data could not be calculated due to low number of events, and is denoted as "+/-99999." DCRp was calculated using Kaplan-Meier method and therefore data are estimated.

End point type

Secondary

End point timeframe

From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

End point values	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Number of subjects analysed	0 ^[18]	0 ^[19]	1	6	12	2	0 ^[20]
Units: days
median (confidence interval 95%)
FLT3 Mutation Positive [N=0, 0, 1, 6, 12, 2, 0]	( to )	( to )	99999 (99999 to 99999)	99999 (57.0 to 99999)	450.0 (43.0 to 99999)	99999 (99999 to 99999)	( to )
FLT3 Mutation Negative [N=0, 0, 0, 0, 0, 0, 0]	( to )	( to )	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	( to )
All Participants [N=0, 0, 1, 6, 12, 2, 0]	( to )	( to )	99999 (99999 to 99999)	99999 (57.0 to 99999)	450.0 (43.0 to 99999)	99999 (99999 to 99999)	( to )

Notes
[18] - Data could not be calculated due to low number of events.
[19] - Data could not be calculated due to low number of events.
[20] - Data could not be calculated due to low number of events.

No statistical analyses for this end point

Secondary: Duration of CRi (DCRi)

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End point title

Duration of CRi (DCRi)

End point description

DCRi was defined as the time from the date of first CRi until the date of documented relapse for participants who achieved CRi. Participants who died without report of relapse and participants who did not relapse were considered non-events and censored at the last relapse-free disease assessment date. The analysis population was the FAS. Only participants who achieved CRi were included in the analysis. Data could not be calculated due to low number of events, and is denoted as "+/-99999." DCRi was calculated using Kaplan-Meier method and therefore data are estimated.

End point type

Secondary

End point timeframe

From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

End point values	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Number of subjects analysed	1	0 ^[21]	7	24	31	1	0 ^[22]
Units: days
median (confidence interval 95%)
FLT3 Mutation Positive [N=1, 0, 5, 23, 30, 1, 0]	99999 (99999 to 99999)	( to )	99999 (79.0 to 99999)	120.0 (56.0 to 383.0)	191.0 (57.0 to 420.0)	99999 (99999 to 99999)	( to )
FLT3 Mutation Negative [N=0, 0, 2, 1, 0, 0, 0]	99999 (99999 to 99999)	( to )	41.0 (22.0 to 60.0)	99.0 (-99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	( to )
All Participants [N=1, 0, 7, 24, 31, 1, 0]	99999 (99999 to 99999)	( to )	79.0 (22.0 to 99999)	120.0 (58.0 to 383.0)	191.0 (57.0 to 420.0)	99999 (99999 to 99999)	( to )

Notes
[21] - Data could not be calculated due to low number of events.
[22] - Data could not be calculated due to low number of events.

No statistical analyses for this end point

Secondary: Duration of CRh (DCRh)

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End point title

Duration of CRh (DCRh)

End point description

DCRh was defined as the time from the date of first CRh until the date of documented relapse for participants who achieved CRh but did not have a best response of CR. Participants who died without report of relapse and participants who did not relapse were considered non-events and censored at the last relapse-free disease assessment date.The analysis population was the FAS. Only participants who achieved CRh were included in the analysis. DCRh was calculated only for participants who were FLT3 mutation positive. Data could not be calculated due to low number of events, and is denoted as "+/-99999." DCRh was calculated using Kaplan-Meier method and therefore data are estimated.

End point type

Secondary

End point timeframe

From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

End point values	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Number of subjects analysed	1	0 ^[23]	1	6	7	2	0 ^[24]
Units: days
median (confidence interval 95%)	99999 (99999 to 99999)	( to )	99999 (99999 to 99999)	64.0 (18.0 to 85.0)	101.0 (29.0 to 99999)	99999 (99999 to 99999)	( to )

Notes
[23] - Data could not be calculated due to low number of events.
[24] - Data could not be calculated due to low number of events.

No statistical analyses for this end point

Secondary: Duration of CRc (DCRc)

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End point title

Duration of CRc (DCRc)

End point description

DCRc was defined as the time from the date of first CRc until the date of documented relapse for participants who achieved CRc. Participants who died without report of relapse and participants who did not relapse were considered non-events and censored at the last relapse-free disease assessment date. The analysis population was the FAS. Only participants who achieved CRc were included in the analysis. Data could not be calculated due to low number of events, and is denoted as "+/-99999." DCRc was calculated using Kaplan-Meier method and therefore data are estimated.

End point type

Secondary

End point timeframe

From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

End point values	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Number of subjects analysed	2	0 ^[25]	7	27	37	3	0 ^[26]
Units: days
median (confidence interval 95%)
FLT3 Mutation Positive [N=1, 0, 5, 26, 36, 3, 0]	99999 (99999 to 99999)	( to )	99999 (79.0 to 99999)	98.0 (57.0 to 307.0)	191.0 (101.0 to 465.0)	99999 (99999 to 99999)	( to )
FLT3 Mutation Negative [N=1, 0, 2, 1, 1, 0, 0]	99999 (99999 to 99999)	( to )	41.0 (22.0 to 60.0)	99.0 (-99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	( to )
All Participants [N=2, 0, 7, 27, 37, 3, 0]	99999 (99999 to 99999)	( to )	79.0 (22.0 to 99999)	98.0 (58.0 to 307.0)	191.0 (101.0 to 465.0)	99999 (99999 to 99999)	( to )

Notes
[25] - Data could not be calculated due to low number of events.
[26] - Data could not be calculated due to low number of events.

No statistical analyses for this end point

Secondary: Duration of CR/CRh (DCRCRh)

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End point title

Duration of CR/CRh (DCRCRh)

End point description

DCRCRh was defined as the time from the date of first DCRCRh until the date of documented relapse for participants who achieved CR or CRh. For participants who achieved both CR and CRh, the first CR date or CRh date, whichever occurred first, was used. Participants who died without report of relapse and participants who did not relapse were considered non-events and censored at the last relapse-free disease assessment date. The analysis population was the FAS. Only participants who achieved CR or CRh were included in the analysis. DCRCRh was calculated only for participants who were FLT3 mutation positive. Data could not be calculated due to low number of events, and is denoted as "+/99999." DCRCRh was calculated using Kaplan-Meier method and therefore data are estimated.

End point type

Secondary

End point timeframe

From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

End point values	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Number of subjects analysed	1	0 ^[27]	3	13	17	3	0 ^[28]
Units: days
median (confidence interval 95%)	99999 (99999 to 99999)	( to )	99999 (99999 to 99999)	307.0 (56.0 to 99999)	308.0 (101.0 to 99999)	99999 (99999 to 99999)	( to )

Notes
[27] - Data could not be calculated due to low number of events.
[28] - Data could not be calculated due to low number of events.

No statistical analyses for this end point

Secondary: Duration of Response

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End point title

Duration of Response

End point description

Duration of response was defined as the time from the date of either first CRc or PR until the date of documented relapse of any type for participants who achieved CRc or PR. Participants who died without report of relapse and participants who did not relapse were considered non-events and censored at the last relapse-free disease assessment date. The analysis population was the FAS. Only participants who achieved CRc or PR were included in the analysis. Data could not be calculated due to low number of events, and is denoted as "+/-99999." Duration of response was calculated using Kaplan-Meier method and therefore data are estimated.

End point type

Secondary

End point timeframe

From date of remission until end of study (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

End point values	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Number of subjects analysed	3	3	10	32	45	6	1
Units: days
median (confidence interval 95%)
FLT3 Mutation Positive [N=2, 3, 8, 30, 43, 6, 1]	99999 (99999 to 99999)	99999 (99999 to 99999)	88.0 (9.0 to 99999)	141.0 (58.0 to 383.0)	220.0 (111.0 to 482.0)	59.0 (15.0 to 59.0)	99999 (99999 to 99999)
FLT3 Mutation Negative [N=1, 0, 2, 2, 2, 0, 0]	99999 (99999 to 99999)	99999 (99999 to 99999)	41.0 (22.0 to 60.0)	109.5 (99.0 to 120.0)	85.0 (-99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)
All Participants [N=3, 3, 10, 32, 45, 6, 1]	99999 (99999 to 99999)	99999 (99999 to 99999)	79.0 (9.0 to 99999)	126.0 (58.0 to 307.0)	220.0 (85.0 to 482.0)	59.0 (15.0 to 59.0)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Time to CR (TTCR)

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End point title

Time to CR (TTCR)

End point description

TTCR was defined as the time from the first dose of study drug until the date of first CR. The analysis population was the FAS. Only participants who achieved CR were included in the analysis. Data could not be calculated due to low number of events, and is denoted as "+/-99999."

End point type

Secondary

End point timeframe

From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

End point values	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Number of subjects analysed	1	0 ^[29]	2	7	10	1	0 ^[30]
Units: days
median (full range (min-max))
FLT3 Mutation Positive [N=0, 0, 2, 7, 10, 1, 0]	99999 (99999 to 99999)	( to )	171.5 (28 to 315)	141.0 (29 to 364)	93.0 (27 to 225)	56.0 (56 to 56)	( to )
FLT3 Mutation Negative [N=1, 0, 0, 0, 0, 0, 0]	30.0 (30 to 30)	( to )	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	( to )
All Participants [N=1, 0, 2, 7, 10, 1, 0]	30.0 (30 to 30)	( to )	171.5 (28 to 315)	141.0 (29 to 364)	93.0 (27 to 225)	56.0 (56 to 56)	( to )

Notes
[29] - Data could not be calculated due to low number of events.
[30] - Data could not be calculated due to low number of events.

No statistical analyses for this end point

Secondary: Time to CRp (TTCRp)

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End point title

Time to CRp (TTCRp)

End point description

TTCRp was defined as the time from the first dose of study drug until the date of first CRp. TTCRp was evaluated for participants who achieved CRp. The analysis population was the FAS. Only participants who achieved CRp were included in the analysis. Data could not be calculated due to low number of events, and is denoted as "+/-99999."

End point type

Secondary

End point timeframe

From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

End point values	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Number of subjects analysed	0 ^[31]	0 ^[32]	1	6	12	2	0 ^[33]
Units: days
median (full range (min-max))
FLT3 Mutation Positive [N=0, 0, 1, 6, 12, 2, 0]	( to )	( to )	140.0 (140 to 140)	195.0 (30 to 418)	84.5 (28 to 392)	29.0 (28 to 30)	( to )
FLT3 Mutation Negative [N=0, 0, 0, 0, 0, 0, 0]	( to )	( to )	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	99999 (99999 to 99999)	( to )
All Participants [N=0, 0, 1, 6, 12, 2, 0]	( to )	( to )	140.0 (140 to 140)	195.0 (30 to 418)	84.5 (28 to 392)	29.0 (28 to 30)	( to )

Notes
[31] - Data could not be calculated due to low number of events.
[32] - Data could not be calculated due to low number of events.
[33] - Data could not be calculated due to low number of events.

No statistical analyses for this end point

Secondary: Time to CRi (TTCRi)

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End point title

Time to CRi (TTCRi)

End point description

TTCRi was defined as the time from the first dose of study drug until the date of first CRi. TTCRi was evaluated for participants who achieved CRi. The analysis population was the FAS. Only participants who achieved CRi were included in the analysis. Data could not be calculated due to low number of events, and is denoted as "+/-99999."

End point type

Secondary

End point timeframe

From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

End point values	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Number of subjects analysed	1	0 ^[34]	7	24	31	1	0 ^[35]
Units: days
median (full range (min-max))
FLT3 Mutation Positive [N=1, 0, 5, 23, 30, 1, 0]	57.0 (57 to 57)	( to )	57.0 (31 to 70)	57.0 (26 to 170)	39.5 (26 to 133)	28.0 (28 to 28)	( to )
FLT3 Mutation Negative [N=0, 0, 2, 1, 1, 0, 0]	99999 (99999 to 99999)	( to )	71.5 (71 to 72)	30.0 (30 to 30)	30.0 (30 to 30)	99999 (99999 to 99999)	( to )
All Participants [N=1, 0, 7, 24, 31, 1, 0]	57.0 (57 to 57)	( to )	64.0 (31 to 72)	43.5 (26 to 170)	35.0 (26 to 133)	28.0 (28 to 28)	( to )

Notes
[34] - Data could not be calculated due to low number of events.
[35] - Data could not be calculated due to low number of events.

No statistical analyses for this end point

Secondary: Time to First CR/CRh (TTFCRCRh)

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End point title

Time to First CR/CRh (TTFCRCRh)

End point description

TTFCRCRh was defined as the time from the first dose of study drug until the date of first either CR or CRh. TTFCRCRh was evaluated for participants who achieved CR or CRh. For participants who achieve both CR and CRh, the first CR date or CRh date, whichever occurs first was used. The analysis population was the FAS. Only participants who achieved CR or CRh were included in the analysis. TTFCRCRh was calculated only for participants who were FLT3 mutation positive.

End point type

Secondary

End point timeframe

From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

End point values	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Number of subjects analysed	1	0 ^[36]	3	13	17	3	0 ^[37]
Units: days
median (full range (min-max))	57.0 (57 to 57)	( to )	57.0 (28 to 140)	59.0 (29 to 280)	57.0 (27 to 245)	28.0 (28 to 30)	( to )

Notes
[36] - Data could not be calculated due to low number of events.
[37] - Data could not be calculated due to low number of events.

No statistical analyses for this end point

Secondary: Time to Best CR/CRh (TTBCRCRh)

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End point title

Time to Best CR/CRh (TTBCRCRh)

End point description

TTBCRCRh was defined as the time from the first dose of study drug until the first date that the best response of CR or CRh was achieved. TTBCRCRh was evaluated for participants who achieved CR or CRh. For participants who achieve both CR and CRh, the first CR date was used. The analysis population was the FAS. Only participants who achieved CR or CRh were included in the analysis. TTBCRCRh was calculated only for participants who were FLT3 mutation positive.

End point type

Secondary

End point timeframe

From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

End point values	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Number of subjects analysed	1	0 ^[38]	3	13	17	3	0 ^[39]
Units: days
median (full range (min-max))	57.0 (57 to 57)	( to )	57.0 (28 to 315)	63.0 (29 to 364)	88.0 (27 to 245)	30.0 (28 to 56)	( to )

Notes
[38] - Data could not be calculated due to low number of events.
[39] - Data could not be calculated due to low number of events.

No statistical analyses for this end point

Secondary: Time to CRc (TTCRc)

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End point title

Time to CRc (TTCRc)

End point description

TTCRc was defined as the time from the first dose of study drug until the date of first CRc. TTCRc was evaluated for participants who achieved CRc. The analysis population was the FAS. Only participants who achieved CRc were included in the analysis. Data could not be calculated due to low number of events, and is denoted as "+/-99999."

End point type

Secondary

End point timeframe

From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

End point values	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Number of subjects analysed	2	0 ^[40]	7	27	37	3	0 ^[41]
Units: days
median (full range (min-max))
FLT3 Mutation Positive [N=1, 0, 5, 26, 36, 3, 0]	57.0 (57 to 57)	( to )	56.0 (28 to 64)	30.0 (26 to 211)	31.5 (26 to 197)	28.0 (28 to 30)	( to )
FLT3 Mutation Negative [N=1, 0, 2, 1, 1, 0, 0]	30.0 (30 to 30)	( to )	71.5 (71 to 72)	30.0 (30 to 30)	30.0 (30 to 30)	99999 (99999 to 99999)	( to )
All Participants [N=2, 0, 7, 27, 37, 3, 0]	43.5 (30 to 57)	( to )	57.0 (28 to 72)	30.0 (26 to 211)	31.0 (26 to 197)	28.0 (28 to 30)	( to )

Notes
[40] - Data could not be calculated due to low number of events
[41] - Data could not be calculated due to low number of events

No statistical analyses for this end point

Secondary: Time to Response (TTR)

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End point title

Time to Response (TTR)

End point description

TTR was defined as the time from the first dose of study drug until the date of either first CRc or PR. TTR was evaluated for participants who achieved CRc or PR. The analysis population was the FAS. Only participants who achieved CRc or PR were included in the analysis. Data could not be calculated due to low number of events, and is denoted as "+/-99999."

End point type

Secondary

End point timeframe

From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

End point values	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Number of subjects analysed	3	3	10	32	45	6	1
Units: days
median (full range (min-max))
FLT3 Mutation Positive [N=2, 3, 8, 30, 43, 6, 1]	61.5 (29 to 94)	57.0 (31 to 64)	31.0 (28 to 59)	29.0 (26 to 211)	29.0 (26 to 197)	28.0 (26 to 61)	31.0 (31 to 31)
FLT3 Mutation Negative [N=1, 0, 2, 2, 2, 0, 0]	30.0 (30 to 30)	99999 (99999 to 99999)	71.5 (71 to 72)	29.5 (29 to 30)	29.5 (29 to 30)	99999 (99999 to 99999)	99999 (99999 to 99999)
All Participants [N=3, 3, 10, 32, 45, 6, 1]	30.0 (29 to 94)	57.0 (31 to 64)	43.5 (28 to 72)	29.0 (26 to 211)	29.0 (26 to 197)	28.0 (26 to 61)	31.0 (31 to 31)

No statistical analyses for this end point

Secondary: Time to Best Response (TTBR)

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End point title

Time to Best Response (TTBR)

End point description

TTBR was defined as the time from the first dose of study drug until the first disease assessment date when participant achieved best response. TTBR was evaluated in participants who achieved best response of CR, CRp, CRi, or PR. The analysis population was the FAS. Only participants who achieved CR, CRp, CRi, or PR were included in the analysis. Data could not be calculated due to low number of events, and is denoted as "+/-99999."

End point type

Secondary

End point timeframe

From first dose of study drug up to end of treatment (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

End point values	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Number of subjects analysed	3	3	10	32	45	6	1
Units: days
median (full range (min-max))
FLT3 Mutation Positive [N=2, 3, 8, 30, 43, 6, 1]	75.5 (57 to 94)	57.0 (31 to 64)	44.0 (28 to 315)	43.5 (26 to 364)	57.0 (26 to 245)	29.0 (26 to 61)	31.0 (31 to 31)
FLT3 Mutation Negative [N=1, 0, 2, 2, 2, 0, 0]	30.0 (30 to 30)	99999 (99999 to 99999)	71.5 (71 to 72)	29.5 (29 to 30)	29.5 (29 to 30)	99999 (99999 to 99999)	99999 (99999 to 99999)
All Participants [N=3, 3, 10, 32, 45, 6, 1]	57.0 (30 to 94)	57.0 (31 to 64)	58.0 (28 to 315)	30.0 (26 to 364)	56.0 (26 to 245)	29.0 (26 to 61)	31.0 (31 to 31)

No statistical analyses for this end point

Secondary: Overall Survival (OS)

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End point title

Overall Survival (OS)

End point description

OS was defined as the time from the date of first dose of study drug until the date of death from any cause. For a participant who was not known to have died by the end of study follow-up, OS was censored at the date of last contact. The analysis population was the FAS. Data could not be calculated due to low number of events, and is denoted as "+/-99999." OS was calculated using Kaplan-Meier method and therefore data are estimated.

End point type

Secondary

End point timeframe

From first dose of study drug up to end of study (median time on study was 157.0 days, minimum of 5 days and maximum of 1320 days)

End point values	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Number of subjects analysed	16	16	24	70	100	20	3
Units: days
median (confidence interval 95%)
FLT3 Mutation Positive [N=14, 8, 12, 56, 89,10, 2]	123.0 (17.0 to 267.0)	199.5 (56.0 to 905.0)	197.5 (61.0 to 329.0)	246.0 (190.0 to 309.0)	214.0 (126.0 to 264.0)	157.0 (20.0 to 218.0)	204.0 (51.0 to 357.0)
FLT3 Mutation Negative [N=2, 8, 12, 14, 11, 10, 1]	99999 (227.0 to 99999)	71.5 (5.0 to 180.0)	136.0 (14.0 to 314.0)	144.0 (83.0 to 195.0)	67.0 (21.0 to 336.0)	68.0 (8.0 to 249.0)	89.0 (-99999 to 99999)
All Participants [N=16, 16, 24, 70, 100, 20, 3]	149.5 (31.0 to 267.0)	95.0 (55.0 to 195.0)	154.0 (74.0 to 299.0)	216.0 (161.0 to 285.0)	176.0 (124.0 to 253.0)	128.5 (36.0 to 199.0)	89.0 (51.0 to 357.0)

No statistical analyses for this end point

Secondary: Event Free Survival (EFS)

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End point title

Event Free Survival (EFS)

End point description

EFS was defined as the time from the date of first dose of study drug until the date of documented relapse, treatment failure or death from any cause, whichever occurred first. For a participant with none of these events, EFS was censored at the date of last relapse-free disease assessment. A participant without post-treatment disease assessment was censored at randomization date. Treatment failure included those participants who discontinued the treatment due to “progressive disease” or “lack of efficacy" without a previous response of CR, CRp, CRi or PR. Treatment failure date referred to the start of new anti-leukemia therapy or the last treatment evaluation date when new anti-leukemia therapy date was not available. For participants who were censored, last relapse-free disease assessment date referred to the participant’s last disease assessment date. The analysis population was the FAS. Data could not be calculated due to low number of events, and is denoted as "+/-99999."

End point type

Secondary

End point timeframe

From first dose of study drug up to end of study (median time on study was 157.0 days, minimum of 5 days and maximum of 1320 days)

End point values	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Number of subjects analysed	16	16	24	70	100	20	3
Units: days
median (confidence interval 95%)
FLT3 Mutation Positive [N=14, 8, 12, 56, 89,10, 2]	52.0 (14.0 to 88.0)	109.0 (29.0 to 357.0)	93.5 (61.0 to 127.0)	112.0 (92.0 to 143.0)	121.0 (92.0 to 155.0)	85.0 (11.0 to 157.0)	86.0 (51.0 to 121.0)
FLT3 Mutation Negative [N=2, 8, 12, 14, 11, 10, 1]	58.0 (-99999 to 99999)	39.0 (5.0 to 67.0)	74.0 (12.0 to 131.0)	85.5 (37.0 to 126.0)	45.0 (21.0 to 113.0)	43.0 (8.0 to 83.0)	71.0 (-99999 to 99999)
All Participants [N=16, 16, 24, 70, 100, 20, 3]	58.0 (19.0 to 88.0)	55.5 (38.0 to 92.0)	76.0 (61.0 to 119.0)	108.0 (90.0 to 126.0)	118.0 (88.0 to 140.0)	65.0 (20.0 to 100.0)	71.0 (51.0 to 121.0)

No statistical analyses for this end point

Secondary: Leukemia Free Survival (LFS)

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End point title

Leukemia Free Survival (LFS)

End point description

LFS was defined as the time from the date of first CRc until the date of documented relapse or death for participants who achieved CRc. For a participant who was not known to have relapsed or died, LFS was censored on the date of last relapse-free disease assessment date. The analysis population was the FAS. Only participants who achieved CRc were included in the analysis. Data could not be calculated due to low number of events, and is denoted as "+/-99999." LFS was calculated using Kaplan-Meier method and therefore data are estimated.

End point type

Secondary

End point timeframe

From first dose of study drug up to end of study (median time on study was 157.0 days, minimum of 5 days and maximum of 1320 days)

End point values	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Number of subjects analysed	2	0 ^[42]	7	27	37	3	0 ^[43]
Units: days
median (confidence interval 95%)
FLT3 Mutation Positive [N=1, 0, 5, 26, 36, 3, 0]	242.0 (-99999 to 99999)	( to )	98.0 (56.0 to 1126.0)	98.0 (58.0 to 187.0)	146.0 (47.0 to 247.0)	296.0 (130.0 to 462.0)	( to )
FLT3 Mutation Negative [N=1, 0, 2, 1, 1, 0, 0]	99999 (99999 to 99999)	( to )	41.0 (22.0 to 60.0)	99.0 (-99999 to 99999)	38.0 (-99999 to 99999)	99999 (99999 to 99999)	( to )
All Participants [N=2, 0, 7, 27, 37, 3, 0]	242.0 (-99999 to 99999)	( to )	79.0 (22.0 to 1126.0)	98.0 (58.0 to 187.0)	146.0 (45.0 to 247.0)	296.0 (130.0 to 462.0)	( to )

Notes
[42] - Data could not be calculated due to low number of events.
[43] - Data could not be calculated due to low number of events.

No statistical analyses for this end point

Secondary: Percentage of Participants Who Achieved Transfusion Conversion

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End point title

Percentage of Participants Who Achieved Transfusion Conversion

End point description

Participants who achieved transfusion conversion were defined as participants who were transfusion dependent at baseline period but became transfusion independent at postbaseline period against participants who were transfusion dependent at baseline period. Participants were considered baseline transfusion dependent if there were RBC or platelet transfusions within the baseline period. Participants were considered postbaseline transfusion independent if they were on treatment >=84 days, and if there was one consecutive 56 days without any RBC or platelet transfusion within postbaseline period. If participants were on treatment >28 days but <84 days, and there was no RBC or platelet transfusion within postbaseline period, or on treatment <=28 days, postbaseline transfusion status was not evaluable. FAS, with participants who were was transfusion dependent at baseline & had evaluable postbaseline transfusion status. Data could not be calculated due to low number of events "+/-99999."

End point type

Secondary

End point timeframe

Baseline (28 days prior to first dose until 28 days after the first dose) and postbaseline (from 29 days after first dose date until last dose date); median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days

End point values	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Number of subjects analysed	7	8	16	49	63	8	2
Units: percentage of participants
number (confidence interval 95%)
FLT3 Mutation Positive [N=6, 5, 8, 40, 57, 4, 1]	0 (-99999 to 99999)	0 (-99999 to 99999)	37.5 (8.5 to 75.5)	27.5 (14.6 to 43.9)	40.4 (27.6 to 54.2)	99999 (99999 to 99999)	99999 (99999 to 99999)
FLT3 Mutation Negative [N=1, 3, 8, 9, 6, 4, 1]	99999 (99999 to 99999)	99999 (99999 to 99999)	12.5 (0.3 to 52.7)	22.2 (2.8 to 60.0)	33.3 (4.3 to 77.7)	99999 (99999 to 99999)	99999 (99999 to 99999)
All Participants [N=7, 8, 16, 49, 63, 8, 2]	99999 (99999 to 99999)	99999 (99999 to 99999)	25.0 (7.3 to 52.4)	26.5 (14.9 to 41.1)	39.7 (27.6 to 52.8)	99999 (99999 to 99999)	99999 (99999 to 99999)

No statistical analyses for this end point

Secondary: Percentage of Participants Who Achieved Transfusion Maintenance

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End point title

Percentage of Participants Who Achieved Transfusion Maintenance

End point description

Participants who achieved transfusion maintenance were defined as participants who were transfusion independent at baseline period and still maintained transfusion independent at postbaseline period against participants who were transfusion independent at baseline period. FAS, with participants who was transfusion independent at baseline and had evaluable postbaseline transfusion status. Data could not be calculated due to low number of events, and is denoted as "+/-99999."

End point type

Secondary

End point timeframe

Baseline (28 days prior to first dose until 28 days after the first dose) and postbaseline (from 29 days after first dose date until last dose date); (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days

End point values	Gilteritinib 20 mg	Gilteritinib 40 mg	Gilteritinib 80 mg	Gilteritinib 120 mg	Gilteritinib 200 mg	Gilteritinib 300 mg	Gilteritinib 450 mg
Number of subjects analysed	0 ^[44]	0 ^[45]	1	7	10	0 ^[46]	1
Units: percentage of participants
number (confidence interval 95%)
FLT3 Mutation Positive [N=0, 0, 1, 4, 10, 0, 1]	( to )	( to )	100.0 (2.5 to 100.0)	75.0 (19.4 to 99.4)	80.0 (44.4 to 97.5)	( to )	100.0 (2.5 to 100)
FLT3 Mutation Negative [N=0, 0, 0, 3, 0, 0, 0]	( to )	( to )	99999 (99999 to 99999)	33.3 (0.8 to 90.6)	99999 (99999 to 99999)	( to )	99999 (99999 to 99999)
All Participants [N=0, 0, 1, 7, 10, 0, 1]	( to )	( to )	100.0 (2.5 to 100.0)	57.1 (18.4 to 90.1)	80.0 (44.4 to 97.5)	( to )	100.0 (2.5 to 100.0)

Notes
[44] - Data could not be calculated due to low number of events.
[45] - Data could not be calculated due to low number of events.
[46] - Data could not be calculated due to low number of events.

No statistical analyses for this end point

Secondary: AUC24 of Gilteritinib in Co-administration with Voriconazole

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End point title

AUC24 of Gilteritinib in Co-administration with Voriconazole ^[47]

End point description

Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 20 mg gilteritinib and voriconazole. Data that could not be calculated due to a sample size of 1 is denoted as "+/-99999."

End point type

Secondary

End point timeframe

Cycle 1 day 15 and cycle 2 day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib)

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: Only participants administered with 20 mg gilteritinib and voriconazole are applicable to this endpoint.

End point values	Gilteritinib 20 mg in Expansion Phase
Number of subjects analysed	1
Units: ng*h/mL
arithmetic mean (standard deviation)
Cycle 2 day 1	919.3 ( 99999 )

No statistical analyses for this end point

Secondary: Cmax of Gilteritinib in Co-administration with Voriconazole

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End point title

Cmax of Gilteritinib in Co-administration with Voriconazole ^[48]

End point description

End point type

Secondary

End point timeframe

Cycle 1 day 15 and cycle 2 day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib)

Notes
[48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only participants administered with 20 mg gilteritinib and voriconazole are applicable to this endpoint.

End point values	Gilteritinib 20 mg in Expansion Phase
Number of subjects analysed	1
Units: ng/mL
arithmetic mean (standard deviation)
Cycle 2 day 1	63.79 ( 99999 )

No statistical analyses for this end point

Secondary: AUClast of Gilteritinib in Co-administration with Voriconazole

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End point title

AUClast of Gilteritinib in Co-administration with Voriconazole ^[49]

End point description

End point type

Secondary

End point timeframe

Cycle 1 day 15 and cycle 2 day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib)

Notes
[49] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only participants administered with 20 mg gilteritinib and voriconazole are applicable to this endpoint.

End point values	Gilteritinib 20 mg in Expansion Phase
Number of subjects analysed	1
Units: ng*h/mL
arithmetic mean (standard deviation)
Cycle 2 day 1	919.3 ( 99999 )

No statistical analyses for this end point

Secondary: Tmax of Gilteritinib in Co-administration with Voriconazole

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End point title

Tmax of Gilteritinib in Co-administration with Voriconazole ^[50]

End point description

Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 20 mg gilteritinib and voriconazole.

End point type

Secondary

End point timeframe

Cycle 1 day 15 and cycle 2 day 1: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (gilteritinib)

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: Only participants administered with 20 mg gilteritinib and voriconazole are applicable to this endpoint.

End point values	Gilteritinib 20 mg in Expansion Phase
Number of subjects analysed	1
Units: hours
median (full range (min-max))
Cycle 2 day 1	2.08 (2.08 to 2.08)

No statistical analyses for this end point

Secondary: AUC24 of Midazolam Administered With and Without Gilteritinib

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End point title

AUC24 of Midazolam Administered With and Without Gilteritinib ^[51]

End point description

Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.

End point type

Secondary

End point timeframe

Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)

Notes
[51] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only participants administered with 300 mg gilteritinib and midazolam are applicable to this endpoint.

End point values	Gilteritinib 300 mg in Expansion Phase
Number of subjects analysed	16
Units: ng*h/mL
arithmetic mean (standard deviation)
Midazolam Alone (Day -1) [N=15]	66.55 ( 57.70 )
Midazolam + Gilteritinib (Cycle 1 Day 15) [N=8]	81.56 ( 65.84 )

No statistical analyses for this end point

Secondary: AUC24 of Metabolite 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib

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End point title

AUC24 of Metabolite 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib ^[52]

End point description

Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.

End point type

Secondary

End point timeframe

Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)

Notes
[52] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only participants administered with 300 mg gilteritinib and midazolam are applicable to this endpoint.

End point values	Gilteritinib 300 mg in Expansion Phase
Number of subjects analysed	16
Units: ng*h/mL
arithmetic mean (standard deviation)
Midazolam Alone (Day -1) [N=15]	20.44 ( 24.80 )
Midazolam + Gilteritinib (Cycle 1 Day 15) [N=8]	23.10 ( 21.64 )

No statistical analyses for this end point

Secondary: Cmax of Midazolam Administered With and Without Gilteritinib

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End point title

Cmax of Midazolam Administered With and Without Gilteritinib ^[53]

End point description

Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.

End point type

Secondary

End point timeframe

Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)

Notes
[53] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only participants administered with 300 mg gilteritinib and midazolam are applicable to this endpoint.

End point values	Gilteritinib 300 mg in Expansion Phase
Number of subjects analysed	16
Units: ng/mL
arithmetic mean (standard deviation)
Midazolam Alone (Day -1) [N=16]	14.68 ( 8.923 )
Midazolam + Gilteritinib (Cycle 1 Day 15) [N=9]	18.45 ( 9.452 )

No statistical analyses for this end point

Secondary: Cmax of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib

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End point title

Cmax of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib ^[54]

End point description

Plasma samples were used for pharmacokinetic assessments.The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.

End point type

Secondary

End point timeframe

Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)

Notes
[54] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only participants administered with 300 mg gilteritinib and midazolam are applicable to this endpoint.

End point values	Gilteritinib 300 mg in Expansion Phase
Number of subjects analysed	16
Units: ng/mL
arithmetic mean (standard deviation)
Midazolam Alone (Day -1) [N=16]	4.562 ( 2.858 )
Midazolam + Gilteritinib (Cycle 1 Day 15) [N=9]	5.053 ( 3.158 )

No statistical analyses for this end point

Secondary: AUClast of Midazolam Administered With and Without Gilteritinib

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End point title

AUClast of Midazolam Administered With and Without Gilteritinib ^[55]

End point description

Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.

End point type

Secondary

End point timeframe

Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)

Notes
[55] - 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: Only participants administered with 300 mg gilteritinib and midazolam are applicable to this endpoint.

End point values	Gilteritinib 300 mg in Expansion Phase
Number of subjects analysed	16
Units: ng*h/mL
arithmetic mean (standard deviation)
Midazolam Alone (Day -1) [N=16]	59.48 ( 59.49 )
Midazolam + Gilteritinib (Cycle 1 Day 15) [N=9]	82.44 ( 64.25 )

No statistical analyses for this end point

Secondary: AUClast of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib

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End point title

AUClast of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib ^[56]

End point description

Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.

End point type

Secondary

End point timeframe

Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)

Notes
[56] - 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: Only participants administered with 300 mg gilteritinib and midazolam are applicable to this endpoint.

End point values	Gilteritinib 300 mg in Expansion Phase
Number of subjects analysed	16
Units: ng*h/mL
arithmetic mean (standard deviation)
Midazolam Alone (Day -1) [N=16]	17.05 ( 24.70 )
Midazolam + Gilteritinib (Cycle 1 Day 15) [N=9]	23.58 ( 22.07 )

No statistical analyses for this end point

Secondary: Tmax of Midazolam Administered With and Without Gilteritinib

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End point title

Tmax of Midazolam Administered With and Without Gilteritinib ^[57]

End point description

Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.

End point type

Secondary

End point timeframe

Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)

Notes
[57] - 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: Only participants administered with 300 mg gilteritinib and midazolam are applicable to this endpoint.

End point values	Gilteritinib 300 mg in Expansion Phase
Number of subjects analysed	16
Units: hours
median (full range (min-max))
Midazolam Alone (Day -1) [N=16]	0.5000 (0.367 to 2.00)
Midazolam + Gilteritinib (Cycle 1 Day 15) [N=9]	1.00 (0.317 to 4.13)

No statistical analyses for this end point

Secondary: Tmax of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib

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End point title

Tmax of 1-Hydroxymidazolam After Administration of Midazolam With and Without Gilteritinib ^[58]

End point description

Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 300 mg gilteritinib and midazolam.

End point type

Secondary

End point timeframe

Day -1 and cycle 1 day 15: predose, 0.5, 1, 2, 4, 6, 24 hours postdose (midazolam)

Notes
[58] - 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: Only participants administered with 300 mg gilteritinib and midazolam are applicable to this endpoint.

End point values	Gilteritinib 300 mg in Expansion Phase
Number of subjects analysed	16
Units: hours
median (full range (min-max))
Midazolam Alone (Day -1) [N=16]	0.5583 (0.483 to 2.00)
Midazolam + Gilteritinib (Cycle 1 Day 15) [N=9]	1.00 (0.317 to 4.13)

No statistical analyses for this end point

Secondary: Area Under the Concentration-time Curve From the Time of Dosing Extrapolated to Time Infinity (AUCinf) of Cephalexin Administered With and Without Gilteritinib

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End point title

Area Under the Concentration-time Curve From the Time of Dosing Extrapolated to Time Infinity (AUCinf) of Cephalexin Administered With and Without Gilteritinib ^[59]

End point description

Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.

End point type

Secondary

End point timeframe

Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)

Notes
[59] - 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: Only participants administered with 200 mg gilteritinib and cephalexin are applicable to this endpoint.

End point values	Gilteritinib 200 mg in Expansion Phase
Number of subjects analysed	20
Units: ng*h/mL
arithmetic mean (standard deviation)
Cephalexin Alone (Day -1) [N=18]	57650 ( 20386 )
Cephalexin + Gilteritinib (Cycle 1 Day 15) [N=13]	51873 ( 18819 )

No statistical analyses for this end point

Secondary: Cmax of Cephalexin Administered With and Without Gilteritinib

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End point title

Cmax of Cephalexin Administered With and Without Gilteritinib ^[60]

End point description

Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.

End point type

Secondary

End point timeframe

Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)

Notes
[60] - 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: Only participants administered with 200 mg gilteritinib and cephalexin are applicable to this endpoint.

End point values	Gilteritinib 200 mg in Expansion Phase
Number of subjects analysed	20
Units: ng/mL
arithmetic mean (standard deviation)
Cephalexin Alone (Day -1) [N=20]	17688 ( 6680 )
Cephalexin + Gilteritinib (Cycle 1 day 15) [N=16]	16075 ( 4606 )

No statistical analyses for this end point

Secondary: AUClast of Cephalexin Administered With and Without Gilteritinib

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End point title

AUClast of Cephalexin Administered With and Without Gilteritinib ^[61]

End point description

Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.

End point type

Secondary

End point timeframe

Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)

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: Only participants administered with 200 mg gilteritinib and cephalexin are applicable to this endpoint.

End point values	Gilteritinib 200 mg in Expansion Phase
Number of subjects analysed	20
Units: ng*h/mL
arithmetic mean (standard deviation)
Cephalexin Alone (Day -1) [N=20]	53183 ( 26877 )
Cephalexin + Gilteritinib (Cycle 1 Day 15) [N=16]	54963 ( 29531 )

No statistical analyses for this end point

Secondary: Tmax of Cephalexin Administered With and Without Gilteritinib

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End point title

Tmax of Cephalexin Administered With and Without Gilteritinib ^[62]

End point description

Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.

End point type

Secondary

End point timeframe

Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)

Notes
[62] - 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: Only participants administered with 200 mg gilteritinib and cephalexin are applicable to this endpoint.

End point values	Gilteritinib 200 mg in Expansion Phase
Number of subjects analysed	20
Units: hours
median (full range (min-max))
Cephalexin Alone (Day -1) [N=20]	1.500 (1.00 to 4.02)
Cephalexin + Gilteritinib (Cycle 1 Day 15) [N=16]	1.483 (1.00 to 5.88)

No statistical analyses for this end point

Secondary: T1/2 of Cephalexin Administered With and Without Gilteritinib

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End point title

T1/2 of Cephalexin Administered With and Without Gilteritinib ^[63]

End point description

Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.

End point type

Secondary

End point timeframe

Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)

Notes
[63] - 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: Only participants administered with 200 mg gilteritinib and cephalexin are applicable to this endpoint.

End point values	Gilteritinib 200 mg in Expansion Phase
Number of subjects analysed	20
Units: hours
arithmetic mean (standard deviation)
Cephalexin Alone (Day -1) [N=20]	1.822 ( 0.5914 )
Cephalexin + Gilteritinib (Cycle 1 Day 15) [N=16]	1.827 ( 0.7175 )

No statistical analyses for this end point

Secondary: Apparent Total Systemic Clearance After Single or Multiple Extravascular Dosing (CL/F) of Cephalexin Administered With and Without Gilteritinib

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End point title

Apparent Total Systemic Clearance After Single or Multiple Extravascular Dosing (CL/F) of Cephalexin Administered With and Without Gilteritinib ^[64]

End point description

Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.

End point type

Secondary

End point timeframe

Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)

Notes
[64] - 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: Only participants administered with 200 mg gilteritinib and cephalexin are applicable to this endpoint.

End point values	Gilteritinib 200 mg in Expansion Phase
Number of subjects analysed	20
Units: L/h
arithmetic mean (standard deviation)
Cephalexin Alone (Day -1) [N=18]	9.713 ( 3.319 )
Cephalexin + Gilteritinib (Cycle 1 Day 15) [N=13]	10.58 ( 2.977 )

No statistical analyses for this end point

Secondary: Apparent Volume of Distribution During the Terminal Elimination Phase After Single Extravascular Dosing (Vz/F) of Cephalexin Administered With and Without Gilteritinib

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End point title

Apparent Volume of Distribution During the Terminal Elimination Phase After Single Extravascular Dosing (Vz/F) of Cephalexin Administered With and Without Gilteritinib ^[65]

End point description

Plasma samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.

End point type

Secondary

End point timeframe

Day -1 and cycle 1 day 15: predose, 0.5, 1, 1.5, 2, 3, 4, 6, 24 hours postdose (cephalexin)

Notes
[65] - 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: Only participants administered with 200 mg gilteritinib and cephalexin are applicable to this endpoint.

End point values	Gilteritinib 200 mg in Expansion Phase
Number of subjects analysed	20
Units: liters
arithmetic mean (standard deviation)
Cephalexin Alone (Day -1) [N=18]	24.07 ( 7.173 )
Cephalexin + Gilteritinib (Cycle 1 Day 15) [N=13]	25.86 ( 5.346 )

No statistical analyses for this end point

Secondary: Amount of Drug Excreted in Urine (Aelast) of Cephalexin Administered With and Without Gilteritinib

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End point title

Amount of Drug Excreted in Urine (Aelast) of Cephalexin Administered With and Without Gilteritinib ^[66]

End point description

Urine samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.

End point type

Secondary

End point timeframe

Day -1 and cycle 1 day 15: 0-3 hours, 3-6 hours, 6-24 hours postdose (cephalexin)

Notes
[66] - 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: Only participants administered with 200 mg gilteritinib and cephalexin are applicable to this endpoint.

End point values	Gilteritinib 200 mg in Expansion Phase
Number of subjects analysed	20
Units: mg
arithmetic mean (standard deviation)
Cephalexin Alone (Day -1) [N=13]	548.9 ( 523.7 )
Cephalexin + Gilteritinib (Cycle 1 Day 15) [N=10]	448.8 ( 306.1 )

No statistical analyses for this end point

Secondary: Fraction of Drug Excreted into Urine in Percentage (%Ae) of Cephalexin Administered With and Without Gilteritinib

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End point title

Fraction of Drug Excreted into Urine in Percentage (%Ae) of Cephalexin Administered With and Without Gilteritinib ^[67]

End point description

Urine samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.

End point type

Secondary

End point timeframe

Day -1 and cycle 1 day 15: 0-3 hours, 3-6 hours, 6-24 hours postdose (cephalexin)

Notes
[67] - 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: Only participants administered with 200 mg gilteritinib and cephalexin are applicable to this endpoint.

End point values	Gilteritinib 200 mg in Expansion Phase
Number of subjects analysed	20
Units: percentage
arithmetic mean (standard deviation)
Cephalexin Alone (Day -1) [N=13]	109.8 ( 104.7 )
Cephalexin + Gilteritinib (Cycle 1 Day 15) [N=10]	89.75 ( 61.21 )

No statistical analyses for this end point

Secondary: Renal Clearance (CLr) of Cephalexin in Administered With and Without Gilteritinib

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End point title

Renal Clearance (CLr) of Cephalexin in Administered With and Without Gilteritinib ^[68]

End point description

Urine samples were used for pharmacokinetic assessments. The analysis population was the PKAS, with participants administered 200 mg gilteritinib and cephalexin.

End point type

Secondary

End point timeframe

Day -1 and cycle 1 day 15: 0-3 hours, 3-6 hours, 6-24 hours postdose (cephalexin)

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: Only participants administered with 200 mg gilteritinib and cephalexin are applicable to this endpoint.

End point values	Gilteritinib 200 mg in Expansion Phase
Number of subjects analysed	20
Units: L/h
arithmetic mean (standard deviation)
Cephalexin Alone (Day -1) [N=13]	8.784 ( 8.727 )
Cephalexin + Gilteritinib (Cycle 1 Day 15) [N=6]	11.04 ( 8.430 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose of study drug up to 30 days after last dose of study drug (median treatment duration was 69.5 days, minimum of 3 days and maximum of 1320 days)

Adverse event reporting additional description

The analysis population was the safety analysis set (SAF), which consisted of all participants who received at least 1 dose of study drug and excluded re-enrolled participants. The total number of deaths (all causes) includes deaths reported after the time frame above.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

Reporting group title

Gilterinib 20 mg in Escalation Phase

Reporting group description

Reporting group title

Gilterinib 40 mg in Escalation Phase

Reporting group description

Reporting group title

Gilterinib 120 mg in Escalation Phase

Reporting group description

Reporting group title

Gilterinib 80 mg in Escalation Phase

Reporting group description

Reporting group title

Gilterinib 200 mg in Escalation Phase

Reporting group description

Participants received a single dose of 200 mg gilteritinib orally on day -2 to evaluate pharmacokinetics of gilteritinib. Then starting on day 1 of cycle 1, participants received 120 mg gilteritinib orally once daily in 28-day cycles until disease progression or participant discontinuation in the escalation phase of the study.

Reporting group title

Gilterinib 300 mg in Escalation Phase

Reporting group description

Reporting group title

Gilterinib 450 mg in Escalation Phase

Reporting group description

Reporting group title

Gilterinib 20 mg in Expansion Phase

Reporting group description

Reporting group title

Gilterinib 40 mg in Expansion Phase

Reporting group description

Reporting group title

Gilterinib 80 mg in Expansion Phase

Reporting group description

Reporting group title

Gilterinib 200 mg in Expansion Phase

Reporting group description

Participants received 200 mg gilteritinib orally once daily starting on day 1 of cycle 1 and continued in 28-day cycles until disease progression or participant discontinuation in the expansion phase of the study. On day -1 and day 15 of cycle 1, certain participants also received 500 mg cephalexin as a single oral dose.

Reporting group title

Gilterinib 120 mg in Expansion Phase

Reporting group description

Reporting group title

Gilterinib 300 mg in Expansion Phase

Reporting group description

Gilterinib 20 mg in Escalation Phase

Gilterinib 40 mg in Escalation Phase

Gilterinib 120 mg in Escalation Phase

Gilterinib 80 mg in Escalation Phase

Gilterinib 200 mg in Escalation Phase

Gilterinib 300 mg in Escalation Phase

Gilterinib 450 mg in Escalation Phase

Gilterinib 20 mg in Expansion Phase

Gilterinib 40 mg in Expansion Phase

Gilterinib 80 mg in Expansion Phase

Gilterinib 200 mg in Expansion Phase

Gilterinib 120 mg in Expansion Phase

Gilterinib 300 mg in Expansion Phase

Total subjects affected by serious adverse events

subjects affected / exposed

2 / 5 (40.00%)

2 / 3 (66.67%)

1 / 3 (33.33%)

2 / 3 (66.67%)

8 / 12 (66.67%)

12 / 13 (92.31%)

19 / 21 (90.48%)

92 / 100 (92.00%)

52 / 66 (78.79%)

14 / 17 (82.35%)

number of deaths (all causes)

number of deaths resulting from adverse events

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

Acute myeloid leukaemia

subjects affected / exposed

1 / 5 (20.00%)

2 / 3 (66.67%)

1 / 3 (33.33%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

2 / 12 (16.67%)

3 / 13 (23.08%)

5 / 21 (23.81%)

20 / 100 (20.00%)

9 / 66 (13.64%)

4 / 17 (23.53%)

occurrences causally related to treatment / all

0 / 1

0 / 2

0 / 1

0 / 0

0 / 1

0 / 0

0 / 2

0 / 3

0 / 8

0 / 25

0 / 10

0 / 5

deaths causally related to treatment / all

0 / 1

0 / 2

0 / 1

0 / 0

0 / 1

0 / 0

0 / 2

0 / 3

0 / 5

0 / 16

0 / 9

0 / 4

Acute myeloid leukaemia recurrent

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Basal cell carcinoma

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Central nervous system leukaemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Leukaemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (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

Squamous cell carcinoma

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

2 / 66 (3.03%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Squamous cell carcinoma of skin

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

2 / 100 (2.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Vascular disorders

Deep vein thrombosis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Embolism

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Haematoma

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

1 / 1

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Haemorrhage

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypertension

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

0 / 66 (0.00%)

1 / 17 (5.88%)

occurrences causally related to treatment / all

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Hypotension

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

1 / 12 (8.33%)

0 / 13 (0.00%)

0 / 21 (0.00%)

4 / 100 (4.00%)

3 / 66 (4.55%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

2 / 4

1 / 4

0 / 0

deaths causally related to treatment / all

0 / 0

Orthostatic hypotension

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Phlebitis deep

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

General disorders and administration site conditions

Asthenia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Chills

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Death

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

2 / 66 (3.03%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 2

0 / 0

Fatigue

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

2 / 66 (3.03%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Mucosal inflammation

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

1 / 17 (5.88%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Multiple organ dysfunction syndrome

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

1 / 13 (7.69%)

0 / 21 (0.00%)

4 / 100 (4.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 6

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 4

0 / 1

0 / 0

Oedema peripheral

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pyrexia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

9 / 100 (9.00%)

9 / 66 (13.64%)

1 / 17 (5.88%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 1

0 / 1

0 / 0

2 / 13

1 / 10

0 / 1

deaths causally related to treatment / all

0 / 0

Sudden death

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (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

Systemic inflammatory response syndrome

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Immune system disorders

Acute graft versus host disease

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Acute graft versus host disease in intestine

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Acute graft versus host disease in skin

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

3 / 100 (3.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 4

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Anaphylactic reaction

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Chronic graft versus host disease in skin

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Graft versus host disease in skin

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (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

Acute promyelocytic leukaemia differentiation syndrome

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Acute respiratory distress syndrome

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Acute respiratory failure

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

3 / 100 (3.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 4

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Aspiration

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Dyspnoea

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

1 / 13 (7.69%)

0 / 21 (0.00%)

2 / 100 (2.00%)

1 / 66 (1.52%)

0 / 17 (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

Epistaxis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Haemoptysis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

1 / 1

0 / 0

Hypoxia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

1 / 13 (7.69%)

1 / 21 (4.76%)

3 / 100 (3.00%)

2 / 66 (3.03%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

1 / 4

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Laryngeal mass

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

1 / 13 (7.69%)

0 / 21 (0.00%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Lung infiltration

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pleural effusion

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

2 / 100 (2.00%)

2 / 66 (3.03%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 3

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pulmonary embolism

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

1 / 17 (5.88%)

occurrences causally related to treatment / all

0 / 0

0 / 1

1 / 1

deaths causally related to treatment / all

0 / 0

1 / 1

Pulmonary haemorrhage

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (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 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

2 / 100 (2.00%)

2 / 66 (3.03%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory failure

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

11 / 100 (11.00%)

1 / 66 (1.52%)

1 / 17 (5.88%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 13

0 / 1

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 5

0 / 1

Psychiatric disorders

Confusional state

subjects affected / exposed

0 / 5 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Mental status changes

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Investigations

Alanine aminotransferase increased

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

2 / 100 (2.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Aspartate aminotransferase increased

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

2 / 100 (2.00%)

0 / 66 (0.00%)

1 / 17 (5.88%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

2 / 2

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Blood bilirubin increased

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

2 / 100 (2.00%)

2 / 66 (3.03%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 3

3 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

Blood creatine phosphokinase increased

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

3 / 100 (3.00%)

2 / 66 (3.03%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

3 / 3

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Blood creatinine increased

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

2 / 100 (2.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 4

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blood lactate dehydrogenase increased

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blood uric acid increased

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (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 / 5 (0.00%)

0 / 3 (0.00%)

1 / 12 (8.33%)

1 / 13 (7.69%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (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

Electrocardiogram QT prolonged

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Liver function test increased

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Platelet count decreased

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

2 / 100 (2.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Transaminases increased

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Troponin I increased

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

White blood cell count increased

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (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

Facial bones fracture

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (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 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

2 / 100 (2.00%)

2 / 66 (3.03%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Hip fracture

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

0 / 66 (0.00%)

1 / 17 (5.88%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Pelvic fracture

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Post procedural haemorrhage

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (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 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Subdural haematoma

subjects affected / exposed

0 / 5 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

2 / 100 (2.00%)

1 / 66 (1.52%)

1 / 17 (5.88%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 2

0 / 1

deaths causally related to treatment / all

0 / 0

Tendon rupture

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Wound complication

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac disorders

Acute myocardial infarction

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Atrial fibrillation

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

3 / 100 (3.00%)

3 / 66 (4.55%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 4

0 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

Atrial thrombosis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Atrioventricular block second degree

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac arrest

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (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

0 / 1

0 / 0

Cardiac failure

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac failure congestive

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

2 / 100 (2.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

1 / 4

0 / 0

deaths causally related to treatment / all

0 / 0

Myocardial infarction

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (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

Myocarditis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

2 / 100 (2.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Pericardial effusion

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pericarditis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Supraventricular tachycardia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

2 / 100 (2.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Tachycardia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Ventricular fibrillation

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

1 / 1

0 / 0

Ventricular tachycardia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (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

Nervous system disorders

Aphasia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cerebral ischaemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (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

Cerebrovascular accident

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Coordination abnormal

subjects affected / exposed

0 / 5 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Encephalopathy

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Haemorrhage intracranial

subjects affected / exposed

1 / 5 (20.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

1 / 12 (8.33%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 2

0 / 0

0 / 2

0 / 0

1 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

1 / 1

0 / 0

0 / 1

0 / 0

Headache

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

0 / 66 (0.00%)

1 / 17 (5.88%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Intracranial pressure increased

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Lethargy

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Loss of consciousness

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (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

Neuralgia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Posterior reversible encephalopathy syndrome

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Presyncope

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Radicular pain

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Seizure

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

2 / 100 (2.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Syncope

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

5 / 100 (5.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 6

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blood and lymphatic system disorders

Anaemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

4 / 100 (4.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 1

0 / 6

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Disseminated intravascular coagulation

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

1 / 17 (5.88%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Febrile neutropenia

subjects affected / exposed

0 / 5 (0.00%)

1 / 3 (33.33%)

2 / 3 (66.67%)

0 / 3 (0.00%)

4 / 12 (33.33%)

7 / 13 (53.85%)

5 / 21 (23.81%)

35 / 100 (35.00%)

18 / 66 (27.27%)

4 / 17 (23.53%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 6

0 / 5

0 / 0

0 / 6

0 / 7

1 / 11

3 / 58

1 / 28

0 / 4

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Haemolytic anaemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Leukocytosis

subjects affected / exposed

1 / 5 (20.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

3 / 100 (3.00%)

2 / 66 (3.03%)

1 / 17 (5.88%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 3

0 / 2

0 / 1

deaths causally related to treatment / all

0 / 0

Neutropenia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

2 / 100 (2.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

1 / 1

0 / 0

Pancytopenia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

2 / 100 (2.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Thrombocytopenia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

2 / 100 (2.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Eye disorders

Conjunctival oedema

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Papilloedema

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorders

Colitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (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

Diarrhoea

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

5 / 100 (5.00%)

5 / 66 (7.58%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 1

2 / 5

1 / 5

0 / 0

deaths causally related to treatment / all

0 / 0

Dysphagia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

0 / 66 (0.00%)

1 / 17 (5.88%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Enteritis

subjects affected / exposed

0 / 5 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Enterocolitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

1 / 13 (7.69%)

0 / 21 (0.00%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastric haemorrhage

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastrointestinal haemorrhage

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

2 / 100 (2.00%)

2 / 66 (3.03%)

1 / 17 (5.88%)

occurrences causally related to treatment / all

0 / 0

1 / 1

1 / 4

0 / 4

1 / 1

deaths causally related to treatment / all

0 / 0

Haematemesis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Haematochezia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (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 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (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 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Large intestinal ulcer

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Lower gastrointestinal haemorrhage

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

2 / 66 (3.03%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

Malabsorption

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nausea

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

3 / 100 (3.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 3

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Neutropenic colitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

2 / 66 (3.03%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Pancreatitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pancreatitis acute

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Rectal haemorrhage

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Rectal tenesmus

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Small intestinal obstruction

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

1 / 100 (1.00%)

0 / 66 (0.00%)

1 / 17 (5.88%)

occurrences causally related to treatment / all

0 / 0

0 / 1

1 / 1

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Stomatitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Swollen tongue

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Upper gastrointestinal haemorrhage

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

0 / 66 (0.00%)

1 / 17 (5.88%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Vomiting

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

2 / 100 (2.00%)

2 / 66 (3.03%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Hepatobiliary disorders

Cholecystitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hepatic failure

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hyperbilirubinaemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

2 / 100 (2.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Skin and subcutaneous tissue disorders

Acute febrile neutrophilic dermatosis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

2 / 100 (2.00%)

2 / 66 (3.03%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Angioedema

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Rash papular

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Skin lesion

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Renal and urinary disorders

Acute kidney injury

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 12 (8.33%)

3 / 13 (23.08%)

3 / 21 (14.29%)

14 / 100 (14.00%)

5 / 66 (7.58%)

1 / 17 (5.88%)

occurrences causally related to treatment / all

0 / 0

0 / 1

1 / 3

0 / 4

3 / 16

2 / 5

0 / 1

deaths causally related to treatment / all

0 / 0

Renal failure

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

1 / 66 (1.52%)

1 / 17 (5.88%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 2

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

Renal injury

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

1 / 13 (7.69%)

0 / 21 (0.00%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Renal tubular necrosis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (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

Urinary retention

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (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

Endocrine disorders

Diabetes insipidus

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Musculoskeletal and connective tissue disorders

Arthralgia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Back pain

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Joint effusion

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

0 / 66 (0.00%)

1 / 17 (5.88%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Muscular weakness

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

2 / 66 (3.03%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Musculoskeletal chest pain

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Myalgia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Myositis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Neck pain

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Necrotising myositis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Osteonecrosis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pain in extremity

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Rhabdomyolysis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

0 / 66 (0.00%)

1 / 17 (5.88%)

occurrences causally related to treatment / all

0 / 0

1 / 1

deaths causally related to treatment / all

0 / 0

Infections and infestations

Abscess limb

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 12 (8.33%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Arthritis bacterial

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (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

Bacteraemia

subjects affected / exposed

1 / 5 (20.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

5 / 21 (23.81%)

5 / 100 (5.00%)

2 / 66 (3.03%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 1

0 / 0

0 / 9

1 / 7

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Bacterial infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (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

Bronchopulmonary aspergillosis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

3 / 100 (3.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 4

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Cellulitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

4 / 100 (4.00%)

4 / 66 (6.06%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 4

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Clostridial infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

0 / 66 (0.00%)

1 / 17 (5.88%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Clostridium bacteraemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

2 / 100 (2.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

Clostridium difficile colitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

6 / 100 (6.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 6

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Clostridium difficile infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

2 / 100 (2.00%)

1 / 66 (1.52%)

1 / 17 (5.88%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 1

deaths causally related to treatment / all

0 / 0

Corona virus infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

0 / 66 (0.00%)

1 / 17 (5.88%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Device related infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (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 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Encephalitis viral

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Enterococcal bacteraemia

subjects affected / exposed

0 / 5 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

2 / 100 (2.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Enterococcal infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

0 / 66 (0.00%)

1 / 17 (5.88%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Enterocolitis infectious

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Epiglottitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Escherichia bacteraemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Escherichia sepsis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Escherichia urinary tract infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Fungaemia

subjects affected / exposed

0 / 5 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastroenteritis viral

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hepatic infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (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

Herpes zoster

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

2 / 100 (2.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Influenza

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

1 / 17 (5.88%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Klebsiella bacteraemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

2 / 100 (2.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Lung infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

7 / 100 (7.00%)

2 / 66 (3.03%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 10

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Oral infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

1 / 13 (7.69%)

0 / 21 (0.00%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Osteomyelitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Otitis externa

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Parainfluenzae virus infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Periodontitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Periorbital infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonia

subjects affected / exposed

0 / 5 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

2 / 3 (66.67%)

0 / 3 (0.00%)

1 / 12 (8.33%)

1 / 13 (7.69%)

2 / 21 (9.52%)

12 / 100 (12.00%)

13 / 66 (19.70%)

1 / 17 (5.88%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

0 / 2

0 / 1

0 / 2

0 / 15

0 / 1

deaths causally related to treatment / all

0 / 0

0 / 2

0 / 0

Pneumonia fungal

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

5 / 100 (5.00%)

5 / 66 (7.58%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 5

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonia haemophilus

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonia parainfluenzae viral

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonia viral

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Post procedural cellulitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pseudomonas infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (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 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory syncytial virus infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

2 / 66 (3.03%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Sepsis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 12 (0.00%)

2 / 13 (15.38%)

7 / 21 (33.33%)

19 / 100 (19.00%)

10 / 66 (15.15%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 8

1 / 25

0 / 10

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 8

0 / 1

0 / 0

Septic shock

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

3 / 21 (14.29%)

4 / 100 (4.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 4

0 / 6

0 / 0

deaths causally related to treatment / all

0 / 0

1 / 2

0 / 3

0 / 0

Sinusitis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

0 / 100 (0.00%)

1 / 66 (1.52%)

1 / 17 (5.88%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Sinusitis fungal

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Skin bacterial infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Skin infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

2 / 100 (2.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 2

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Soft tissue infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

2 / 66 (3.03%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Staphylococcal bacteraemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (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

Staphylococcal sepsis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

2 / 100 (2.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 4

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 2

0 / 0

Streptococcal bacteraemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

2 / 66 (3.03%)

1 / 17 (5.88%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 3

1 / 1

deaths causally related to treatment / all

0 / 0

Streptococcal sepsis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (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

Systemic candida

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

0 / 66 (0.00%)

1 / 17 (5.88%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Systemic mycosis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

1 / 13 (7.69%)

0 / 21 (0.00%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Tooth abscess

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Tooth infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Toxic shock syndrome

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

1 / 13 (7.69%)

0 / 21 (0.00%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Upper respiratory tract infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

0 / 100 (0.00%)

3 / 66 (4.55%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

Urinary tract infection

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

2 / 21 (9.52%)

2 / 100 (2.00%)

3 / 66 (4.55%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 4

0 / 0

deaths causally related to treatment / all

0 / 0

Urinary tract infection bacterial

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Urinary tract infection enterococcal

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

0 / 100 (0.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Urosepsis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Metabolism and nutrition disorders

Dehydration

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

1 / 66 (1.52%)

1 / 17 (5.88%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Diabetic ketoacidosis

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

0 / 100 (0.00%)

0 / 66 (0.00%)

0 / 17 (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

Failure to thrive

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

1 / 66 (1.52%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hyperkalaemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (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 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypocalcaemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hyponatraemia

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

1 / 21 (4.76%)

1 / 100 (1.00%)

2 / 66 (3.03%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

1 / 4

0 / 0

deaths causally related to treatment / all

0 / 0

Tumour lysis syndrome

subjects affected / exposed

0 / 5 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 13 (0.00%)

0 / 21 (0.00%)

1 / 100 (1.00%)

0 / 66 (0.00%)

0 / 17 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

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

Non-serious adverse events	Gilterinib 20 mg in Escalation Phase	Gilterinib 40 mg in Escalation Phase	Gilterinib 120 mg in Escalation Phase	Gilterinib 80 mg in Escalation Phase	Gilterinib 200 mg in Escalation Phase	Gilterinib 300 mg in Escalation Phase	Gilterinib 450 mg in Escalation Phase	Gilterinib 20 mg in Expansion Phase	Gilterinib 40 mg in Expansion Phase	Gilterinib 80 mg in Expansion Phase	Gilterinib 200 mg in Expansion Phase	Gilterinib 120 mg in Expansion Phase	Gilterinib 300 mg in Expansion Phase
Total subjects affected by non serious adverse events
subjects affected / exposed	5 / 5 (100.00%)	2 / 3 (66.67%)	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	3 / 3 (100.00%)	12 / 12 (100.00%)	12 / 13 (92.31%)	20 / 21 (95.24%)	97 / 100 (97.00%)	62 / 66 (93.94%)	16 / 17 (94.12%)
Vascular disorders
Flushing
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 21 (0.00%)	1 / 100 (1.00%)	0 / 66 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	1	0	1
Haematoma
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	1 / 21 (4.76%)	6 / 100 (6.00%)	2 / 66 (3.03%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	1	0	1	0	1	8	2	0
Hot flush
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	2 / 100 (2.00%)	2 / 66 (3.03%)	0 / 17 (0.00%)
occurrences all number	1	0	0	1	0	0	0	0	0	0	2	2	0
Hypertension
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 13 (7.69%)	1 / 21 (4.76%)	16 / 100 (16.00%)	7 / 66 (10.61%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	0	1	1	1	34	7	2
Hypotension
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	3 / 21 (14.29%)	25 / 100 (25.00%)	10 / 66 (15.15%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	0	1	0	4	32	11	1
Orthostatic hypotension
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	8 / 100 (8.00%)	3 / 66 (4.55%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	8	3	0
Pallor
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	2 / 21 (9.52%)	0 / 100 (0.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0	1	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 13 (0.00%)	3 / 21 (14.29%)	19 / 100 (19.00%)	6 / 66 (9.09%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0	2	0	2	0	3	20	8	0
Chills
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	1 / 21 (4.76%)	12 / 100 (12.00%)	5 / 66 (7.58%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0	0	0	1	0	1	15	5	0
Face oedema
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	2 / 21 (9.52%)	2 / 100 (2.00%)	2 / 66 (3.03%)	0 / 17 (0.00%)
occurrences all number	0	0	1	0	0	0	0	1	0	3	2	2	0
Fatigue
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	3 / 3 (100.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	4 / 12 (33.33%)	5 / 13 (38.46%)	8 / 21 (38.10%)	32 / 100 (32.00%)	27 / 66 (40.91%)	4 / 17 (23.53%)
occurrences all number	1	0	0	2	6	2	3	5	6	11	47	38	4
Gait disturbance
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	1 / 100 (1.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	1	0	0
Generalised oedema
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	2 / 100 (2.00%)	1 / 66 (1.52%)	1 / 17 (5.88%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	2	1	1
Local swelling
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Localised oedema
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	5 / 100 (5.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	5	2	0
Malaise
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	5 / 100 (5.00%)	2 / 66 (3.03%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	5	3	0
Mucosal inflammation
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	11 / 100 (11.00%)	7 / 66 (10.61%)	0 / 17 (0.00%)
occurrences all number	0	1	0	1	0	0	0	0	0	0	13	9	0
Nodule
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	0 / 100 (0.00%)	1 / 66 (1.52%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	2	1
Oedema
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	3 / 21 (14.29%)	6 / 100 (6.00%)	3 / 66 (4.55%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0	0	0	1	0	5	7	5	0
Oedema peripheral
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	4 / 12 (33.33%)	2 / 13 (15.38%)	5 / 21 (23.81%)	31 / 100 (31.00%)	17 / 66 (25.76%)	1 / 17 (5.88%)
occurrences all number	0	1	1	0	0	1	1	4	2	11	48	22	2
Pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	6 / 100 (6.00%)	6 / 66 (9.09%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	9	7	0
Peripheral swelling
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	1 / 21 (4.76%)	4 / 100 (4.00%)	3 / 66 (4.55%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	2	6	4	0
Pyrexia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	3 / 13 (23.08%)	3 / 21 (14.29%)	24 / 100 (24.00%)	18 / 66 (27.27%)	3 / 17 (17.65%)
occurrences all number	0	0	0	0	0	0	0	1	3	3	33	25	3
Serositis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Immune system disorders
Graft versus host disease
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	3 / 66 (4.55%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	4	0
Seasonal allergy
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	1 / 21 (4.76%)	1 / 100 (1.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	1	1	1	0
Reproductive system and breast disorders
Nipple pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	1	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Atelectasis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 21 (0.00%)	1 / 100 (1.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	1	0	0
Cough
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	1 / 13 (7.69%)	7 / 21 (33.33%)	26 / 100 (26.00%)	18 / 66 (27.27%)	3 / 17 (17.65%)
occurrences all number	1	0	0	0	1	0	0	3	1	7	29	27	3
Dysphonia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	2 / 100 (2.00%)	1 / 66 (1.52%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	2	0	0	0	0	2	1	1
Dyspnoea
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)	5 / 13 (38.46%)	4 / 21 (19.05%)	28 / 100 (28.00%)	19 / 66 (28.79%)	2 / 17 (11.76%)
occurrences all number	0	0	0	1	0	0	0	4	5	5	38	23	2
Dyspnoea exertional
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	3 / 100 (3.00%)	6 / 66 (9.09%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	3	7	1
Epistaxis
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	3 / 12 (25.00%)	3 / 13 (23.08%)	3 / 21 (14.29%)	20 / 100 (20.00%)	16 / 66 (24.24%)	4 / 17 (23.53%)
occurrences all number	0	1	0	0	0	1	1	3	3	3	24	18	4
Haemoptysis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	2 / 100 (2.00%)	2 / 66 (3.03%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	2	2	0
Hypoxia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 13 (7.69%)	2 / 21 (9.52%)	11 / 100 (11.00%)	5 / 66 (7.58%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	1	0	1	1	2	14	8	0
Nasal congestion
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 13 (0.00%)	3 / 21 (14.29%)	9 / 100 (9.00%)	3 / 66 (4.55%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	4	9	4	0
Oropharyngeal pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	2 / 13 (15.38%)	0 / 21 (0.00%)	8 / 100 (8.00%)	5 / 66 (7.58%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	2	0	11	6	0
Pharyngeal disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Pleural effusion
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	1 / 21 (4.76%)	10 / 100 (10.00%)	2 / 66 (3.03%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	1	0	1	0	1	14	2	0
Rales
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 21 (0.00%)	1 / 100 (1.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	1	1	0
Rhinorrhoea
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	1 / 100 (1.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	1	0	0
Sinus pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Tachypnoea
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	1 / 100 (1.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0	0	1	0	0
Upper-airway cough syndrome
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	2 / 100 (2.00%)	4 / 66 (6.06%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	3	4	0
Wheezing
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 21 (0.00%)	5 / 100 (5.00%)	2 / 66 (3.03%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	6	2	0
Psychiatric disorders
Agitation
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	1 / 21 (4.76%)	3 / 100 (3.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	3	0	0
Anxiety
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 13 (7.69%)	1 / 21 (4.76%)	6 / 100 (6.00%)	5 / 66 (7.58%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	1	1	6	5	0
Confusional state
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	3 / 21 (14.29%)	10 / 100 (10.00%)	4 / 66 (6.06%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	0	0	2	3	12	4	1
Depression
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	6 / 100 (6.00%)	3 / 66 (4.55%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	6	3	0
Disorientation
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 21 (0.00%)	1 / 100 (1.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	1	0	0
Insomnia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 12 (16.67%)	1 / 13 (7.69%)	3 / 21 (14.29%)	13 / 100 (13.00%)	8 / 66 (12.12%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	1	0	2	1	3	14	9	1
Mental status changes
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	2 / 21 (9.52%)	2 / 100 (2.00%)	0 / 66 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	1	0	0	1	2	2	0	1
Sleep disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	2 / 21 (9.52%)	0 / 100 (0.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0	0	0
Product issues
Device occlusion
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Investigations
Activated partial thromboplastin time prolonged
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 21 (0.00%)	4 / 100 (4.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	1	2	0	0	5	1	0
Alanine aminotransferase increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 12 (8.33%)	1 / 13 (7.69%)	3 / 21 (14.29%)	25 / 100 (25.00%)	16 / 66 (24.24%)	2 / 17 (11.76%)
occurrences all number	0	0	0	1	0	1	1	2	1	9	46	26	3
Aspartate aminotransferase increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	2 / 3 (66.67%)	1 / 12 (8.33%)	1 / 13 (7.69%)	3 / 21 (14.29%)	35 / 100 (35.00%)	20 / 66 (30.30%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1	1	1	4	3	1	9	61	33	2
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 12 (8.33%)	0 / 13 (0.00%)	3 / 21 (14.29%)	15 / 100 (15.00%)	10 / 66 (15.15%)	0 / 17 (0.00%)
occurrences all number	1	0	0	1	0	1	1	1	0	12	19	12	0
Blood bilirubin increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	2 / 13 (15.38%)	3 / 21 (14.29%)	12 / 100 (12.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	0	0	1	1	0	0	0	2	3	3	22	1	0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	15 / 100 (15.00%)	5 / 66 (7.58%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	27	9	1
Blood creatinine increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	2 / 13 (15.38%)	4 / 21 (19.05%)	19 / 100 (19.00%)	13 / 66 (19.70%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1	0	0	0	1	2	9	40	23	1
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 21 (0.00%)	7 / 100 (7.00%)	3 / 66 (4.55%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	9	4	0
Blood phosphorus decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 21 (0.00%)	0 / 100 (0.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	1	0
Blood thyroid stimulating hormone increased
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0
Blood urea increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	2 / 100 (2.00%)	0 / 66 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	0	1
Cardiac murmur
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	2 / 21 (9.52%)	0 / 100 (0.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0	1	0
Chest X-ray abnormal
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 21 (0.00%)	1 / 100 (1.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	1	0	0
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	9 / 100 (9.00%)	9 / 66 (13.64%)	0 / 17 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	1	11	13	0
International normalised ratio increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 13 (7.69%)	1 / 21 (4.76%)	5 / 100 (5.00%)	4 / 66 (6.06%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	0	1	2	1	7	7	1
Liver function test increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	3 / 100 (3.00%)	1 / 66 (1.52%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	4	1	1
Neutrophil count decreased
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 13 (0.00%)	1 / 21 (4.76%)	14 / 100 (14.00%)	8 / 66 (12.12%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0	2	0	4	0	1	29	16	0
Platelet count decreased
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	2 / 12 (16.67%)	3 / 13 (23.08%)	1 / 21 (4.76%)	17 / 100 (17.00%)	12 / 66 (18.18%)	1 / 17 (5.88%)
occurrences all number	3	0	0	1	0	2	1	8	4	1	37	26	1
Transaminases increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	5 / 100 (5.00%)	5 / 66 (7.58%)	1 / 17 (5.88%)
occurrences all number	0	0	1	0	0	1	0	0	0	1	6	5	1
Ultrasound liver abnormal
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Volume blood increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Weight decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 13 (7.69%)	0 / 21 (0.00%)	6 / 100 (6.00%)	3 / 66 (4.55%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	1	0	7	3	0
Weight increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	12 / 100 (12.00%)	2 / 66 (3.03%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	18	5	0
White blood cell count decreased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	13 / 100 (13.00%)	4 / 66 (6.06%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	30	14	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 12 (8.33%)	1 / 13 (7.69%)	3 / 21 (14.29%)	10 / 100 (10.00%)	3 / 66 (4.55%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	1	3	11	3	0
Fall
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 12 (8.33%)	0 / 13 (0.00%)	2 / 21 (9.52%)	18 / 100 (18.00%)	11 / 66 (16.67%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	0	2	22	15	0
Incision site pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Infusion related reaction
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	3 / 100 (3.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	5	0	0
Periorbital haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	0 / 100 (0.00%)	0 / 66 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	1
Post procedural haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	0 / 100 (0.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	1	0	0	0
Procedural pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	1 / 100 (1.00%)	1 / 66 (1.52%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	1	1
Stoma site pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	0	0	0
Transfusion reaction
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	1 / 100 (1.00%)	3 / 66 (4.55%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	2	0	0	0	1	1	3	1
Cardiac disorders
Angina pectoris
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 13 (0.00%)	0 / 21 (0.00%)	2 / 100 (2.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	3	0	0	2	0	0
Atrial fibrillation
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	5 / 100 (5.00%)	3 / 66 (4.55%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	5	3	0
Atrial flutter
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Palpitations
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	2 / 21 (9.52%)	3 / 100 (3.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	3	0	0
Pericardial effusion
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	1 / 21 (4.76%)	3 / 100 (3.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	1	3	1	0
Sinus bradycardia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	2 / 100 (2.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	1	2	0	0
Sinus tachycardia
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	2 / 13 (15.38%)	1 / 21 (4.76%)	6 / 100 (6.00%)	2 / 66 (3.03%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0	0	0	1	2	2	7	2	0
Tachycardia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	1 / 21 (4.76%)	12 / 100 (12.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0	0	0	1	0	1	13	1	0
Nervous system disorders
Cognitive disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	2 / 100 (2.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	2	0	0
Dizziness
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 13 (7.69%)	5 / 21 (23.81%)	26 / 100 (26.00%)	17 / 66 (25.76%)	0 / 17 (0.00%)
occurrences all number	0	1	0	1	0	0	0	1	1	6	34	19	0
Dysaesthesia
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	9 / 100 (9.00%)	4 / 66 (6.06%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	10	6	0
Dysgeusia
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	1 / 13 (7.69%)	1 / 21 (4.76%)	11 / 100 (11.00%)	9 / 66 (13.64%)	2 / 17 (11.76%)
occurrences all number	0	1	0	1	0	0	0	2	1	1	12	9	2
Headache
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 12 (16.67%)	1 / 13 (7.69%)	3 / 21 (14.29%)	14 / 100 (14.00%)	10 / 66 (15.15%)	0 / 17 (0.00%)
occurrences all number	0	0	2	0	0	1	0	2	1	4	20	14	0
Hyperaesthesia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	4 / 100 (4.00%)	2 / 66 (3.03%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	4	2	0
Lethargy
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	2 / 21 (9.52%)	3 / 100 (3.00%)	1 / 66 (1.52%)	1 / 17 (5.88%)
occurrences all number	1	0	0	1	0	0	0	0	0	2	3	1	1
Memory impairment
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0
Neuropathy peripheral
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	5 / 100 (5.00%)	7 / 66 (10.61%)	2 / 17 (11.76%)
occurrences all number	0	0	0	0	0	0	2	0	0	1	6	9	2
Paraesthesia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	7 / 100 (7.00%)	6 / 66 (9.09%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1	1	0	0	0	0	0	12	7	1
Peripheral sensory neuropathy
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 21 (0.00%)	1 / 100 (1.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	1	0	0
Presyncope
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	7 / 100 (7.00%)	3 / 66 (4.55%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	8	3	0
Sciatica
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Somnolence
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	1 / 21 (4.76%)	2 / 100 (2.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	2	1	0
Syncope
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	6 / 100 (6.00%)	2 / 66 (3.03%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	6	3	0
Tremor
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	6 / 100 (6.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	1	0	0	1	0	0	0	0	0	0	7	2	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 5 (40.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 12 (16.67%)	4 / 13 (30.77%)	7 / 21 (33.33%)	33 / 100 (33.00%)	27 / 66 (40.91%)	6 / 17 (35.29%)
occurrences all number	2	0	0	3	0	1	0	4	4	10	65	84	6
Febrile neutropenia
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 13 (0.00%)	1 / 21 (4.76%)	15 / 100 (15.00%)	7 / 66 (10.61%)	3 / 17 (17.65%)
occurrences all number	1	0	0	0	0	0	0	2	0	1	20	8	3
Hyperfibrinogenaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Leukocytosis
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	1 / 21 (4.76%)	4 / 100 (4.00%)	4 / 66 (6.06%)	2 / 17 (11.76%)
occurrences all number	1	0	0	0	0	0	0	0	1	1	6	4	2
Lymphadenopathy
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	1 / 66 (1.52%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	1
Neutropenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	12 / 100 (12.00%)	5 / 66 (7.58%)	2 / 17 (11.76%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	29	28	2
Thrombocytopenia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	3 / 21 (14.29%)	19 / 100 (19.00%)	12 / 66 (18.18%)	2 / 17 (11.76%)
occurrences all number	0	0	1	0	0	0	0	0	1	6	44	27	2
Ear and labyrinth disorders
Ear discomfort
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Ear pain
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 13 (0.00%)	0 / 21 (0.00%)	3 / 100 (3.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0	0	0	2	0	0	3	0	0
Eye disorders
Blepharitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	2 / 100 (2.00%)	4 / 66 (6.06%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	4	0
Cataract
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	4 / 66 (6.06%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	6	0
Cataract nuclear
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 21 (0.00%)	0 / 100 (0.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	1	0
Conjunctival haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	4 / 21 (19.05%)	3 / 100 (3.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	4	3	0	0
Dry eye
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	6 / 100 (6.00%)	8 / 66 (12.12%)	0 / 17 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	1	7	10	0
Eye oedema
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	1 / 100 (1.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	1	0	0
Eye pruritus
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	1 / 100 (1.00%)	1 / 66 (1.52%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	1	1
Glaucoma
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Lacrimation increased
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	2 / 66 (3.03%)	0 / 17 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	3	0
Periorbital oedema
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	2 / 21 (9.52%)	5 / 100 (5.00%)	3 / 66 (4.55%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	9	3	0
Retinal exudates
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0
Retinal haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	3 / 66 (4.55%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	3	0
Vision blurred
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	6 / 100 (6.00%)	5 / 66 (7.58%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	6	8	0
Vitreous detachment
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	1	0
Vitreous floaters
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	3 / 100 (3.00%)	4 / 66 (6.06%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	3	4	0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 21 (0.00%)	7 / 100 (7.00%)	1 / 66 (1.52%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	8	1	1
Abdominal pain
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 12 (8.33%)	1 / 13 (7.69%)	1 / 21 (4.76%)	15 / 100 (15.00%)	5 / 66 (7.58%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	1	0	1	1	1	1	19	6	0
Abdominal pain lower
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	1	0
Abdominal pain upper
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 21 (0.00%)	1 / 100 (1.00%)	3 / 66 (4.55%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	1	3	1
Abdominal tenderness
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Aphthous ulcer
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Colitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	2 / 100 (2.00%)	2 / 66 (3.03%)	0 / 17 (0.00%)
occurrences all number	0	0	1	0	0	0	1	0	0	0	2	2	0
Constipation
subjects affected / exposed	1 / 5 (20.00%)	1 / 3 (33.33%)	2 / 3 (66.67%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 13 (7.69%)	5 / 21 (23.81%)	32 / 100 (32.00%)	12 / 66 (18.18%)	1 / 17 (5.88%)
occurrences all number	1	1	2	1	1	1	0	2	1	5	36	14	1
Diarrhoea
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 12 (8.33%)	2 / 13 (15.38%)	5 / 21 (23.81%)	45 / 100 (45.00%)	27 / 66 (40.91%)	5 / 17 (29.41%)
occurrences all number	0	0	1	1	0	2	2	1	2	12	71	44	6
Dry mouth
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 13 (7.69%)	2 / 21 (9.52%)	10 / 100 (10.00%)	4 / 66 (6.06%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	0	1	1	2	10	4	1
Dyspepsia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 21 (0.00%)	3 / 100 (3.00%)	3 / 66 (4.55%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	3	3	0
Dysphagia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 21 (0.00%)	7 / 100 (7.00%)	2 / 66 (3.03%)	2 / 17 (11.76%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	8	2	2
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	4 / 100 (4.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	1	5	0	0
Gingival bleeding
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	1 / 21 (4.76%)	2 / 100 (2.00%)	2 / 66 (3.03%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	2	1	2	2	0
Gingival pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 21 (0.00%)	1 / 100 (1.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	1	1	0
Haemorrhoids
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 13 (7.69%)	1 / 21 (4.76%)	6 / 100 (6.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	1	1	8	1	0
Melaena
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	1 / 21 (4.76%)	1 / 100 (1.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	1	1	0	0
Mouth haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	8 / 100 (8.00%)	2 / 66 (3.03%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0	1	9	2	0
Mouth ulceration
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	4 / 100 (4.00%)	4 / 66 (6.06%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	5	5	1
Nausea
subjects affected / exposed	2 / 5 (40.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	3 / 13 (23.08%)	4 / 21 (19.05%)	28 / 100 (28.00%)	15 / 66 (22.73%)	1 / 17 (5.88%)
occurrences all number	3	0	0	3	0	0	0	1	3	5	37	22	1
Oesophagitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	1 / 100 (1.00%)	1 / 66 (1.52%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	1	1
Oral mucosal blistering
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	2 / 21 (9.52%)	1 / 100 (1.00%)	2 / 66 (3.03%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	3	2	1
Oral pain
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	2 / 100 (2.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	3	1	0
Proctalgia
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	1	0
Rectal haemorrhage
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 21 (0.00%)	4 / 100 (4.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	4	1	0
Salivary hypersecretion
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Stomatitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 12 (8.33%)	1 / 13 (7.69%)	0 / 21 (0.00%)	14 / 100 (14.00%)	8 / 66 (12.12%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	1	1	1	1	0	15	9	1
Tongue coated
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 21 (0.00%)	1 / 100 (1.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	1	0	0
Vomiting
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	1 / 13 (7.69%)	5 / 21 (23.81%)	22 / 100 (22.00%)	13 / 66 (19.70%)	1 / 17 (5.88%)
occurrences all number	1	0	0	2	0	0	0	3	1	6	31	16	1
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	2 / 21 (9.52%)	6 / 100 (6.00%)	2 / 66 (3.03%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	12	2	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	5 / 66 (7.58%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	6	0
Blood blister
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	2 / 100 (2.00%)	1 / 66 (1.52%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	2	1	1
Decubitus ulcer
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	2 / 100 (2.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	1	3	1	0
Dermatitis acneiform
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Drug eruption
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	4 / 100 (4.00%)	5 / 66 (7.58%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	4	5	0
Dry skin
subjects affected / exposed	1 / 5 (20.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	2 / 21 (9.52%)	3 / 100 (3.00%)	3 / 66 (4.55%)	0 / 17 (0.00%)
occurrences all number	1	1	0	0	0	0	0	0	0	4	5	3	0
Ecchymosis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	2 / 21 (9.52%)	8 / 100 (8.00%)	3 / 66 (4.55%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	1	0	1	0	3	8	3	1
Eccrine squamous syringometaplasia
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0
Erythema
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	2 / 21 (9.52%)	4 / 100 (4.00%)	3 / 66 (4.55%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	4	4	1
Erythema multiforme
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 21 (0.00%)	1 / 100 (1.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	1	0	0
Hyperhidrosis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	3 / 21 (14.29%)	4 / 100 (4.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	4	4	1	0
Pain of skin
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	5 / 100 (5.00%)	1 / 66 (1.52%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	5	1	1
Petechiae
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 13 (0.00%)	0 / 21 (0.00%)	14 / 100 (14.00%)	0 / 66 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1	1	0	0	4	0	0	14	0	1
Photosensitivity reaction
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 21 (0.00%)	1 / 100 (1.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	1	1	0
Pigmentation disorder
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 21 (0.00%)	1 / 100 (1.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	1	0	0
Pruritus
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	2 / 21 (9.52%)	7 / 100 (7.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	1	0	0	1	0	2	12	0	0
Rash
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 21 (0.00%)	11 / 100 (11.00%)	11 / 66 (16.67%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0	0	1	0	1	0	13	11	0
Rash maculo-papular
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	1 / 13 (7.69%)	1 / 21 (4.76%)	7 / 100 (7.00%)	3 / 66 (4.55%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	1	1	9	3	0
Rash papular
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	0	0	2	0	0	0	1
Skin lesion
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	5 / 100 (5.00%)	1 / 66 (1.52%)	2 / 17 (11.76%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	5	1	4
Swelling face
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	2 / 66 (3.03%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	2	0
Renal and urinary disorders
Dysuria
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	7 / 100 (7.00%)	3 / 66 (4.55%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	1	8	3	0
Haematuria
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	6 / 100 (6.00%)	3 / 66 (4.55%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	6	4	0
Pollakiuria
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 21 (0.00%)	7 / 100 (7.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	1	0	7	0	0
Urinary incontinence
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	4 / 100 (4.00%)	5 / 66 (7.58%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	5	6	0
Urinary retention
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	7 / 100 (7.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	8	0	0
Endocrine disorders
Hypothyroidism
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	3 / 100 (3.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	3	1	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	4 / 21 (19.05%)	16 / 100 (16.00%)	12 / 66 (18.18%)	1 / 17 (5.88%)
occurrences all number	0	0	0	1	0	0	0	0	0	4	23	15	1
Back pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	2 / 21 (9.52%)	9 / 100 (9.00%)	8 / 66 (12.12%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	2	11	9	0
Bone pain
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	1 / 21 (4.76%)	7 / 100 (7.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	1	0	0	1	0	0	0	1	0	1	7	1	0
Flank pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	1 / 100 (1.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	1	0	0
Muscle spasms
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	4 / 100 (4.00%)	3 / 66 (4.55%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	1	0	0	0	0	1	4	4	0
Muscular weakness
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 21 (0.00%)	4 / 100 (4.00%)	7 / 66 (10.61%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	1	0	4	7	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 21 (0.00%)	0 / 100 (0.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	1	0
Musculoskeletal pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	7 / 100 (7.00%)	2 / 66 (3.03%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	7	2	0
Myalgia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 13 (7.69%)	0 / 21 (0.00%)	12 / 100 (12.00%)	5 / 66 (7.58%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	1	0	0	1	1	0	14	5	0
Myopathy
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Neck pain
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 21 (0.00%)	3 / 100 (3.00%)	4 / 66 (6.06%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	3	5	0
Pain in extremity
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 3 (33.33%)	1 / 12 (8.33%)	0 / 13 (0.00%)	2 / 21 (9.52%)	11 / 100 (11.00%)	10 / 66 (15.15%)	0 / 17 (0.00%)
occurrences all number	0	1	1	0	1	1	1	1	0	3	15	13	0
Pain in jaw
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 13 (0.00%)	1 / 21 (4.76%)	0 / 100 (0.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	1	0	1	0
Infections and infestations
Abscess limb
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Bacteraemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	2 / 21 (9.52%)	2 / 100 (2.00%)	3 / 66 (4.55%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	2	3	0
Candida infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	2 / 100 (2.00%)	4 / 66 (6.06%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	4	0
Cellulitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	2 / 21 (9.52%)	1 / 100 (1.00%)	5 / 66 (7.58%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	3	1	6	0
Clostridium difficile infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	1 / 21 (4.76%)	2 / 100 (2.00%)	4 / 66 (6.06%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	2	4	0
Enterococcal bacteraemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	2 / 100 (2.00%)	1 / 66 (1.52%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	1	1
Gingivitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Herpes virus infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 21 (0.00%)	1 / 100 (1.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	1	0	0
Herpes zoster
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 21 (0.00%)	1 / 100 (1.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	1	0	0
Influenza
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	5 / 100 (5.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	5	1	0
Laryngitis fungal
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0
Lip infection
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	1 / 100 (1.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	1	0	0
Lung infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 21 (0.00%)	5 / 100 (5.00%)	2 / 66 (3.03%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	5	2	0
Oral candidiasis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	1 / 21 (4.76%)	2 / 100 (2.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0	0	0	1	0	1	2	0	0
Oral herpes
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	2	0
Pharyngitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 21 (0.00%)	1 / 100 (1.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	1	0	0
Pneumonia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	5 / 100 (5.00%)	5 / 66 (7.58%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	2	6	6	0
Sinusitis
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 12 (8.33%)	0 / 13 (0.00%)	1 / 21 (4.76%)	1 / 100 (1.00%)	2 / 66 (3.03%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	0	1	1	2	0
Skin infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	1 / 21 (4.76%)	3 / 100 (3.00%)	3 / 66 (4.55%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	1	1	3	3	0
Upper respiratory tract infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	2 / 13 (15.38%)	1 / 21 (4.76%)	5 / 100 (5.00%)	7 / 66 (10.61%)	0 / 17 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	2	1	11	9	0
Urinary tract infection
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	2 / 21 (9.52%)	5 / 100 (5.00%)	9 / 66 (13.64%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	2	7	9	0
Urinary tract infection bacterial
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	1 / 21 (4.76%)	3 / 100 (3.00%)	4 / 66 (6.06%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	4	7	0
Urinary tract infection enterococcal
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 13 (0.00%)	0 / 21 (0.00%)	1 / 100 (1.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	1	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 13 (7.69%)	3 / 21 (14.29%)	19 / 100 (19.00%)	11 / 66 (16.67%)	1 / 17 (5.88%)
occurrences all number	0	0	0	3	0	0	0	1	1	4	21	13	1
Dehydration
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 21 (0.00%)	10 / 100 (10.00%)	1 / 66 (1.52%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	2	0	10	1	0
Fluid overload
subjects affected / exposed	0 / 5 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	2 / 100 (2.00%)	2 / 66 (3.03%)	0 / 17 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	2	2	0
Fluid retention
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	2 / 100 (2.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	2	0	0
Hypercalcaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0
Hyperglycaemia
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	14 / 100 (14.00%)	5 / 66 (7.58%)	0 / 17 (0.00%)
occurrences all number	1	0	1	0	0	0	2	0	0	0	16	7	0
Hyperkalaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	1 / 13 (7.69%)	1 / 21 (4.76%)	9 / 100 (9.00%)	5 / 66 (7.58%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	1	2	10	6	0
Hyperphosphataemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	1 / 21 (4.76%)	1 / 100 (1.00%)	2 / 66 (3.03%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	2	1	2	0
Hyperuricaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	2 / 13 (15.38%)	0 / 21 (0.00%)	10 / 100 (10.00%)	4 / 66 (6.06%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	2	0	11	4	0
Hypoalbuminaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 12 (8.33%)	1 / 13 (7.69%)	4 / 21 (19.05%)	18 / 100 (18.00%)	7 / 66 (10.61%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	1	2	1	15	28	15	2
Hypocalcaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 12 (8.33%)	2 / 13 (15.38%)	3 / 21 (14.29%)	23 / 100 (23.00%)	11 / 66 (16.67%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	1	1	2	17	50	23	1
Hypochloraemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	0 / 66 (0.00%)	1 / 17 (5.88%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1
Hypoglycaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	0 / 21 (0.00%)	3 / 100 (3.00%)	2 / 66 (3.03%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	4	2	0
Hypokalaemia
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	5 / 12 (41.67%)	2 / 13 (15.38%)	2 / 21 (9.52%)	25 / 100 (25.00%)	10 / 66 (15.15%)	0 / 17 (0.00%)
occurrences all number	1	0	0	1	0	1	0	9	3	11	33	20	0
Hypomagnesaemia
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 13 (7.69%)	3 / 21 (14.29%)	17 / 100 (17.00%)	13 / 66 (19.70%)	0 / 17 (0.00%)
occurrences all number	1	0	0	0	0	0	0	2	1	3	25	19	0
Hyponatraemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 13 (7.69%)	2 / 21 (9.52%)	20 / 100 (20.00%)	8 / 66 (12.12%)	1 / 17 (5.88%)
occurrences all number	0	0	0	2	0	0	0	0	1	8	26	16	1
Hypophosphataemia
subjects affected / exposed	1 / 5 (20.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 13 (0.00%)	1 / 21 (4.76%)	11 / 100 (11.00%)	6 / 66 (9.09%)	2 / 17 (11.76%)
occurrences all number	2	0	0	0	0	0	0	1	0	1	13	10	2
Hypoproteinaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	2 / 100 (2.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	2	0	0
Hypovolaemia
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	2 / 100 (2.00%)	0 / 66 (0.00%)	0 / 17 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	2	0	0
Iron overload
subjects affected / exposed	0 / 5 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 13 (0.00%)	0 / 21 (0.00%)	0 / 100 (0.00%)	4 / 66 (6.06%)	0 / 17 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	4	0

More information

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Were there any global substantial amendments to the protocol? Yes

16 Jul 2013

The changes include: ● Revised the first primary objective to determination of MTD rather than determination of DLT. ● Added clarifying text to better describe the dose escalation cohort (Cohort 1) and the dose expansion cohort (Cohort 2), Schedule of Assessments, and Intrapatient escalation and reduction. ● Amended exclusion criteria No. 4 to read on-going grade 2 or greater toxicity from prior therapy would prohibit participation in this first-in-human-trial. Amended exclusion criteria No. 5 to clarify that timing of the transplant is within 2 months from cycle 1 day 1. Added exclusion criteria No. 12 to respond to the lack of available pharmacokinetic data to determine potential pharmacodynamic drug interactions. Therefore, this exclusion criterion excludes patients treated with concomitant medications targeting serotonin 5-hydroxytryptamine receptor 1 (5HT1R) or 5-hydroxytryptamine 2B receptors (5HT2BRs) or sigma nonspecific receptors. ● Added text prohibiting any other treatment AML during therapy with gilteritinib with the exception of hydroxyurea up to 2 g daily to keep the absolute blast count below 50000. ● Amended the text regarding grade 3 nonhematologic toxicity, grade 3 nausea, and hematologic toxicity related to prolonged myelosuppression to include parameters of absolute neutrophil counts (ANC) < 500 for more than 21 days. ● Provided clarification on the description of “no clinical benefit” to indicate patients will be taken off treatment if there is no clinical response after 2 cycles of therapy. ● Removed the reference to a patient dosing diary for cycle 1. ● Revised continuous reassessment method (CRM) to Bayesian logistic regression modeling throughout the protocol. ● Primary endpoint was revised to reflect tolerability as the true endpoint, deleting text specific to determination of DLTs as the description of DLT is already outlined in the protocol.

16 Jul 2013

The changes include(cont'd): ● Added text identifying Cohort 1 as the escalation Cohort and the DLT observation period for this cohort is 30 days. Amended the Schedule of Assessments to include assessment of thyroid function studies as well as cycle 1 day 4 assessments for institutional standard of care lab testing. Added Interactive Response Technology (IRT) transaction dates and investigational product (IP) dispensing dates for when site visits include sending the patient home with IP. ● The description of the study drug packaging and labeling was changed to reflect new configuration of 14 tablets per blister card. ● Dose modification guidelines in Protocol Section 5.1.2 were further outlined to include hematologic toxicities and 2 tables were added. Protocol Table 7 was revised to describe Dose Reduction guidelines. Protocol Table 8 was developed to describe Dose Escalation guidelines. ● Added thyroid function tests to the chemistry panel. ● Protocol Appendix 12.1 describing the lists of prohibited medications was revised to include a nonexhaustive list of drugs targeting serotonin receptors and to provide guidance that a list of drugs that target sigma nonspecific receptor is not available, but that Investigators must be responsible for consulting drug label information when prescribing concomitant medications. ● Updated the common serious AEs in AML by revising the list to include the events of pneumonia, sinusitis and bleeding hemorrhage.

21 Jan 2014

The changes include(cont'd): ● Updated the instructions for missed doses and moved the instructions to the appropriate section in protocol. ● Clarified the required assessments and frequency of assessments after a patient dose escalation event. ● Clarified the Sponsor reporting requirements for treatment compliance deviations. ● Removed reticulocyte parameter from the hematology panel. Updated bone marrow text to read aspirate and biopsy. Corrected tube size and type for phosphorylation samples. Corrected the coagulation tests being performed. Corrected tube size for chemistry and coagulation samples. ● For visual acuity (VA) measurements, allow for the use of early treatment diabetic retinopathy study (ETDRS) or Snellen charts. ● Updated the total blood volumes as listed in Section 5.8. ● Corrected full analysis set (FAS) definition to read “The FAS will consist of all patients who are enrolled and receive at least 1 dose of study drug and who have at least 1 posttreatment data point. This will be the primary analysis set for efficacy analyses.” ● Added Ophthalmologic Assessment section to Analysis of Safety. ● Clarified that individual patient data will be reviewed at the dose escalation meetings.

21 Jan 2014

The changes include: ● Moved pharmacodynamic parameters from secondary to exploratory endpoints. Removed STAT5 and added S6 phosphorylation to pharmacodynamics parameters. Added event-free survival to secondary endpoints. ● Study design was updated to allow changing to a modified 3 + 3 design and testing all dose levels based on the recommendation of the dose escalation committee’s assessment of pharmacokinetic data. ● Included additional patient replacement guidance to the protocol. ● For pharmacokinetic, pharmacodynamic and PIA samples, added the following collection windows: o Predose – Within 30 minutes before drug administration o Post dose 0.5, 1, and 2 hours – Within ± 10 minutes of nominal time o Post dose 4 and 6 hours – Within ± 20 minutes of nominal time o Post dose 24 hours – Within ± 90 minutes of nominal time ● For ophthalmologic assessments, a ± 3-day window for the procedure was added for all assessments after screening. ● Changed the text ‘Bone Marrow Aspiration or Biopsy’ to ‘Bone Marrow Aspiration and Biopsy’ in the Protocol Schedule of Assessments, applicable footnotes and protocol text. ● In Protocol Schedule of Assessments 2B and throughout the protocol, the CYP3A4 inhibitor, voriconazole (200 mg oral q 12 hours) was specified. In addition, voriconazole was to be provided by Astellas. ● In Protocol Schedule of Assessments 2D and throughout the protocol, the dose and route (2 mg of syrup [1.0 mL] by mouth) for midazolam was specified. In addition, midazolam was to be provided by Astellas. ● Updated the Protocol Table titles for 2B, 2C and 2D to be consistent with titles listed in Section 5.6.1 Pharmacokinetics. Added S6 Phosphorylation and removed STAT5. ● Added information on AXL and its role in AML, with supporting literature to Introduction and Literature sections, respectively. ● Added Cohort 1 instructions for use of the IRT system.

28 Jan 2014

The changes include: The limit on the maximum dose of hydroxyurea that can be used was increased to 5 g, and the duration was limited to 2 weeks.

19 May 2014

The changes include (cont'd):● Added text allowing patients that have a contraindication to voriconazole and/or midazolam to participate without the DDI component. ● Added text allowing the voriconazole DDI study to be conducted at the next lowest dose level if the original dose level was closed before 12 patients participated in the DDI study. ● Allowed for a Chest X-ray performed within 2 weeks of screening to be used to fulfill the screening requirement. ● Added a footnote to the bone marrow biopsy, which allows for the procedure not to be repeated if collected within 2 weeks of the visit to the Protocol Posttreatment Schedule of Assessments. ● Added a line item for the end of treatment IRT transaction to the Protocol Posttreatment Schedule of Assessments. ● Added a ± 1 day visit window for the weekly assessment visits after a patient dose escalation event. ● Clarified that the initial 15 day restriction on CYP3A4 inhibitor use in Cohort 2 was limited to patients randomized to Protocol Table 2B: Schedule of Assessments with CYP3A4 inhibitor voriconazole and Protocol Table 2D: Schedule of Assessments with CYP3A4 induction study. ● Amended protocol to allow gilteritinib to be available in 10, 40 and 100 mg tablets. Study drug in US continued to be packaged as blistered 10 and 100 mg tablets and incorporated 40 mg tablets provided in bottles. ● Restricted Cohort 2 DDI study participation to US only.

07 Jul 2014

The changes include: ● Updated the number of patients. ● Further expanded select dose levels for efficacy evaluation. ● Modified the allowable collection window for screening bone marrow to 21 days. ● Modified the rescreening restrictions from the protocol to allow for up to 2 rescreenings of a patient. ● Corrected inclusion criteria No. 5 by removing the waiting period for immunosuppression therapies.

23 Sep 2014

The changes include: ● Modified the discontinuation criteria to allow patients experiencing clinical benefit but that have not achieved partial response or CRc to remain on treatment. ● Allowed re-enrollment of patients who discontinued treatment for reasons other than toxicity or disease progression.

15 Dec 2014

The changes include: ● Updated the number of patients to reflect the actual enrollment to Cohort 1 and an increase in the total number patients to be enrolled in the dose expansion for Cohort 2. ● Revised required duration for birth control and ova donation for women from 30 days to 45 days and birth control and semen donation for men from 90 to 105 days. ● Restricted the use of strong inhibitors or inducers of P-glycoprotein (P-gp) and MATE1, and added precautions around concomitant use of substrates of other CYP enzymes, P-gp and breast cancer resistance protein. ● Allowed patients to resume treatment with gilteritinib after hematopoietic stem cell transplant (HSCT). ● Added safety data from an interim analysis of Study 2215-CL-0101 to the protocol. ● Removed the restriction that allowed Cohort 2 patients to dose escalate only once. ● Updated protocol to require discussion with the Medical Monitor before resumption of treatment for patients who have drug interruptions of greater than 15 days for events unrelated to study drug. ● Added aldolase to the chemistry panel for the central laboratory. ● Included language that additional testing for metabolites of gilteritinib may be performed.

26 May 2015

The changes include: ● Added MATE1 Substrate Drug-drug Interaction Substudy for US sites only. ● Removed electroretinography examination. ● Updated safety data from an interim analysis of Study 2215-CL-0101 to the protocol. ● Required patients in CRc to only have bone marrow collections every 3 cycles for 1 year following study start. After that, bone marrow were only required as clinically indicated and at end of study. ● Changed definition of red blood cell (RBC) transfusion independence from 4 weeks without infusion to 1 week.

18 Aug 2015

The changes include: ● Removed statement requiring 15 evaluable patients to be enrolled in the Cohort 2 MATE1 substudy. ● Three new exclusion criteria were added related to screening electrocardiogram (ECG) and laboratory results: o Exclusion criteria number 11 was added to exclude patients with mean Fridericia-corrected QT interval (QTcF) > 450 msec at screening based on central reading. o Exclusion criteria number 12 was added to exclude patients with long corrected QT interval (QTc) syndrome at screening. o Exclusion criteria number 13 was added to exclude patients with hypokalemia and hypomagnesemia at screening (defined as values below the lower limit of normal [LLN]). ● Added a confirmatory ECG to be performed on day 9 and an Investigator assessment to consider a dose reduction for a patient if the mean QTcF for a patient from day 1 to day 8 has increased > 30 msec with no other known etiology. ● Clarified that the mean QTcF of the triplicate ECG tracings based on central reading would be used for all treatment decisions. ● Added a criterion to the dose medication modification category: Consider reducing dose of gilteritinib if the mean QTcF from day 1 to day 8 has increased > 30 msec and this is confirmed on day 9 and without any other etiology. ● Revised dose reduction criteria related to grade 3 events related to gilteritinib.

02 Jun 2017

The changes include: ● Revised study design: o Subjects who were receiving ASP2215 treatment and did not meet any 2215- CL-0101 discontinuation criteria may have been eligible to continue to receive ASP2215 treatment in a rollover study, 2215-CL-0109. o Subjects who chose not to participate or were not eligible for Study 2215-CL-0109 completed their participation in Study 2215-CL-0101 by completing the End of Treatment follow-up visit upon activation of Study 2215-CL-0109 at the institution. o Subjects in Study 2215-CL-0101 who were being followed for Long-term Follow-up at the time of study closure will be discontinued from any further follow-up. ● Concomitant medication guidelines were updated to exclude strong inducers of cytochrome P450 (CYP) 3A, strong inhibitors or inducers of P-gp and drugs that target 5HT1R and 5HT2BR receptors. Drugs known to prolong QT or QTc intervals should be used with caution. Updated list of excluded concomitant medications. ● Updated contact details of key sponsor’s personnel. ● Updated the study period to current planned end date of 2017. ● Three inclusion criteria were updated related to pregnancy and contraception: o For female subjects the period after study participation during which the subject cannot become pregnant or donate ova was lengthened from 45 days to 180 days and for breastfeeding was lengthened from 45 days to 60 days. o For male subjects the period after study participation during which the subject must use contraception and not donate sperm was lengthened from 105 days to 120 days. o For female subjects and female partners of male subjects, pregnancy reporting was lengthened from 90 to 180 days from the discontinuation of dosing. ● Minor administrative-type changes, e.g., typos, format, numbering, consistency were made throughout the protocol.

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.

None reported

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Clinical trials

Clinical Trial Results: A Phase 1/2 Open-Label, Dose Escalation Study Investigating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ASP2215 in Patients with Relapsed or Refractory Acute Myeloid Leukemia

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Participants with Dose Limiting Toxicities (DLTs)

Primary: Number of Participants with Dose Limiting Toxicities (DLTs)

Primary: Number of Participants with Adverse Events (AEs)

Primary: Number of Participants with Adverse Events (AEs)

Primary: Area Under the Concentration-time Curve Over the 24-Hour Dosing Interval (AUC24) after Single and Multiple Doses of Gilteritinib

Primary: Area Under the Concentration-time Curve Over the 24-Hour Dosing Interval (AUC24) after Single and Multiple Doses of Gilteritinib

Primary: Maximum Concentration (Cmax) after Single and Multiple Doses of Gilteritinib

Primary: Maximum Concentration (Cmax) after Single and Multiple Doses of Gilteritinib

Primary: Area Under the Concentration-time Curve from the Time of Dosing to the Last Measurable Concentration (AUClast) after Single and Multiple Doses of Gilteritinib

Primary: Area Under the Concentration-time Curve from the Time of Dosing to the Last Measurable Concentration (AUClast) after Single and Multiple Doses of Gilteritinib

Primary: Time to Observed Cmax (tmax) after Single and Multiple Doses of Gilteritinib

Primary: Time to Observed Cmax (tmax) after Single and Multiple Doses of Gilteritinib

Primary: Terminal Elimination Half-life (t1/2) After Multiple Doses of Gilteritinib

Primary: Terminal Elimination Half-life (t1/2) After Multiple Doses of Gilteritinib

Primary: Accumulation Ratio After Multiple Doses of Gilteritinib

Primary: Accumulation Ratio After Multiple Doses of Gilteritinib

Secondary: Percentage of Participants with Complete Remission (CR) During the First 2 Cycles

Secondary: Percentage of Participants with Complete Remission (CR) During the First 2 Cycles

Secondary: Percentage of Participants with CR During Treatment

Secondary: Percentage of Participants with CR During Treatment

Secondary: Percentage of Participants with CR with Incomplete Platelet Recovery (CRp)

Secondary: Percentage of Participants with CR with Incomplete Platelet Recovery (CRp)

Secondary: Percentage of Participants with CR with Incomplete Hematological Recovery (CRi)

Secondary: Percentage of Participants with CR with Incomplete Hematological Recovery (CRi)

Secondary: Percentage of Participants with Complete Remission with Partial Hematologic Recovery (CRh)

Secondary: Percentage of Participants with Complete Remission with Partial Hematologic Recovery (CRh)

Secondary: Percentage of Participants with Composite CR (CRc)

Secondary: Percentage of Participants with Composite CR (CRc)

Secondary: Percentage of Participants with Partial Remission (PR)

Secondary: Percentage of Participants with Partial Remission (PR)

Secondary: Percentage of Participants with Best Response

Secondary: Percentage of Participants with Best Response

Secondary: Percentage of Participants with Complete Remission and Complete Remission with Partial Hematologic Recovery (CR/CRh)

Secondary: Percentage of Participants with Complete Remission and Complete Remission with Partial Hematologic Recovery (CR/CRh)

Secondary: Duration of CR (DCR)

Secondary: Duration of CR (DCR)

Secondary: Duration of CRp (DCRp)

Secondary: Duration of CRp (DCRp)

Secondary: Duration of CRi (DCRi)

Secondary: Duration of CRi (DCRi)

Secondary: Duration of CRh (DCRh)

Secondary: Duration of CRh (DCRh)

Secondary: Duration of CRc (DCRc)

Secondary: Duration of CRc (DCRc)

Secondary: Duration of CR/CRh (DCRCRh)

Secondary: Duration of CR/CRh (DCRCRh)

Secondary: Duration of Response

Secondary: Duration of Response

Secondary: Time to CR (TTCR)

Secondary: Time to CR (TTCR)

Secondary: Time to CRp (TTCRp)

Secondary: Time to CRp (TTCRp)

Secondary: Time to CRi (TTCRi)

Secondary: Time to CRi (TTCRi)

Secondary: Time to First CR/CRh (TTFCRCRh)

Secondary: Time to First CR/CRh (TTFCRCRh)

Secondary: Time to Best CR/CRh (TTBCRCRh)

Secondary: Time to Best CR/CRh (TTBCRCRh)

Secondary: Time to CRc (TTCRc)

Secondary: Time to CRc (TTCRc)

Secondary: Time to Response (TTR)

Secondary: Time to Response (TTR)

Secondary: Time to Best Response (TTBR)

Secondary: Time to Best Response (TTBR)

Secondary: Overall Survival (OS)

Secondary: Overall Survival (OS)

Secondary: Event Free Survival (EFS)

Secondary: Event Free Survival (EFS)

Secondary: Leukemia Free Survival (LFS)

Secondary: Leukemia Free Survival (LFS)

Clinical Trial Results:
A Phase 1/2 Open-Label, Dose Escalation Study Investigating the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of ASP2215 in Patients with Relapsed or Refractory Acute Myeloid Leukemia