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Clinical Trial Results:
A Phase I/II Study to Assess the Safety and Efficacy of MK-3475 in Combination with Trametinib and Dabrafenib in Subjects with Advanced Melanoma

Summary
EudraCT number	2015-000681-55
Trial protocol	DK IT
Global end of trial date	14 Jul 2021

Results information
Results version number	v1(current)
This version publication date	17 Jul 2022
First version publication date	17 Jul 2022
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

3475-022

ISRCTN number

US NCT number

NCT02130466

WHO universal trial number (UTN)

Sponsor organisation name

Merck Sharp & Dohme LLC

Sponsor organisation address

126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ, United States, 07065

Public contact

Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com

Scientific contact

Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.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

14 Jul 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

14 Jul 2021

Global end of trial reached?

Yes

Global end of trial date

14 Jul 2021

Was the trial ended prematurely?

Main objective of the trial

This was a 5-part dose-finding/efficacy study of pembrolizumab(Pembro)+dabrafenib(D)+trametinib(T) in participants with advanced melanoma (BRAF mutant or wild-type) and solid tumors. The parts follow: Parts (P) 1, 2 (melanoma): determined the maximum tolerated dose (MTD)/maximum administered dose (MAD) for Pembro+D+T and dose confirmation; P3 (melanoma): Pembro+D+T versus placebo+D+T; P4 (melanoma or solid tumors): determined the MTD/MAD of Pembro+T; and P5 (melanoma or solid tumors): confirmation of dose(s) in P4 and evaluated the safety/efficacy of Pembro+T. The P5 expansion cohort was not pursued with Amendment 5 (21-Mar-2019). The primary hypotheses for P1, 2, 4, 5 were that treatment regimens were sufficiently well-tolerated to permit clinical investigation. P3 was that Pembro+D+T improved progression-free survival compared with placebo+D+T. P1, 2 planned to explore backup combinations, if needed, of Pembro+T or Pembro+D concurrently with the Pembro+D+T arm.

Protection of trial subjects

This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.

Background therapy

Evidence for comparator

Actual start date of recruitment

29 May 2014

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 35

Country: Number of subjects enrolled

Canada: 16

Country: Number of subjects enrolled

Denmark: 14

Country: Number of subjects enrolled

Israel: 18

Country: Number of subjects enrolled

Italy: 59

Country: Number of subjects enrolled

New Zealand: 12

Country: Number of subjects enrolled

United States: 30

Worldwide total number of subjects

184

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)

124

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

For Parts 1 and 2 of the study the optional pembrolizumab+trametinib arm was added to the study but the optional pembrolizumab+dabrafenib arm was not implemented.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Part 1:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg

Arm description

Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by intravenous (IV) infusion on Days 1 and 22 of each 6-week cycle (Q6W); 150 mg/day total dabrafenib orally, in a divided dose, twice a day (BID) starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally once a day (QD) starting on Day 1 and continuing up until study treatment discontinuation.

Arm type

Experimental

Investigational medicinal product name

pembrolizumab

Investigational medicinal product code

Other name

MK-3475 KEYTRUDA®

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

2 mg/kg pembrolizumab administered by intravenous (IV) infusion on Days 1 and 22 of each 6-week cycle (Q6W) continuing up until study treatment discontinuation

Investigational medicinal product name

dabrafenib

Investigational medicinal product code

Other name

TAFINLAR®

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

150 mg/day total dabrafenib administered orally, in a divided dose, twice a day (BID) starting on Day 1 and continuing up until study treatment discontinuation

Investigational medicinal product name

trametinib

Investigational medicinal product code

Other name

MEKINIST®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

2 mg trametinib administered orally once a day (QD) starting on Day 1 and continuing up until study treatment discontinuation

Part 1:pembrolizumab 2 mg/kg+trametinib 2 mg

Arm description

Participants with BRAF wild-type melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.

Arm type

Experimental

Investigational medicinal product name

pembrolizumab

Investigational medicinal product code

Other name

MK-3475 KEYTRUDA®

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W continuing up until study treatment discontinuation

Investigational medicinal product name

trametinib

Investigational medicinal product code

Other name

MEKINIST®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

2 mg trametinib administered orally QD starting on Day 1 and continuing up until study treatment discontinuation

Part 1:pembrolizumab 2 mg/kg+trametinib 1.5 mg

Arm description

Participants with BRAF wild-type melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W and 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.

Arm type

Experimental

Investigational medicinal product name

trametinib

Investigational medicinal product code

Other name

MEKINIST®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

1.5 mg trametinib administered orally QD starting on Day 1 and continuing up until study treatment discontinuation

Investigational medicinal product name

pembrolizumab

Investigational medicinal product code

Other name

MK-3475 KEYTRUDA®

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W continuing up until study treatment discontinuation

Part 2:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg

Arm description

Participants with BRAF mutant melanoma received 2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.

Arm type

Experimental

Investigational medicinal product name

pembrolizumab

Investigational medicinal product code

Other name

MK-3475 KEYTRUDA®

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W continuing up until study treatment discontinuation

Investigational medicinal product name

trametinib

Investigational medicinal product code

Other name

MEKINIST®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

2 mg trametinib administered orally QD starting on Day 1 and continuing up until study treatment discontinuation

Investigational medicinal product name

dabrafenib

Investigational medicinal product code

Other name

TAFINLAR®

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

150 mg/day total dabrafenib administered orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation

Part 2:pembrolizumab 2 mg/kg+trametinib 1.5 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

pembrolizumab

Investigational medicinal product code

Other name

MK-3475 KEYTRUDA®

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W continuing up until study treatment discontinuation

Investigational medicinal product name

trametinib

Investigational medicinal product code

Other name

MEKINIST®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

1.5 mg trametinib administered orally QD starting on Day 1 and continuing up until study treatment discontinuation

Part 3:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

pembrolizumab

Investigational medicinal product code

Other name

MK-3475 KEYTRUDA®

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

2 mg/kg pembrolizumab administered by IV infusion on Days 1 and 22 Q6W continuing up until study treatment discontinuation

Investigational medicinal product name

trametinib

Investigational medicinal product code

Other name

MEKINIST®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

2 mg trametinib administered orally QD starting on Day 1 and continuing up until study treatment discontinuation

Investigational medicinal product name

dabrafenib

Investigational medicinal product code

Other name

TAFINLAR®

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

150 mg/day total dabrafenib administered orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation

Part 3:placebo+dabrafenib 150 mg+trametinib 2 mg

Arm description

Participants with BRAF mutant melanoma received saline placebo administered by IV infusion on Days 1 and 22 Q6W; 150 mg/day total dabrafenib orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation; and 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.

Arm type

Placebo

Investigational medicinal product name

placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

saline placebo administered by IV infusion on Days 1 and 22 Q6W continuing up until study treatment discontinuation

Investigational medicinal product name

trametinib

Investigational medicinal product code

Other name

MEKINIST®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

2 mg trametinib administered orally QD starting on Day 1 and continuing up until study treatment discontinuation

Investigational medicinal product name

dabrafenib

Investigational medicinal product code

Other name

TAFINLAR®

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

150 mg/day total dabrafenib administered orally, in a divided dose, BID starting on Day 1 and continuing up until study treatment discontinuation

Part 4:4 weeks trametinib (Tra) 2mg; pembrolizumab+Tra 2mg

Arm description

Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 4 weeks. Starting with Week 5, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 of each 3-week cycle (Q3W) and a concurrent dosing schedule of 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.

Arm type

Experimental

Investigational medicinal product name

pembrolizumab

Investigational medicinal product code

Other name

MK-3475 KEYTRUDA®

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

200 mg pembrolizumab administered by IV infusion on Day 29 and continuing every 3 weeks (Q3W) up until study treatment discontinuation

Investigational medicinal product name

trametinib

Investigational medicinal product code

Other name

MEKINIST®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

2 mg trametinib administered orally QD starting on Day 1 and continuing up until study treatment discontinuation

Part 4:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg

Arm description

Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.

Arm type

Experimental

Investigational medicinal product name

trametinib

Investigational medicinal product code

Other name

MEKINIST®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

1.5 mg trametinib administered orally QD starting on Day 1 and continuing up until study treatment discontinuation

Investigational medicinal product name

pembrolizumab

Investigational medicinal product code

Other name

MK-3475 KEYTRUDA®

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

200 mg pembrolizumab administered by IV infusion on Day 15 and continuing Q3W up until study treatment discontinuation

Part 4:4 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg

Arm description

Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 4 weeks. Starting with Week 5, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 1.5 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.

Arm type

Experimental

Investigational medicinal product name

pembrolizumab

Investigational medicinal product code

Other name

MK-3475 KEYTRUDA®

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

200 mg pembrolizumab administered by IV infusion on Day 29 and continuing Q3W up until study treatment discontinuation

Investigational medicinal product name

trametinib

Investigational medicinal product code

Other name

MEKINIST®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

1.5 mg trametinib administered orally QD starting on Day 1 and continuing up until study treatment discontinuation

Part 4:2 weeks Tra 2mg; pembrolizumab+Tra 2mg intermittent

Arm description

Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 2 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation.

Arm type

Experimental

Investigational medicinal product name

trametinib

Investigational medicinal product code

Other name

MEKINIST®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

2 mg trametinib administered orally QD for 2 weeks then, starting with Week 3, an intermittent dosing schedule of 2 mg trametinib administered orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation

Investigational medicinal product name

pembrolizumab

Investigational medicinal product code

Other name

MK-3475 KEYTRUDA®

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

200 mg pembrolizumab administered by IV infusion on Day 15 and continuing Q3W up until study treatment discontinuation

Part 4:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg intermittent

Arm description

Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 1.5 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation.

Arm type

Experimental

Investigational medicinal product name

trametinib

Investigational medicinal product code

Other name

MEKINIST®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

1.5 mg trametinib administered orally QD for 2 weeks then, starting with Week 3, an intermittent dosing schedule of 1.5 mg trametinib administered orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation

Investigational medicinal product name

pembrolizumab

Investigational medicinal product code

Other name

MK-3475 KEYTRUDA®

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

200 mg pembrolizumab administered by IV infusion on Day 15 and continuing Q3W up until study treatment discontinuation

Part 5:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg

Arm description

Arm type

Experimental

Investigational medicinal product name

trametinib

Investigational medicinal product code

Other name

MEKINIST®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

1.5 mg trametinib administered orally QD starting on Day 1 and continuing up until study treatment discontinuation

Investigational medicinal product name

pembrolizumab

Investigational medicinal product code

Other name

MK-3475 KEYTRUDA®

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

200 mg pembrolizumab administered by IV infusion on Day 15 and continuing Q3W up until study treatment discontinuation

Part 5:2 weeks Tra 2mg; pembrolizumab+Tra 2mg intermittent

Arm description

Arm type

Experimental

Investigational medicinal product name

pembrolizumab

Investigational medicinal product code

Other name

MK-3475 KEYTRUDA®

Pharmaceutical forms

Solution for injection/infusion

Routes of administration

Intravenous use

Dosage and administration details

200 mg pembrolizumab administered by IV infusion on Day 15 and continuing Q3W up until study treatment discontinuation

Investigational medicinal product name

trametinib

Investigational medicinal product code

Other name

MEKINIST®

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Number of subjects in period 1	Part 1:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg	Part 1:pembrolizumab 2 mg/kg+trametinib 2 mg	Part 1:pembrolizumab 2 mg/kg+trametinib 1.5 mg	Part 2:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg	Part 2:pembrolizumab 2 mg/kg+trametinib 1.5 mg	Part 3:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg	Part 3:placebo+dabrafenib 150 mg+trametinib 2 mg	Part 4:4 weeks trametinib (Tra) 2mg; pembrolizumab+Tra 2mg	Part 4:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg	Part 4:4 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg	Part 4:2 weeks Tra 2mg; pembrolizumab+Tra 2mg intermittent	Part 4:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg intermittent	Part 5:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg	Part 5:2 weeks Tra 2mg; pembrolizumab+Tra 2mg intermittent
Started	7	3	2	8	2	60	60	3	4	5	6	3	12	9
Treated	7	3	2	8	2	60	60	3	4	5	6	3	12	9
Completed	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Not completed	7	3	2	8	2	60	60	3	4	5	6	3	12	9
Adverse event, serious fatal	4	1	1	3	2	30	45	2	3	4	5	3	11	7
Consent withdrawn by subject	1	-	-	-	-	1	-	-	1	-	-	-	-	-
Physician decision	-	-	-	-	-	1	1	-	-	-	-	-	-	-
Lost to follow-up	1	-	-	-	-	1	-	-	-	-	-	-	1	-
Participation in Study Discontinued by Sponsor	1	2	1	5	-	27	14	1	-	1	1	-	-	2

Baseline characteristics

Top of page

Reporting group title

Part 1:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg

Reporting group description

Reporting group title

Part 1:pembrolizumab 2 mg/kg+trametinib 2 mg

Reporting group description

Reporting group title

Part 1:pembrolizumab 2 mg/kg+trametinib 1.5 mg

Reporting group description

Reporting group title

Part 2:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg

Reporting group description

Reporting group title

Part 2:pembrolizumab 2 mg/kg+trametinib 1.5 mg

Reporting group description

Reporting group title

Part 3:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg

Reporting group description

Reporting group title

Part 3:placebo+dabrafenib 150 mg+trametinib 2 mg

Reporting group description

Reporting group title

Part 4:4 weeks trametinib (Tra) 2mg; pembrolizumab+Tra 2mg

Reporting group description

Reporting group title

Part 4:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg

Reporting group description

Reporting group title

Part 4:4 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg

Reporting group description

Reporting group title

Part 4:2 weeks Tra 2mg; pembrolizumab+Tra 2mg intermittent

Reporting group description

Reporting group title

Part 4:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg intermittent

Reporting group description

Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 1.5 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation.

Reporting group title

Part 5:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg

Reporting group description

Reporting group title

Part 5:2 weeks Tra 2mg; pembrolizumab+Tra 2mg intermittent

Reporting group description

Reporting group values	Part 1:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg	Part 1:pembrolizumab 2 mg/kg+trametinib 2 mg	Part 1:pembrolizumab 2 mg/kg+trametinib 1.5 mg	Part 2:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg	Part 2:pembrolizumab 2 mg/kg+trametinib 1.5 mg	Part 3:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg	Part 3:placebo+dabrafenib 150 mg+trametinib 2 mg	Part 4:4 weeks trametinib (Tra) 2mg; pembrolizumab+Tra 2mg	Part 4:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg	Part 4:4 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg	Part 4:2 weeks Tra 2mg; pembrolizumab+Tra 2mg intermittent	Part 4:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg intermittent	Part 5:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg	Part 5:2 weeks Tra 2mg; pembrolizumab+Tra 2mg intermittent	Total
Number of subjects	7	3	2	8	2	60	60	3	4	5	6	3	12	9	184
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Adults (18-64 years)	5	2	0	7	0	44	37	3	3	3	4	2	7	7	124
From 65-84 years	2	1	2	1	1	16	23	0	1	2	2	1	5	2	59
85 years and over	0	0	0	0	1	0	0	0	0	0	0	0	0	0	1
Age Continuous
Units: years
arithmetic mean (standard deviation)	52.0 ( 14.0 )	54.0 ( 15.7 )	68.0 ( 2.8 )	42.0 ( 14.2 )	83.0 ( 5.7 )	55.3 ( 12.0 )	57.2 ( 14.6 )	47.3 ( 19.9 )	50.0 ( 18.0 )	57.0 ( 18.0 )	55.5 ( 17.9 )	58.0 ( 12.2 )	55.7 ( 14.1 )	55.9 ( 13.3 )	-
Sex: Female, Male
Units: Participants
Female	3	0	1	5	0	27	24	0	2	3	5	2	8	6	86
Male	4	3	1	3	2	33	36	3	2	2	1	1	4	3	98
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Asian	0	0	0	0	0	0	1	1	0	0	1	1	1	0	5
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Black or African American	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
White	7	3	2	8	2	60	59	2	4	5	5	2	11	9	179
More than one race	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Unknown or Not Reported	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	0	0	0	0	0	0	1	0	0	2	0	0	0	0	3
Not Hispanic or Latino	7	3	2	7	2	57	57	3	2	2	4	2	12	9	169
Unknown or Not Reported	0	0	0	1	0	3	2	0	2	1	2	1	0	0	12
BRAF Mutation Status
BRAF mutation testing was required for study inclusion and was done using methodology that detects both V600E and V600K mutations. Tumors that were BRAF mutation positive (V600 E or K) were eligible for treatment with pembrolizumab + trametinib + dabrafenib or trametinib + dabrafenib. Tumors that were BRAF mutation negative (wild type) were eligible for treatment with pembrolizumab + trametinib.
Units: Subjects
Mutant (BRAF Positive)	7	0	0	8	0	60	60	0	0	0	0	0	0	0	135
Wild Type (BRAF Negative)	0	3	2	0	2	0	0	1	1	0	2	1	5	5	22
Undetermined	0	0	0	0	0	0	0	0	1	2	2	0	6	1	12
Data Missing	0	0	0	0	0	0	0	2	2	3	2	2	1	3	15

End points

Top of page

Reporting group title

Part 1:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg

Reporting group description

Reporting group title

Part 1:pembrolizumab 2 mg/kg+trametinib 2 mg

Reporting group description

Reporting group title

Part 1:pembrolizumab 2 mg/kg+trametinib 1.5 mg

Reporting group description

Reporting group title

Part 2:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg

Reporting group description

Reporting group title

Part 2:pembrolizumab 2 mg/kg+trametinib 1.5 mg

Reporting group description

Reporting group title

Part 3:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg

Reporting group description

Reporting group title

Part 3:placebo+dabrafenib 150 mg+trametinib 2 mg

Reporting group description

Reporting group title

Part 4:4 weeks trametinib (Tra) 2mg; pembrolizumab+Tra 2mg

Reporting group description

Reporting group title

Part 4:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg

Reporting group description

Reporting group title

Part 4:4 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg

Reporting group description

Reporting group title

Part 4:2 weeks Tra 2mg; pembrolizumab+Tra 2mg intermittent

Reporting group description

Reporting group title

Part 4:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg intermittent

Reporting group description

Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 1.5 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation.

Reporting group title

Part 5:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg

Reporting group description

Reporting group title

Part 5:2 weeks Tra 2mg; pembrolizumab+Tra 2mg intermittent

Reporting group description

Subject analysis set title

Pooled Parts 1+2:pembrolizumab+dabrafenib+1.5/2 mg trametinib

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants pooled from Parts 1 and 2 received 2 mg/kg pembrolizumab in combination with dabrafenib and 2 mg trametinib OR 2 mg/kg pembrolizumab and 1.5 or 2 mg trametinib (without dabrafenib) Q6W continuing up until study treatment discontinuation.

Subject analysis set title

Part 3: 2 mg/kg pembrolizumab+dabrafenib+trametinib

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received 2 mg/kg pembrolizumab in combination with 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.

Subject analysis set title

Part 3: placebo+dabrafenib+trametinib

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received saline placebo in combination with 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.

Subject analysis set title

Part 4: 200 mg pembrolizumab+trametinib

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received 2 mg or 1.5 mg trametinib orally QD for 2 or 4 weeks (depending on treatment regimen). Starting with Week 3 or 5 (depending on initial trametinib interval), participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of trametinib orally QD continuing up until study treatment discontinuation.

Subject analysis set title

Part 5: 200 mg pembrolizumab+trametinib

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received 2 mg or 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of trametinib orally QD continuing up until study treatment discontinuation.

Subject analysis set title

Part 4: 200 mg pembrolizumab+2 mg trametinib

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received 2 mg trametinib orally QD for 2 or 4 weeks (depending on treatment regimen). Starting with Week 3 or 5 (depending on initial trametinib interval), participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of 2 mg trametinib orally QD continuing up until study treatment discontinuation.

Subject analysis set title

Part 4: 200 mg pembrolizumab+1.5 mg trametinib

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received 1.5 mg trametinib orally QD for 2 or 4 weeks (depending on treatment regimen). Starting with Week 3 or 5 (depending on initial trametinib interval), participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of 1.5 mg trametinib orally QD continuing up until study treatment discontinuation.

Subject analysis set title

Part 5: 200 mg pembrolizumab+2 mg trametinib

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received 2 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of 2 mg trametinib orally QD continuing up until study treatment discontinuation.

Subject analysis set title

Part 5: 200 mg pembrolizumab+1.5 mg trametinib

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent or concurrent dose schedule of 1.5 mg trametinib orally QD continuing up until study treatment discontinuation.

Subject analysis set title

Pooled Parts1+2:pembrolizumab and/or dabrafenib+2mg trametinib

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants pooled from Parts 1 and 2 received 2 mg/kg pembrolizumab and/or 150 mg dabrafenib and 2 mg trametinib Q6W continuing up until study treatment discontinuation.

Subject analysis set title

Pooled Parts 1+2:pembrolizumab+1.5 mg trametinib

Subject analysis set type

Sub-group analysis

Subject analysis set description

Participants pooled from Parts 1 and 2 received 2 mg/kg pembrolizumab in combination with 1.5 mg trametinib Q6W continuing up until study treatment discontinuation.

Primary: Parts 1, 2, 4, and 5: Number of Participants Who Experienced Dose-limiting Toxicities (DLTs)

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End point title

Parts 1, 2, 4, and 5: Number of Participants Who Experienced Dose-limiting Toxicities (DLTs) ^[1] ^[2]

End point description

DLTs were graded using National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. Events were considered a DLT if occurred during the DLT evaluation period and met ≥1 of the following: significant hematologic toxicity; significant Grade ≥3 non-hematologic toxicity not previously identified or known to occur and cannot be controlled with routine supportive measures; drug-related toxicity that results in an interruption of any component of study therapy for >21 consecutive days and cannot be controlled ≤2 weeks from onset; any other Grade ≥2 non-hematological toxicity that is dose limiting with some exceptions; and liver chemistries meeting study stopping guidelines. The DLT evaluable population included all participants in Parts 1, 2, 4, and 5 who received ≥66% of planned treatments during the DLT observation period or discontinued treatment due to a DLT. Per protocol, DLT outcome analysis did not include Part 3.

End point type

Primary

End point timeframe

Up to approximately 6 weeks

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 was no statistical analysis planned for this endpoint.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis for this endpoint was prespecified to be for Parts 1, 2, 4, and 5 only. There was no statistical analysis planned for this endpoint.

End point values	Part 1:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg	Part 1:pembrolizumab 2 mg/kg+trametinib 2 mg	Part 1:pembrolizumab 2 mg/kg+trametinib 1.5 mg	Part 2:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg	Part 2:pembrolizumab 2 mg/kg+trametinib 1.5 mg	Part 4:4 weeks trametinib (Tra) 2mg; pembrolizumab+Tra 2mg	Part 4:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg	Part 4:4 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg	Part 4:2 weeks Tra 2mg; pembrolizumab+Tra 2mg intermittent	Part 4:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg intermittent	Part 5:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg	Part 5:2 weeks Tra 2mg; pembrolizumab+Tra 2mg intermittent
Number of subjects analysed	7	3	2	8	2	3	4	5	6	3	12	9
Units: Participants	1	1	1	2	1	2	0	0	2	0	4	2

No statistical analyses for this end point

Primary: Part 2: Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator in Participants Without BRAF V600 E or K Mutations

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End point title

Part 2: Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator in Participants Without BRAF V600 E or K Mutations ^[3] ^[4]

End point description

ORR was defined as the percentage of participants without BRAF V600 E or K mutation who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: divided into very good partial response [VGPR; >60% tumor reduction] and moderate partial response [MPR; >30-≤60% tumor reduction]) per RECIST 1.1 as assessed by investigator. The analysis population included all enrolled participants without BRAF V600 E or K mutations in Part 2. The percentage of participants who experienced a CR or PR based on RECIST 1.1 as assessed by investigator were reported.

End point type

Primary

End point timeframe

Up to approximately 85 months

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: There was no statistical analysis planned for this endpoint.
[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: Analysis for this endpoint was prespecified to be only for a specific population in Part 2. There was no statistical analysis planned for this endpoint.

End point values	Part 2:pembrolizumab 2 mg/kg+trametinib 1.5 mg
Number of subjects analysed	2
Units: Percentage of Participants
number (confidence interval 95%)	50.0 (1.3 to 98.7)

No statistical analyses for this end point

Primary: Part 5: ORR per RECIST 1.1 as Assessed by Investigator in Participants Without BRAF V600 E or K Mutations or With Solid Tumors Irrespective of BRAF Status

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End point title

Part 5: ORR per RECIST 1.1 as Assessed by Investigator in Participants Without BRAF V600 E or K Mutations or With Solid Tumors Irrespective of BRAF Status ^[5] ^[6]

End point description

ORR was defined as the percentage of participants without BRAF V600 E or K mutation who had a Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: divided into very good partial response [VGPR; >60% tumor reduction] and moderate partial response [MPR; >30-≤60% tumor reduction]) per RECIST 1.1 as assessed by investigator. The analysis population included all enrolled participants without BRAF V600 E or K mutations in Part 5. The percentage of participants who experienced a CR or PR based on RECIST 1.1 as assessed by investigator were reported.

End point type

Primary

End point timeframe

Up to approximately 85 months

Notes
[5] - 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 was no statistical analysis planned for this endpoint.
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis for this endpoint was prespecified to be for Part 5 only. There was no statistical analysis planned for this endpoint.

End point values	Part 5:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg	Part 5:2 weeks Tra 2mg; pembrolizumab+Tra 2mg intermittent
Number of subjects analysed	12	9
Units: Percentage of Participants
number (confidence interval 95%)	0.0 (0.0 to 26.5)	33.3 (7.5 to 70.1)

No statistical analyses for this end point

Primary: Part 3: Progression-Free Survival (PFS) Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations

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End point title

Part 3: Progression-Free Survival (PFS) Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations ^[7]

End point description

PFS was defined as the time from randomization to the first documented disease progression (PD) or death due to any cause, whichever occurred first, based on RECIST 1.1 by investigator review. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions was also considered PD. PFS was analyzed using the Kaplan-Meier method and was reported in months. 9999=Upper limit for PFS not reached at time of data cut-off due to insufficient number of participants with an event. Statistical analysis used a Cox regression model with treatment as a covariate and stratified by Eastern Cooperative Oncology Group performance status and Lactate Dehydrogenase. The analysis population included all randomized participants with BRAF V600 E or K mutations in Part 3.

End point type

Primary

End point timeframe

Up to approximately 85 months

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis for this endpoint was prespecified to be for Part 3 only.

End point values	Part 3:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg	Part 3:placebo+dabrafenib 150 mg+trametinib 2 mg
Number of subjects analysed	60	60
Units: Months
median (confidence interval 95%)	17.0 (11.3 to 9999)	9.9 (6.7 to 15.6)

PFS: Pembrolizumab versus Placebo

Statistical analysis description

Cox regression model

Comparison groups

Part 3:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg v Part 3:placebo+dabrafenib 150 mg+trametinib 2 mg

Number of subjects included in analysis

120

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.46

Confidence interval

level

95%

sides

2-sided

lower limit

0.29

upper limit

0.74

Primary: Parts 1, 2, 4, and 5: Number of Participants Who Experienced an Adverse Event (AE)

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End point title

Parts 1, 2, 4, and 5: Number of Participants Who Experienced an Adverse Event (AE) ^[8] ^[9]

End point description

An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE was any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the study drug, was also an AE. The analysis population included all participants who received at least one dose of study treatment in Parts 1, 2, 4, and 5. The number of participants who experienced an AE was reported. Per protocol, AE outcome analysis did not include Part 3.

End point type

Primary

End point timeframe

Up to approximately 32 months

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 was no statistical analysis planned 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: Analysis for this endpoint was prespecified to be for Parts 1, 2, 4, and 5 only. There was no statistical analysis planned for this endpoint.

End point values	Part 1:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg	Part 1:pembrolizumab 2 mg/kg+trametinib 2 mg	Part 1:pembrolizumab 2 mg/kg+trametinib 1.5 mg	Part 2:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg	Part 2:pembrolizumab 2 mg/kg+trametinib 1.5 mg	Part 4:4 weeks trametinib (Tra) 2mg; pembrolizumab+Tra 2mg	Part 4:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg	Part 4:4 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg	Part 4:2 weeks Tra 2mg; pembrolizumab+Tra 2mg intermittent	Part 4:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg intermittent	Part 5:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg	Part 5:2 weeks Tra 2mg; pembrolizumab+Tra 2mg intermittent
Number of subjects analysed	7	3	2	8	2	3	4	5	6	3	12	9
Units: Participants	7	3	2	8	2	3	4	5	6	3	11	9

No statistical analyses for this end point

Primary: Parts 1, 2, 4, and 5: Number of Participants Who Discontinued Study Treatment Due to an AE

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End point title

Parts 1, 2, 4, and 5: Number of Participants Who Discontinued Study Treatment Due to an AE ^[10] ^[11]

End point description

An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily had to have a causal relationship with this treatment. An AE was any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a pre-existing condition that was temporally associated with the use of the study drug, was also an AE. The analysis population included all participants who received at least one dose of study treatment in Parts 1, 2, 4, and 5. The number of participants who discontinued study treatment due to an AE was reported. Per protocol, discontinuation outcome analysis did not include Part 3.

End point type

Primary

End point timeframe

Up to approximately 29 months

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 was no statistical analysis planned 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: Analysis for this endpoint was prespecified to be for Parts 1, 2, 4, and 5 only. There was no statistical analysis planned for this endpoint.

End point values	Part 1:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg	Part 1:pembrolizumab 2 mg/kg+trametinib 2 mg	Part 1:pembrolizumab 2 mg/kg+trametinib 1.5 mg	Part 2:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg	Part 2:pembrolizumab 2 mg/kg+trametinib 1.5 mg	Part 4:4 weeks trametinib (Tra) 2mg; pembrolizumab+Tra 2mg	Part 4:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg	Part 4:4 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg	Part 4:2 weeks Tra 2mg; pembrolizumab+Tra 2mg intermittent	Part 4:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg intermittent	Part 5:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg	Part 5:2 weeks Tra 2mg; pembrolizumab+Tra 2mg intermittent
Number of subjects analysed	7	3	2	8	2	3	4	5	6	3	12	9
Units: Participants	2	2	1	5	2	1	0	4	2	1	2	2

No statistical analyses for this end point

Secondary: Part 1: ORR per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations

Top of page

End point title

Part 1: ORR per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations ^[12]

End point description

ORR was defined as the percentage of participants who had a CR (Disappearance of all target lesions) or a PR (divided into very good partial response [VGPR; >60% tumor reduction] and moderate partial response [MPR; >30-≤60% tumor reduction]) per RECIST 1.1 as assessed by investigator. The analysis population included all enrolled participants with BRAF V600 E or K mutations in Part 1. The percentage of participants who experienced a CR or PR as assessed by the investigator was presented.

End point type

Secondary

End point timeframe

Up to approximately 85 months

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis for this endpoint was prespecified to be only for a specific population in Part 1. There was no statistical analysis planned for this endpoint.

End point values	Part 1:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg
Number of subjects analysed	7
Units: Percentage of participants
number (confidence interval 95%)	57.1 (18.4 to 90.1)

No statistical analyses for this end point

Secondary: Part 2: ORR per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations

Top of page

End point title

Part 2: ORR per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations ^[13]

End point description

ORR was defined as the percentage of participants who had a CR (Disappearance of all target lesions) or a PR (divided into very good partial response [VGPR; >60% tumor reduction] and moderate partial response [MPR; >30-≤60% tumor reduction]) per RECIST 1.1 as assessed by investigator. The analysis population included all enrolled participants with BRAF V600 E or K mutations in Part 2. The percentage of participants who experienced a CR or PR as assessed by the investigator was presented.

End point type

Secondary

End point timeframe

Up to approximately 85 months

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis for this endpoint was prespecified to be only for a specific population in Part 2. There was no statistical analysis planned for this endpoint.

End point values	Part 2:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg
Number of subjects analysed	8
Units: Percentage of Participants
number (confidence interval 95%)	75.0 (34.9 to 96.8)

No statistical analyses for this end point

Secondary: Part 3: ORR per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations

Top of page

End point title

Part 3: ORR per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations ^[14]

End point description

ORR was defined as the percentage of participants who had a CR (Disappearance of all target lesions) or a PR (divided into very good partial response [VGPR; >60% tumor reduction] and moderate partial response [MPR; >30-≤60% tumor reduction]) per RECIST 1.1 as assessed by investigator. The analysis population included all randomized participants with BRAF V600 E or K mutations in Part 3. The percentage of participants who experienced a CR or PR as assessed by the investigator was presented.

End point type

Secondary

End point timeframe

Up to approximately 85 months

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis for this endpoint was prespecified to be for Part 3 only. There was no statistical analysis planned for this endpoint.

End point values	Part 3:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg	Part 3:placebo+dabrafenib 150 mg+trametinib 2 mg
Number of subjects analysed	60	60
Units: Percentage of Participants
number (confidence interval 95%)	65.0 (51.6 to 76.9)	71.7 (58.6 to 82.5)

No statistical analyses for this end point

Secondary: Part 3: Duration of Response (DOR) per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations

Top of page

End point title

Part 3: Duration of Response (DOR) per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations ^[15]

End point description

For participants who demonstrated a confirmed CR (Disappearance of all target lesions) or a confirmed PR (divided by VGPR [>60% tumor reduction] and MPR [>30-≤60% tumor reduction]) per RECIST 1.1 as assessed by the investigator, DOR was defined as the time from first documented evidence of CR or PR until progressive disease (PD). Per RECIST 1.1, PD was defined as at least a 20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also have demonstrated an absolute increase of at least 5 mm. The appearance of one or more new lesions was also considered PD. The analysis population included all randomized participants with BRAF V600 E or K mutations who had a confirmed CR or PR in Part 3. The DOR as assessed by the investigator was analyzed using Kaplan-Meier method and reported in months. 9999=Upper limit for DOR was not reached at time of data cut-off due to insufficient number of responding participants with relapse.

End point type

Secondary

End point timeframe

Up to approximately 85 months

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis for this endpoint was prespecified to be for Part 3 only. There was no statistical analysis planned for this endpoint.

End point values	Part 3:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg	Part 3:placebo+dabrafenib 150 mg+trametinib 2 mg
Number of subjects analysed	39	43
Units: Months
median (confidence interval 95%)	30.2 (14.1 to 9999)	12.1 (6.0 to 15.7)

No statistical analyses for this end point

Secondary: Part 3: Overall Survival (OS) in Participants With BRAF V600 E or K Mutations

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End point title

Part 3: Overall Survival (OS) in Participants With BRAF V600 E or K Mutations ^[16]

End point description

OS was defined as the time from randomization to death due to any cause. OS was analyzed using the Kaplan-Meier method and was reported in months. Statistical analysis used a Cox regression model with treatment as a covariate and stratified by Eastern Cooperative Oncology Group performance status and Lactate Dehydrogenase. The analysis population included all randomized participants with BRAF V600 E or K mutations in Part 3. 9999=Upper limit for OS was not reached at time of data cut-off due to insufficient number of participants with an event.

End point type

Secondary

End point timeframe

Up to approximately 85 months

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Analysis for this endpoint was prespecified to be for Part 3 only.

End point values	Part 3:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg	Part 3:placebo+dabrafenib 150 mg+trametinib 2 mg
Number of subjects analysed	60	60
Units: Months
median (confidence interval 95%)	46.3 (23.9 to 9999)	26.3 (18.2 to 38.6)

OS: Pembrolizumab versus Placebo

Statistical analysis description

Cox regression model

Comparison groups

Part 3:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg v Part 3:placebo+dabrafenib 150 mg+trametinib 2 mg

Number of subjects included in analysis

120

Analysis specification

Pre-specified

Analysis type

other

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.6

Confidence interval

level

95%

sides

2-sided

lower limit

0.38

upper limit

0.95

Secondary: Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination with Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2

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End point title

Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination with Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2

End point description

Cmax was defined as the maximum concentration of pembrolizumab observed after administration of 2 mg/kg pembrolizumab in combination with dabrafenib and/or trametinib. Blood samples were collected at multiple time points to estimate the Cmax of pembrolizumab. All participants who received pembrolizumab from Parts 1 and 2 were treated as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The analysis population consisted of all participants pooled from Parts 1 and 2 who received ≥1 dose of 2 mg/kg pembrolizumab and who had available data for the analysis of Cmax. The Cmax of pembrolizumab is presented.

End point type

Secondary

End point timeframe

Cycle 1 Day 1: predose, postdose, 24 - 96 hours (hrs) postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

End point values	Pooled Parts 1+2:pembrolizumab+dabrafenib+1.5/2 mg trametinib
Number of subjects analysed	21
Units: µg/mL
arithmetic mean (standard deviation)	52.3 ( 9.9 )

No statistical analyses for this end point

Secondary: Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination with Dabrafenib and Trametinib in Participants From Part 3

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End point title

Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination with Dabrafenib and Trametinib in Participants From Part 3

End point description

Cmax was defined as the maximum concentration of pembrolizumab observed after administration of 2 mg/kg pembrolizumab in combination with dabrafenib and trametinib. Blood samples were collected at multiple time points to estimate the Cmax of pembrolizumab. The analysis population consisted of all participants from Part 3 who received ≥1 dose of 2 mg/kg pembrolizumab and who had available data for the analysis of Cmax. The Cmax of pembrolizumab is presented.

End point type

Secondary

End point timeframe

Cycle 1 Day 1: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

End point values	Part 3: 2 mg/kg pembrolizumab+dabrafenib+trametinib
Number of subjects analysed	58
Units: µg/mL
arithmetic mean (standard deviation)	48.9 ( 11.4 )

No statistical analyses for this end point

Secondary: Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination with Trametinib in Participants From Part 4

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End point title

Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination with Trametinib in Participants From Part 4

End point description

Cmax was defined as the maximum concentration of pembrolizumab observed after administration of 200 mg pembrolizumab in combination with trametinib. Blood samples were collected at multiple time points to estimate the Cmax of pembrolizumab. The analysis population consisted of all participants from Part 4 who received ≥1 dose of 200 mg pembrolizumab and who had available data for the analysis of Cmax. The Cmax of pembrolizumab is presented.

End point type

Secondary

End point timeframe

Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

End point values	Part 4: 200 mg pembrolizumab+trametinib
Number of subjects analysed	14
Units: µg/mL
arithmetic mean (standard deviation)	77.8 ( 16.1 )

No statistical analyses for this end point

Secondary: Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination with Trametinib in Participants From Part 5

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End point title

Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination with Trametinib in Participants From Part 5

End point description

Cmax was defined as the maximum concentration of pembrolizumab observed after administration of 200 mg pembrolizumab in combination with trametinib. Blood samples were collected at multiple time points to estimate the Cmax of pembrolizumab. The analysis population consisted of all participants from Part 5 who received ≥1 dose of 200 mg pembrolizumab and who had available data for the analysis of Cmax.

End point type

Secondary

End point timeframe

Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

End point values	Part 5: 200 mg pembrolizumab+trametinib
Number of subjects analysed	0 ^[17]
Units: µg/mL
arithmetic mean (standard deviation)	( )

Notes
[17] - There were no participants with data available for the analysis of the Cmax of pembrolizumab.

No statistical analyses for this end point

Secondary: Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination with Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2

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End point title

Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination with Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2

End point description

Ctrough was defined as the lowest concentration of pembrolizumab that occurred immediately prior to the next dose of 2 mg/kg pembrolizumab administered in combination with dabrafenib and/or trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of pembrolizumab. All participants who received pembrolizumab from Parts 1 and 2 were treated as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The analysis population consisted of all participants pooled from Parts 1 and 2 who received ≥1 dose of 2 mg/kg pembrolizumab and who had available data for the analysis of Ctrough. The Ctrough of pembrolizumab is presented.

End point type

Secondary

End point timeframe

Cycle 1 Day 1: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

End point values	Pooled Parts 1+2:pembrolizumab+dabrafenib+1.5/2 mg trametinib
Number of subjects analysed	20
Units: µg/mL
arithmetic mean (standard deviation)	11.2 ( 2.6 )

No statistical analyses for this end point

Secondary: Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination with Dabrafenib and Trametinib in Participants From Part 3

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End point title

Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination with Dabrafenib and Trametinib in Participants From Part 3

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 1: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

End point values	Part 3: 2 mg/kg pembrolizumab+dabrafenib+trametinib
Number of subjects analysed	49
Units: µg/mL
arithmetic mean (standard deviation)	10.6 ( 3.4 )

No statistical analyses for this end point

Secondary: Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination with Trametinib in Participants From Part 4

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End point title

Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination with Trametinib in Participants From Part 4

End point description

Ctrough was defined as the lowest concentration of pembrolizumab that occurred immediately prior to the next dose of 200 mg pembrolizumab administered in combination with trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of pembrolizumab. The analysis population consisted of all participants from Part 4 who received ≥1 dose of 200 mg pembrolizumab and who had available data for the analysis of Ctrough. The Ctrough of pembrolizumab is presented.

End point type

Secondary

End point timeframe

Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

End point values	Part 4: 200 mg pembrolizumab+trametinib
Number of subjects analysed	15
Units: µg/mL
arithmetic mean (standard deviation)	17.0 ( 7.1 )

No statistical analyses for this end point

Secondary: Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination with Trametinib in Participants From Part 5

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End point title

Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination with Trametinib in Participants From Part 5

End point description

Ctrough was defined as the lowest concentration of pembrolizumab that occurred immediately prior to the next dose of 200 mg pembrolizumab administered in combination with trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of pembrolizumab. The analysis population consisted of all participants from Part 5 who received ≥1 dose of 200 mg pembrolizumab and who had available data for the analysis of Ctrough. The Ctrough of pembrolizumab is presented.

End point type

Secondary

End point timeframe

Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

End point values	Part 5: 200 mg pembrolizumab+trametinib
Number of subjects analysed	0 ^[18]
Units: µg/mL
arithmetic mean (standard deviation)	( )

Notes
[18] - There were no participants with data available for the analysis of the Ctrough of pembrolizumab.

No statistical analyses for this end point

Secondary: Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2

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End point title

Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2

End point description

Cmax was defined as the maximum concentration of dabrafenib observed after administration of 150 mg dabrafenib in combination with 2 mg/kg pembrolizumab and 2 mg trametinib. Blood samples were collected at multiple time points to estimate the Cmax of dabrafenib. All participants who received dabrafenib from Parts 1 and 2 were treated as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The analysis population consisted of all participants pooled from Parts 1 and 2 who received ≥1 dose of 150 mg dabrafenib and who had available data for the analysis of Cmax. The Cmax of dabrafenib is presented.

End point type

Secondary

End point timeframe

Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Pooled Parts1+2:pembrolizumab and/or dabrafenib+2mg trametinib
Number of subjects analysed	13
Units: ng/mL
arithmetic mean (standard deviation)	683 ( 905 )

No statistical analyses for this end point

Secondary: Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3

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End point title

Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 3: 2 mg/kg pembrolizumab+dabrafenib+trametinib
Number of subjects analysed	53
Units: ng/mL
arithmetic mean (standard deviation)	643 ( 643 )

No statistical analyses for this end point

Secondary: Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with Placebo and 2 mg Trametinib in Participants From Part 3

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End point title

Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with Placebo and 2 mg Trametinib in Participants From Part 3

End point description

Cmax was defined as the maximum concentration of dabrafenib observed after administration of 150 mg dabrafenib in combination with saline placebo and 2 mg trametinib. Blood samples were collected at multiple time points to estimate the Cmax of dabrafenib. The analysis population consisted of all participants from Part 3 who received ≥1 dose of 150 mg dabrafenib and placebo and who had available data for the analysis of Cmax. The Cmax of dabrafenib is presented.

End point type

Secondary

End point timeframe

Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 3: placebo+dabrafenib+trametinib
Number of subjects analysed	58
Units: ng/mL
arithmetic mean (standard deviation)	642 ( 829 )

No statistical analyses for this end point

Secondary: Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2

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End point title

Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2

End point description

Ctrough was defined as the lowest concentration of dabrafenib that occurred immediately prior to the next dose of 150 mg dabrafenib administered in combination with 2 mg/kg pembrolizumab and 2 mg trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of dabrafenib. All participants who received dabrafenib from Parts 1 and 2 were treated as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The analysis population consisted of all participants pooled from Parts 1 and 2 who received ≥1 dose of 150 mg dabrafenib and who had available data for the analysis of Ctrough. The Ctrough of dabrafenib is presented.

End point type

Secondary

End point timeframe

Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Pooled Parts1+2:pembrolizumab and/or dabrafenib+2mg trametinib
Number of subjects analysed	14
Units: ng/mL
arithmetic mean (standard deviation)	156 ( 367 )

No statistical analyses for this end point

Secondary: Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3

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End point title

Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3

End point description

Ctrough was defined as the lowest concentration of dabrafenib that occurred immediately prior to the next dose of 150 mg dabrafenib administered in combination with 2 mg/kg pembrolizumab and 2 mg trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of dabrafenib. The analysis population consisted of all participants from Part 3 who received ≥1 dose of 150 mg dabrafenib and pembrolizumab and who had available data for the analysis of Ctrough. The Ctrough of dabrafenib is presented.

End point type

Secondary

End point timeframe

Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 3: 2 mg/kg pembrolizumab+dabrafenib+trametinib
Number of subjects analysed	55
Units: ng/mL
arithmetic mean (standard deviation)	103 ( 204 )

No statistical analyses for this end point

Secondary: Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with Placebo and 2 mg Trametinib in Participants From Part 3

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End point title

Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with Placebo and 2 mg Trametinib in Participants From Part 3

End point description

Ctrough was defined as the lowest concentration of dabrafenib that occurred immediately prior to the next dose of 150 mg dabrafenib administered in combination with saline placebo and 2 mg trametinib. Blood samples were collected at multiple time points to estimate the Ctrough of dabrafenib. The analysis population consisted of all participants from Part 3 who received ≥1 dose of 150 mg dabrafenib and placebo and who had available data for the analysis of Ctrough. The Ctrough of dabrafenib is presented.

End point type

Secondary

End point timeframe

Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 3: placebo+dabrafenib+trametinib
Number of subjects analysed	58
Units: ng/mL
arithmetic mean (standard deviation)	183 ( 384 )

No statistical analyses for this end point

Secondary: Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination with 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2

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End point title

Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination with 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2

End point description

Cmax was defined as the maximum concentration of trametinib observed after administration of 2 mg trametinib in combination with 2 mg/kg pembrolizumab and 150 mg dabrafenib. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. All participants who received 2 mg trametinib from Parts 1 and 2 were treated as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The analysis population consisted of all participants pooled from Parts 1 and 2 who received ≥1 dose of 2 mg trametinib and who had available data for the analysis of Cmax. The Cmax of trametinib is presented.

End point type

Secondary

End point timeframe

Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Pooled Parts1+2:pembrolizumab and/or dabrafenib+2mg trametinib
Number of subjects analysed	13
Units: ng/mL
arithmetic mean (standard deviation)	19.3 ( 8.13 )

No statistical analyses for this end point

Secondary: Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg Trametinib in Combination with 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2

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End point title

Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg Trametinib in Combination with 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2

End point description

Cmax was defined as the maximum concentration of trametinib observed after administration of 1.5 mg trametinib in combination with 2 mg/kg pembrolizumab. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. All participants who received 1.5 mg trametinib from Parts 1 and 2 were treated as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The analysis population consisted of all participants pooled from Parts 1 and 2 who received ≥1 dose of 1.5 mg trametinib and who had available data for the analysis of Cmax. The Cmax of trametinib is presented.

End point type

Secondary

End point timeframe

Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Pooled Parts 1+2:pembrolizumab+1.5 mg trametinib
Number of subjects analysed	3
Units: ng/mL
arithmetic mean (standard deviation)	30.3 ( 17.7 )

No statistical analyses for this end point

Secondary: Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination with 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3

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End point title

Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination with 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 3: 2 mg/kg pembrolizumab+dabrafenib+trametinib
Number of subjects analysed	47
Units: ng/mL
arithmetic mean (standard deviation)	16.3 ( 6.80 )

No statistical analyses for this end point

Secondary: Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination with Placebo and 150 mg Dabrafenib in Participants From Part 3

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End point title

Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination with Placebo and 150 mg Dabrafenib in Participants From Part 3

End point description

Cmax was defined as the maximum concentration of trametinib observed after administration of 2 mg trametinib in combination with saline placebo and 150 mg dabrafenib. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. The analysis population consisted of all participants from Part 3 who received ≥1 dose of 2 mg trametinib and placebo and who had available data for the analysis of Cmax. The Cmax of trametinib is presented.

End point type

Secondary

End point timeframe

Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 3: placebo+dabrafenib+trametinib
Number of subjects analysed	53
Units: ng/mL
arithmetic mean (standard deviation)	16.2 ( 6.15 )

No statistical analyses for this end point

Secondary: Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 4

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End point title

Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 4

End point description

Cmax was defined as the maximum concentration of trametinib observed after administration of 2 mg trametinib in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. The analysis population consisted of all participants from Part 4 who received ≥1 dose of 2 mg trametinib and who had available data for the analysis of Cmax. The Cmax of trametinib is presented.

End point type

Secondary

End point timeframe

Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 4: 200 mg pembrolizumab+2 mg trametinib
Number of subjects analysed	4
Units: ng/mL
arithmetic mean (standard deviation)	18.5 ( 12.9 )

No statistical analyses for this end point

Secondary: Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 4

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End point title

Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 4

End point description

Cmax was defined as the maximum concentration of trametinib observed after administration of 1.5 mg trametinib in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. The analysis population consisted of all participants from Part 4 who received ≥1 dose of 1.5 mg trametinib and who had available data for the analysis of Cmax. The Cmax of trametinib is presented.

End point type

Secondary

End point timeframe

Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 4: 200 mg pembrolizumab+1.5 mg trametinib
Number of subjects analysed	7
Units: ng/mL
arithmetic mean (standard deviation)	16.7 ( 7.62 )

No statistical analyses for this end point

Secondary: Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg of Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 5

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End point title

Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg of Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 5

End point description

Cmax was defined as the maximum concentration of trametinib observed after administration of 2 mg trametinib in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. The analysis population consisted of all participants from Part 5 who received ≥1 dose of 2 mg trametinib and who had available data for the analysis of Cmax. The Cmax of trametinib is presented.

End point type

Secondary

End point timeframe

Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 5: 200 mg pembrolizumab+2 mg trametinib
Number of subjects analysed	3
Units: ng/mL
arithmetic mean (standard deviation)	7.54 ( 8.89 )

No statistical analyses for this end point

Secondary: Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 5

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End point title

Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 5

End point description

Cmax was defined as the maximum concentration of trametinib observed after administration of 1.5 mg trametinib in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Cmax of trametinib. The analysis population consisted of all participants from Part 5 who received ≥1 dose of 1.5 mg trametinib and who had available data for the analysis of Cmax. The Cmax of trametinib is presented.

End point type

Secondary

End point timeframe

Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 5: 200 mg pembrolizumab+1.5 mg trametinib
Number of subjects analysed	8
Units: ng/mL
arithmetic mean (standard deviation)	14.3 ( 7.75 )

No statistical analyses for this end point

Secondary: Trough Concentration (Ctrough) of Trametinib Following Administration of 1.5 mg Trametinib in Combination with 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2

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End point title

Trough Concentration (Ctrough) of Trametinib Following Administration of 1.5 mg Trametinib in Combination with 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2

End point description

Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 1.5 mg trametinib administered in combination with 2 mg/kg pembrolizumab. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. All participants who received 1.5 mg trametinib from Parts 1 and 2 were treated as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The analysis population consisted of all participants pooled from Parts 1 and 2 who received ≥1 dose of 1.5 mg trametinib and who had available data for the analysis of Ctrough. The Ctrough of trametinib is presented.

End point type

Secondary

End point timeframe

Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Pooled Parts 1+2:pembrolizumab+1.5 mg trametinib
Number of subjects analysed	3
Units: ng/mL
arithmetic mean (standard deviation)	20.5 ( 9.23 )

No statistical analyses for this end point

Secondary: Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination with 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2

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End point title

Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination with 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2

End point description

Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 2 mg trametinib administered in combination with 2 mg/kg pembrolizumab and 150 mg dabrafenib. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. All participants who received 2 mg trametinib from Parts 1 and 2 were treated as a single arm and analyzed as a single study population for this outcome measure since Part 2 was the dose confirmation phase of Part 1. The analysis population consisted of all participants pooled from Parts 1 and 2 who received ≥1 dose of 2 mg trametinib and who had available data for the analysis of Ctrough. The Ctrough of trametinib is presented.

End point type

Secondary

End point timeframe

Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Pooled Parts1+2:pembrolizumab and/or dabrafenib+2mg trametinib
Number of subjects analysed	14
Units: ng/mL
arithmetic mean (standard deviation)	13.7 ( 9.39 )

No statistical analyses for this end point

Secondary: Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination with 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3

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End point title

Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination with 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3

End point description

Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 2 mg trametinib administered in combination with 2 mg/kg pembrolizumab and 150 mg dabrafenib. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. The analysis population consisted of all participants from Part 3 who received ≥1 dose of 2 mg trametinib and pembrolizumab and who had available data for the analysis of Ctrough. The Ctrough of trametinib is presented.

End point type

Secondary

End point timeframe

Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 3: 2 mg/kg pembrolizumab+dabrafenib+trametinib
Number of subjects analysed	54
Units: ng/mL
arithmetic mean (standard deviation)	9.93 ( 5.48 )

No statistical analyses for this end point

Secondary: Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination with Placebo and 150 mg Dabrafenib in Participants From Part 3

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End point title

Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination with Placebo and 150 mg Dabrafenib in Participants From Part 3

End point description

Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 2 mg trametinib administered in combination with saline placebo and 150 mg dabrafenib. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. The analysis population consisted of all participants from Part 3 who received ≥1 dose of 2 mg trametinib and placebo and who had available data for the analysis of Ctrough. The Ctrough of trametinib is presented.

End point type

Secondary

End point timeframe

Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 3: placebo+dabrafenib+trametinib
Number of subjects analysed	58
Units: ng/mL
arithmetic mean (standard deviation)	10.7 ( 5.14 )

No statistical analyses for this end point

Secondary: Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 4

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End point title

Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 4

End point description

Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 2 mg trametinib administered in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. The analysis population consisted of all participants from Part 4 who received ≥1 dose of 2 mg trametinib and who had available data for the analysis of Ctrough. The Ctrough of trametinib is presented.

End point type

Secondary

End point timeframe

Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 4: 200 mg pembrolizumab+2 mg trametinib
Number of subjects analysed	6
Units: ng/mL
arithmetic mean (standard deviation)	12.3 ( 9.45 )

No statistical analyses for this end point

Secondary: Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg of Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 5

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End point title

Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg of Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 5

End point description

Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 2 mg trametinib administered in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. The analysis population consisted of all participants from Part 5 who received ≥1 dose of 2 mg trametinib and who had available data for the analysis of Ctrough. The Ctrough of trametinib is presented.

End point type

Secondary

End point timeframe

Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 5: 200 mg pembrolizumab+2 mg trametinib
Number of subjects analysed	8
Units: ng/mL
arithmetic mean (standard deviation)	6.69 ( 5.9 )

No statistical analyses for this end point

Secondary: Trough Concentration (Ctrough) of Trametinib Following Administration of 1.5 mg Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 4

Top of page

End point title

Trough Concentration (Ctrough) of Trametinib Following Administration of 1.5 mg Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 4

End point description

Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 1.5 mg trametinib administered in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. The analysis population consisted of all participants from Part 4 who received ≥1 dose of 1.5 mg trametinib and who had available data for the analysis of Ctrough. The Ctrough of trametinib is presented.

End point type

Secondary

End point timeframe

Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 4: 200 mg pembrolizumab+1.5 mg trametinib
Number of subjects analysed	7
Units: ng/mL
arithmetic mean (standard deviation)	8.64 ( 5.65 )

No statistical analyses for this end point

Secondary: Trough Concentration (Ctrough) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 5

Top of page

End point title

Trough Concentration (Ctrough) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 5

End point description

Ctrough was defined as the lowest concentration of trametinib that occurred immediately prior to the next dose of 1.5 mg trametinib administered in combination with 200 mg pembrolizumab. Blood samples were collected at multiple time points to estimate the Ctrough of trametinib. The analysis population consisted of all participants from Part 5 who received ≥1 dose of 1.5 mg trametinib and who had available data for the analysis of Ctrough. The Ctrough of trametinib is presented.

End point type

Secondary

End point timeframe

Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 5: 200 mg pembrolizumab+1.5 mg trametinib
Number of subjects analysed	9
Units: ng/mL
arithmetic mean (standard deviation)	10.6 ( 6.79 )

No statistical analyses for this end point

Secondary: Clearance (Cl) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination with Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2

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End point title

Clearance (Cl) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination with Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2

End point description

Blood samples were to be collected at pre-specified time points for analysis of the Cl of pembrolizumab, defined as the volume of plasma from which pembrolizumab is eliminated per unit time following pembrolizumab administration. As specified by the protocol, the Cl of pembrolizumab was only to be analyzed if required and no data were collected since, by the time of final analysis, pembrolizumab pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of pembrolizumab characterized across indications.

End point type

Secondary

End point timeframe

Cycle 1 Day 1: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

End point values	Pooled Parts 1+2:pembrolizumab+dabrafenib+1.5/2 mg trametinib
Number of subjects analysed	0 ^[19]
Units: Liters/hour (L/hr)
geometric mean (geometric coefficient of variation)	( )

Notes
[19] - The analysis was not performed.

No statistical analyses for this end point

Secondary: Clearance (Cl) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination with Dabrafenib and Trametinib in Participants From Part 3

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End point title

Clearance (Cl) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination with Dabrafenib and Trametinib in Participants From Part 3

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 1: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

End point values	Part 3: 2 mg/kg pembrolizumab+dabrafenib+trametinib
Number of subjects analysed	0 ^[20]
Units: L/hr
geometric mean (geometric coefficient of variation)	( )

Notes
[20] - The analysis was not performed.

No statistical analyses for this end point

Secondary: Clearance (Cl) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination with Trametinib in Participants From Part 4

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End point title

Clearance (Cl) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination with Trametinib in Participants From Part 4

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

End point values	Part 4: 200 mg pembrolizumab+trametinib
Number of subjects analysed	0 ^[21]
Units: L/hr
geometric mean (geometric coefficient of variation)	( )

Notes
[21] - The analysis was not performed.

No statistical analyses for this end point

Secondary: Clearance (Cl) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination with Trametinib in Participants From Part 5

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End point title

Clearance (Cl) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination with Trametinib in Participants From Part 5

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

End point values	Part 5: 200 mg pembrolizumab+trametinib
Number of subjects analysed	0 ^[22]
Units: L/hr
geometric mean (geometric coefficient of variation)	( )

Notes
[22] - The analysis was not performed.

No statistical analyses for this end point

Secondary: Clearance (Cl) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2

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End point title

Clearance (Cl) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2

End point description

Blood samples were to be collected at pre-specified time points for analysis of the Cl of dabrafenib, defined as the volume of plasma from which dabrafenib is eliminated per unit time following dabrafenib administration. As specified by the protocol, the Cl of dabrafenib was only to be analyzed if required and no data were collected since, by the time of final analysis, dabrafenib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of dabrafenib characterized across indications.

End point type

Secondary

End point timeframe

Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Pooled Parts1+2:pembrolizumab and/or dabrafenib+2mg trametinib
Number of subjects analysed	0 ^[23]
Units: L/hr
geometric mean (geometric coefficient of variation)	( )

Notes
[23] - The analysis was not performed.

No statistical analyses for this end point

Secondary: Clearance (Cl) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3

Top of page

End point title

Clearance (Cl) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 3: 2 mg/kg pembrolizumab+dabrafenib+trametinib
Number of subjects analysed	0 ^[24]
Units: L/hr
geometric mean (geometric coefficient of variation)	( )

Notes
[24] - The analysis was not performed.

No statistical analyses for this end point

Secondary: Clearance (Cl) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with Placebo and 2 mg Trametinib in Participants From Part 3

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End point title

Clearance (Cl) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with Placebo and 2 mg Trametinib in Participants From Part 3

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 3: placebo+dabrafenib+trametinib
Number of subjects analysed	0 ^[25]
Units: L/hr
geometric mean (geometric coefficient of variation)	( )

Notes
[25] - The analysis was not performed.

No statistical analyses for this end point

Secondary: Clearance (Cl) of Trametinib Following Administration of 2 mg Trametinib in Combination with 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2

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End point title

Clearance (Cl) of Trametinib Following Administration of 2 mg Trametinib in Combination with 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2

End point description

Blood samples were to be collected at pre-specified time points for analysis of the Cl of trametinib, defined as the volume of plasma from which trametinib is eliminated per unit time following trametinib administration. As specified by the protocol, the Cl of trametinib was only to be analyzed if required and no data were collected since, by the time of final analysis, trametinib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of trametinib characterized across indications.

End point type

Secondary

End point timeframe

Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Pooled Parts1+2:pembrolizumab and/or dabrafenib+2mg trametinib
Number of subjects analysed	0 ^[26]
Units: L/hr
geometric mean (geometric coefficient of variation)	( )

Notes
[26] - The analysis was not performed.

No statistical analyses for this end point

Secondary: Clearance (Cl) of Trametinib Following Administration of 1.5 mg Trametinib in Combination with 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2

Top of page

End point title

Clearance (Cl) of Trametinib Following Administration of 1.5 mg Trametinib in Combination with 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Pooled Parts 1+2:pembrolizumab+1.5 mg trametinib
Number of subjects analysed	0 ^[27]
Units: L/hr
geometric mean (geometric coefficient of variation)	( )

Notes
[27] - The analysis was not performed.

No statistical analyses for this end point

Secondary: Clearance (Cl) of Trametinib Following Administration of 2 mg Trametinib in Combination with 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3

Top of page

End point title

Clearance (Cl) of Trametinib Following Administration of 2 mg Trametinib in Combination with 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 3: 2 mg/kg pembrolizumab+dabrafenib+trametinib
Number of subjects analysed	0 ^[28]
Units: L/hr
geometric mean (geometric coefficient of variation)	( )

Notes
[28] - The analysis was not performed.

No statistical analyses for this end point

Secondary: Clearance (Cl) of Trametinib Following Administration of 2 mg Trametinib in Combination with Placebo and 150 mg Dabrafenib in Participants From Part 3

Top of page

End point title

Clearance (Cl) of Trametinib Following Administration of 2 mg Trametinib in Combination with Placebo and 150 mg Dabrafenib in Participants From Part 3

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 3: placebo+dabrafenib+trametinib
Number of subjects analysed	0 ^[29]
Units: L/hr
geometric mean (geometric coefficient of variation)	( )

Notes
[29] - The analysis was not performed.

No statistical analyses for this end point

Secondary: Clearance (Cl) of Trametinib Following Administration of 2 mg Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 4

Top of page

End point title

Clearance (Cl) of Trametinib Following Administration of 2 mg Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 4

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 4: 200 mg pembrolizumab+2 mg trametinib
Number of subjects analysed	0 ^[30]
Units: L/hr
geometric mean (geometric coefficient of variation)	( )

Notes
[30] - The analysis was not performed.

No statistical analyses for this end point

Secondary: Clearance (Cl) of Trametinib Following Administration of 1.5 mg Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 4

Top of page

End point title

Clearance (Cl) of Trametinib Following Administration of 1.5 mg Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 4

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 4: 200 mg pembrolizumab+1.5 mg trametinib
Number of subjects analysed	0 ^[31]
Units: L/hr
geometric mean (geometric coefficient of variation)	( )

Notes
[31] - The analysis was not performed.

No statistical analyses for this end point

Secondary: Clearance (Cl) of Trametinib Following Administration of 2 mg of Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 5

Top of page

End point title

Clearance (Cl) of Trametinib Following Administration of 2 mg of Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 5

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 5: 200 mg pembrolizumab+2 mg trametinib
Number of subjects analysed	0 ^[32]
Units: L/hr
geometric mean (geometric coefficient of variation)	( )

Notes
[32] - The analysis was not performed.

No statistical analyses for this end point

Secondary: Clearance (Cl) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 5

Top of page

End point title

Clearance (Cl) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 5

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 5: 200 mg pembrolizumab+1.5 mg trametinib
Number of subjects analysed	0 ^[33]
Units: L/hr
geometric mean (geometric coefficient of variation)	( )

Notes
[33] - The analysis was not performed.

No statistical analyses for this end point

Secondary: Volume of Distribution (Vc) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination with Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2

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End point title

Volume of Distribution (Vc) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination with Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2

End point description

Blood samples were to be collected at pre-specified time points for analysis of the Vc of pembrolizumab, defined as the theoretical volume that would be necessary to contain the total amount of administered pembrolizumab at the same concentration that it is observed in the blood plasma. As specified by the protocol, the Vc of pembrolizumab was only to be analyzed if required and no data were collected since, by the time of final analysis, pembrolizumab pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of pembrolizumab characterized across indications.

End point type

Secondary

End point timeframe

Cycle 1 Day 1: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

End point values	Pooled Parts 1+2:pembrolizumab+dabrafenib+1.5/2 mg trametinib
Number of subjects analysed	0 ^[34]
Units: Liters
geometric mean (geometric coefficient of variation)	( )

Notes
[34] - The analysis was not performed.

No statistical analyses for this end point

Secondary: Volume of Distribution (Vc) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination with Dabrafenib and Trametinib in Participants From Part 3

Top of page

End point title

Volume of Distribution (Vc) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination with Dabrafenib and Trametinib in Participants From Part 3

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 1: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 22: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

End point values	Part 3: 2 mg/kg pembrolizumab+dabrafenib+trametinib
Number of subjects analysed	0 ^[35]
Units: Liters
geometric mean (geometric coefficient of variation)	( )

Notes
[35] - The analysis was not performed.

No statistical analyses for this end point

Secondary: Volume of Distribution (Vc) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination with Trametinib in Participants From Part 4

Top of page

End point title

Volume of Distribution (Vc) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination with Trametinib in Participants From Part 4

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

End point values	Part 4: 200 mg pembrolizumab+trametinib
Number of subjects analysed	0 ^[36]
Units: Liters
geometric mean (geometric coefficient of variation)	( )

Notes
[36] - The analysis was not performed.

No statistical analyses for this end point

Secondary: Volume of Distribution (Vc) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination with Trametinib in Participants From Part 5

Top of page

End point title

Volume of Distribution (Vc) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination with Trametinib in Participants From Part 5

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 15: predose, postdose, 24 - 96 hrs postdose; Cycle 1 Day 36: predose, postdose; Cycle 2 Day 1: predose, postdose. Each cycle is a 21-day cycle.

End point values	Part 5: 200 mg pembrolizumab+trametinib
Number of subjects analysed	0 ^[37]
Units: Liters
geometric mean (geometric coefficient of variation)	( )

Notes
[37] - The analysis was not performed.

No statistical analyses for this end point

Secondary: Volume of Distribution (Vc) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2

Top of page

End point title

Volume of Distribution (Vc) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2

End point description

Blood samples were to be collected at pre-specified time points for analysis of the Vc of dabrafenib, defined as the theoretical volume that would be necessary to contain the total amount of administered dabrafenib at the same concentration that it is observed in the blood plasma. As specified by the protocol, the Vc of dabrafenib was only to be analyzed if required and no data were collected since, by the time of final analysis, dabrafenib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of dabrafenib characterized across indications.

End point type

Secondary

End point timeframe

Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Pooled Parts1+2:pembrolizumab and/or dabrafenib+2mg trametinib
Number of subjects analysed	0 ^[38]
Units: Liters
geometric mean (geometric coefficient of variation)	( )

Notes
[38] - The analysis was not performed.

No statistical analyses for this end point

Secondary: Volume of Distribution (Vc) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3

Top of page

End point title

Volume of Distribution (Vc) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 3: 2 mg/kg pembrolizumab+dabrafenib+trametinib
Number of subjects analysed	0 ^[39]
Units: Liters
geometric mean (geometric coefficient of variation)	( )

Notes
[39] - The analysis was not performed.

No statistical analyses for this end point

Secondary: Volume of Distribution (Vc) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with Placebo and 2 mg Trametinib in Participants From Part 3

Top of page

End point title

Volume of Distribution (Vc) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with Placebo and 2 mg Trametinib in Participants From Part 3

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 3: placebo+dabrafenib+trametinib
Number of subjects analysed	0 ^[40]
Units: Liters
geometric mean (geometric coefficient of variation)	( )

Notes
[40] - The analysis was not performed.

No statistical analyses for this end point

Secondary: Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg Trametinib in Combination with 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2

Top of page

End point title

Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg Trametinib in Combination with 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2

End point description

Blood samples were to be collected at pre-specified time points for analysis of the Vc of trametinib, defined as the theoretical volume that would be necessary to contain the total amount of administered trametinib at the same concentration that it is observed in the blood plasma. As specified by the protocol, the Vc of trametinib was only to be analyzed if required and no data were collected since, by the time of final analysis, trametinib pharmacokinetics (PK) in melanoma participants had been well characterized and found to be consistent with the overall clinical pharmacology of trametinib characterized across indications.

End point type

Secondary

End point timeframe

Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Pooled Parts1+2:pembrolizumab and/or dabrafenib+2mg trametinib
Number of subjects analysed	0 ^[41]
Units: Liters
geometric mean (geometric coefficient of variation)	( )

Notes
[41] - The analysis was not performed.

No statistical analyses for this end point

Secondary: Volume of Distribution (Vc) of Trametinib Following Administration of 1.5 mg Trametinib in Combination with 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2

Top of page

End point title

Volume of Distribution (Vc) of Trametinib Following Administration of 1.5 mg Trametinib in Combination with 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Pooled Parts 1+2:pembrolizumab+1.5 mg trametinib
Number of subjects analysed	0 ^[42]
Units: Liters
geometric mean (geometric coefficient of variation)	( )

Notes
[42] - The analysis was not performed.

No statistical analyses for this end point

Secondary: Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg Trametinib in Combination with 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3

Top of page

End point title

Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg Trametinib in Combination with 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 3: 2 mg/kg pembrolizumab+dabrafenib+trametinib
Number of subjects analysed	0 ^[43]
Units: Liters
geometric mean (geometric coefficient of variation)	( )

Notes
[43] - The analysis was not performed.

No statistical analyses for this end point

Secondary: Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg Trametinib in Combination with Placebo and 150 mg Dabrafenib in Participants From Part 3

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End point title

Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg Trametinib in Combination with Placebo and 150 mg Dabrafenib in Participants From Part 3

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 22: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 3: placebo+dabrafenib+trametinib
Number of subjects analysed	0 ^[44]
Units: Liters
geometric mean (geometric coefficient of variation)	( )

Notes
[44] - The analysis was not performed.

No statistical analyses for this end point

Secondary: Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 4

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End point title

Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 4

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 4: 200 mg pembrolizumab+2 mg trametinib
Number of subjects analysed	0 ^[45]
Units: Liters
geometric mean (geometric coefficient of variation)	( )

Notes
[45] - The analysis was not performed.

No statistical analyses for this end point

Secondary: Volume of Distribution (Vc) of Trametinib Following Administration of 1.5 mg Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 4

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End point title

Volume of Distribution (Vc) of Trametinib Following Administration of 1.5 mg Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 4

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 4: 200 mg pembrolizumab+1.5 mg trametinib
Number of subjects analysed	0 ^[46]
Units: Liters
geometric mean (geometric coefficient of variation)	( )

Notes
[46] - The analysis was not performed.

No statistical analyses for this end point

Secondary: Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg of Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 5

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End point title

Volume of Distribution (Vc) of Trametinib Following Administration of 2 mg of Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 5

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 5: 200 mg pembrolizumab+2 mg trametinib
Number of subjects analysed	0 ^[47]
Units: Liters
geometric mean (geometric coefficient of variation)	( )

Notes
[47] - The analysis was not performed.

No statistical analyses for this end point

Secondary: Volume of Distribution (Vc) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 5

Top of page

End point title

Volume of Distribution (Vc) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 5

End point description

End point type

Secondary

End point timeframe

Cycle 1 Day 36: predose, postdose, 4 - 6 hrs postdose. Each cycle is a 21-day cycle.

End point values	Part 5: 200 mg pembrolizumab+1.5 mg trametinib
Number of subjects analysed	0 ^[48]
Units: Liters
geometric mean (geometric coefficient of variation)	( )

Notes
[48] - The analysis was not performed.

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Up to approximately 85 months

Adverse event reporting additional description

All-cause mortality=all randomized participants and AEs=all participants who received ≥1 dose of treatment. Per protocol, disease progression (DP) was not considered an AE unless related to treatment. Medical Dictionary for Regulatory Activities (MedDRA) terms neoplasm progression (NP), malignant NP, and DP not related to treatment were excluded.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.0

Reporting group title

Part 1:pembrolizumab 2 mg/kg+dabrafenib150 mg+trametinib 2 mg

Reporting group description

Reporting group title

Part 1:pembrolizumab 2 mg/kg+trametinib 2 mg

Reporting group description

Reporting group title

Part 1:pembrolizumab 2 mg/kg+trametinib 1.5 mg

Reporting group description

Reporting group title

Part 2:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg

Reporting group description

Reporting group title

Part 2:pembrolizumab 2 mg/kg+trametinib 1.5 mg

Reporting group description

Reporting group title

Part 3:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg

Reporting group description

Reporting group title

Part 3:placebo+dabrafenib 150 mg+trametinib 2 mg

Reporting group description

Reporting group title

Part 4:4 weeks trametinib (Tra) 2mg; pembrolizumab+Tra 2mg

Reporting group description

Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 2 mg trametinib orally QD for 4 weeks. Starting with Week 5, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and a concurrent dosing schedule of 2 mg trametinib orally QD starting on Day 1 and continuing up until study treatment discontinuation.

Reporting group title

Part 4:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg

Reporting group description

Reporting group title

Part 4:4 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg

Reporting group description

Reporting group title

Part 4:2 weeks Tra 2mg; pembrolizumab+Tra 2mg intermittent

Reporting group description

Reporting group title

Part 4:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg intermittent

Reporting group description

Participants with BRAF wild-type melanoma or solid tumors (irrespective of BRAF status) received 1.5 mg trametinib orally QD for 2 weeks. Starting with Week 3, participants received 200 mg pembrolizumab administered by IV infusion on Day 1 Q3W and an intermittent dose schedule of 1.5 mg trametinib orally QD with 1 week OFF trametinib and 2 weeks ON trametinib continuing up until study treatment discontinuation.

Reporting group title

Part 5:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg

Reporting group description

Reporting group title

Part 5:2 weeks Tra 2mg; pembrolizumab+Tra 2mg intermittent

Reporting group description

Part 1:pembrolizumab 2 mg/kg+dabrafenib150 mg+trametinib 2 mg

Part 1:pembrolizumab 2 mg/kg+trametinib 2 mg

Part 1:pembrolizumab 2 mg/kg+trametinib 1.5 mg

Part 2:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg

Part 2:pembrolizumab 2 mg/kg+trametinib 1.5 mg

Part 3:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg

Part 3:placebo+dabrafenib 150 mg+trametinib 2 mg

Part 4:4 weeks trametinib (Tra) 2mg; pembrolizumab+Tra 2mg

Part 4:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg

Part 4:4 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg

Part 4:2 weeks Tra 2mg; pembrolizumab+Tra 2mg intermittent

Part 4:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg intermittent

Part 5:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg

Part 5:2 weeks Tra 2mg; pembrolizumab+Tra 2mg intermittent

Total subjects affected by serious adverse events

subjects affected / exposed

1 / 7 (14.29%)

0 / 3 (0.00%)

1 / 2 (50.00%)

3 / 8 (37.50%)

1 / 2 (50.00%)

36 / 60 (60.00%)

20 / 60 (33.33%)

1 / 3 (33.33%)

1 / 4 (25.00%)

4 / 5 (80.00%)

4 / 6 (66.67%)

1 / 3 (33.33%)

4 / 12 (33.33%)

2 / 9 (22.22%)

number of deaths (all causes)

number of deaths resulting from adverse events

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

Angiosarcoma

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (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 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

2 / 60 (3.33%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Bowen's disease

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

1 / 60 (1.67%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Breast cancer

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

1 / 60 (1.67%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Skin angiosarcoma

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Squamous cell carcinoma

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

1 / 60 (1.67%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Squamous cell carcinoma of skin

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

1 / 60 (1.67%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vascular disorders

Arterial thrombosis

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

0 / 3 (0.00%)

1 / 4 (25.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Deep vein thrombosis

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

2 / 60 (3.33%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Hypertension

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypotension

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

1 / 4 (25.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

General disorders and administration site conditions

Chills

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

2 / 60 (3.33%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Death

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (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

Influenza like illness

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

1 / 60 (1.67%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Mucosal haemorrhage

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 5 (20.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Oedema peripheral

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (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

1 / 7 (14.29%)

0 / 3 (0.00%)

0 / 2 (0.00%)

1 / 8 (12.50%)

0 / 2 (0.00%)

5 / 60 (8.33%)

8 / 60 (13.33%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

1 / 6 (16.67%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

1 / 1

0 / 0

1 / 1

0 / 0

8 / 9

7 / 9

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory, thoracic and mediastinal disorders

Dyspnoea

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

1 / 60 (1.67%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumomediastinum

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 5 (20.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonitis

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

6 / 60 (10.00%)

1 / 60 (1.67%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 5 (20.00%)

1 / 6 (16.67%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

7 / 7

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

1 / 1

0 / 0

Pulmonary embolism

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

1 / 4 (25.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (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

Tonsillar hypertrophy

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (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 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

1 / 8 (12.50%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 5 (20.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Amylase increased

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 5 (20.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Aspartate aminotransferase increased

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

1 / 8 (12.50%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 5 (20.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blood creatinine increased

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

1 / 60 (1.67%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gamma-glutamyltransferase increased

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

1 / 8 (12.50%)

0 / 2 (0.00%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Lipase increased

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 5 (20.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Injury, poisoning and procedural complications

Tendon rupture

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac disorders

Atrial fibrillation

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

1 / 60 (1.67%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Mitral valve incompetence

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Myocardial infarction

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

1 / 2 (50.00%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (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

Tachycardia

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nervous system disorders

Acute motor axonal neuropathy

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

1 / 60 (1.67%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Brain oedema

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

1 / 6 (16.67%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cerebral haemorrhage

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Haemorrhagic stroke

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Headache

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Peripheral motor neuropathy

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Sciatica

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

1 / 8 (12.50%)

0 / 2 (0.00%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blood and lymphatic system disorders

Anaemia

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

1 / 3 (33.33%)

0 / 4 (0.00%)

0 / 5 (0.00%)

1 / 6 (16.67%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Febrile neutropenia

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

1 / 3 (33.33%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (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

Neutropenia

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

1 / 60 (1.67%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Thrombocytopenia

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

1 / 3 (33.33%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Eye disorders

Detachment of retinal pigment epithelium

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Retinal detachment

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

1 / 60 (1.67%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Uveitis

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

1 / 60 (1.67%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorders

Colitis

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Diarrhoea

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

2 / 60 (3.33%)

1 / 60 (1.67%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Discoloured vomit

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Dysphagia

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 5 (20.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Faeces discoloured

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Lip swelling

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hepatobiliary disorders

Cholecystitis

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Drug-induced liver injury

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Immune-mediated hepatitis

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

1 / 8 (12.50%)

0 / 2 (0.00%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Skin and subcutaneous tissue disorders

Eczema

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

1 / 60 (1.67%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Rash erythematous

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

1 / 6 (16.67%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (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 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

1 / 12 (8.33%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nephrolithiasis

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

1 / 2 (50.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Renal impairment

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

1 / 60 (1.67%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Tubulointerstitial nephritis

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

2 / 60 (3.33%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Endocrine disorders

Hypophysitis

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (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

Muscular weakness

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

1 / 6 (16.67%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Myalgia

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Myositis

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

1 / 2 (50.00%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Infections and infestations

Abdominal infection

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Bacterial sepsis

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 5 (20.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cellulitis

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

1 / 5 (20.00%)

1 / 6 (16.67%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastroenteritis

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

1 / 60 (1.67%)

1 / 3 (33.33%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (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 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

1 / 60 (1.67%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (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 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Lymphangitis

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Meningitis aseptic

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

1 / 6 (16.67%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Parotitis

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Peritonitis bacterial

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

1 / 9 (11.11%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Pneumonia

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

2 / 60 (3.33%)

0 / 60 (0.00%)

0 / 3 (0.00%)

1 / 4 (25.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

1 / 3 (33.33%)

1 / 12 (8.33%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Pneumonia chlamydial

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

1 / 12 (8.33%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory tract infection

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

1 / 6 (16.67%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Sepsis

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

2 / 60 (3.33%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Septic shock

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

1 / 60 (1.67%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Streptococcal infection

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

1 / 9 (11.11%)

occurrences causally related to treatment / all

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Tubo-ovarian abscess

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Upper respiratory tract infection

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

1 / 60 (1.67%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Metabolism and nutrition disorders

Diabetes mellitus

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

1 / 60 (1.67%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Fluid retention

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

1 / 60 (1.67%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

0 / 12 (0.00%)

0 / 9 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypocalcaemia

subjects affected / exposed

0 / 7 (0.00%)

0 / 3 (0.00%)

0 / 2 (0.00%)

0 / 8 (0.00%)

0 / 2 (0.00%)

0 / 60 (0.00%)

0 / 3 (0.00%)

0 / 4 (0.00%)

0 / 5 (0.00%)

0 / 6 (0.00%)

0 / 3 (0.00%)

1 / 12 (8.33%)

0 / 9 (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	Part 1:pembrolizumab 2 mg/kg+dabrafenib150 mg+trametinib 2 mg	Part 1:pembrolizumab 2 mg/kg+trametinib 2 mg	Part 1:pembrolizumab 2 mg/kg+trametinib 1.5 mg	Part 2:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg	Part 2:pembrolizumab 2 mg/kg+trametinib 1.5 mg	Part 3:pembrolizumab 2 mg/kg+dabrafenib 150 mg+trametinib 2 mg	Part 3:placebo+dabrafenib 150 mg+trametinib 2 mg	Part 4:4 weeks trametinib (Tra) 2mg; pembrolizumab+Tra 2mg	Part 4:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg	Part 4:4 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg	Part 4:2 weeks Tra 2mg; pembrolizumab+Tra 2mg intermittent	Part 4:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg intermittent	Part 5:2 weeks Tra 1.5mg; pembrolizumab+Tra 1.5mg	Part 5:2 weeks Tra 2mg; pembrolizumab+Tra 2mg intermittent
Total subjects affected by non serious adverse events
subjects affected / exposed	7 / 7 (100.00%)	3 / 3 (100.00%)	2 / 2 (100.00%)	8 / 8 (100.00%)	2 / 2 (100.00%)	60 / 60 (100.00%)	58 / 60 (96.67%)	3 / 3 (100.00%)	4 / 4 (100.00%)	5 / 5 (100.00%)	6 / 6 (100.00%)	3 / 3 (100.00%)	11 / 12 (91.67%)	9 / 9 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	1 / 2 (50.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	4 / 60 (6.67%)	2 / 60 (3.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	2	1	0	0	6	3	0	0	0	0	0	0	0
Cancer pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Melanocytic naevus
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	1	0	0	0	0	0	0	0	0
Vascular disorders
Axillary vein thrombosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0
Deep vein thrombosis
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	1	0	0
Flushing
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Hot flush
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 60 (0.00%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	2	0	0	1	0	0	0	0	0	0	0
Hypertension
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	4 / 60 (6.67%)	3 / 60 (5.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 12 (8.33%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	12	4	0	0	1	0	1	1	1
Hypertensive crisis
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Hypotension
subjects affected / exposed	1 / 7 (14.29%)	1 / 3 (33.33%)	1 / 2 (50.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	6 / 60 (10.00%)	10 / 60 (16.67%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	2	1	1	0	0	7	13	1	0	0	1	0	1	0
Lymphoedema
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	2 / 60 (3.33%)	2 / 60 (3.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	2	2	0	0	0	0	0	1	0
Phlebitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	0
Thrombosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	3 / 7 (42.86%)	1 / 3 (33.33%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	19 / 60 (31.67%)	11 / 60 (18.33%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	3 / 12 (25.00%)	1 / 9 (11.11%)
occurrences all number	3	1	0	0	0	33	14	1	0	0	0	0	4	1
Axillary pain
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	2 / 60 (3.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	3	0	0	0	0	0	0	0
Catheter site pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	1
Chest pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	3 / 8 (37.50%)	0 / 2 (0.00%)	2 / 60 (3.33%)	2 / 60 (3.33%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	3	0	2	2	1	0	0	0	0	0	0
Chills
subjects affected / exposed	6 / 7 (85.71%)	2 / 3 (66.67%)	0 / 2 (0.00%)	6 / 8 (75.00%)	0 / 2 (0.00%)	21 / 60 (35.00%)	23 / 60 (38.33%)	0 / 3 (0.00%)	2 / 4 (50.00%)	3 / 5 (60.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	21	2	0	12	0	59	51	0	2	5	1	0	0	0
Face oedema
subjects affected / exposed	1 / 7 (14.29%)	1 / 3 (33.33%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	0 / 60 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	2	0	0	0	2	0	0	1	1	1	0	0	0
Facial pain
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Fatigue
subjects affected / exposed	4 / 7 (57.14%)	1 / 3 (33.33%)	2 / 2 (100.00%)	6 / 8 (75.00%)	1 / 2 (50.00%)	22 / 60 (36.67%)	25 / 60 (41.67%)	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 5 (20.00%)	4 / 6 (66.67%)	1 / 3 (33.33%)	3 / 12 (25.00%)	3 / 9 (33.33%)
occurrences all number	5	1	2	10	2	37	41	1	0	1	4	1	3	3
Feeling abnormal
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Feeling cold
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 60 (0.00%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	2	0	0	1	0	0	0	0	0	0	0
Feeling hot
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	2 / 60 (3.33%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	2	1	0	0	0	0	0	0	0
Generalised oedema
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Impaired healing
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 2 (50.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0
Influenza like illness
subjects affected / exposed	2 / 7 (28.57%)	2 / 3 (66.67%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	8 / 60 (13.33%)	8 / 60 (13.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	2	2	0	0	0	15	12	0	0	1	0	0	0	0
Localised oedema
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0
Malaise
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	1	2	0	0	1	0	0	1	0
Medical device site rash
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	0
Mucosal inflammation
subjects affected / exposed	1 / 7 (14.29%)	1 / 3 (33.33%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	3 / 60 (5.00%)	1 / 60 (1.67%)	2 / 3 (66.67%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 9 (11.11%)
occurrences all number	1	2	0	0	0	4	1	2	0	0	0	0	1	1
Non-cardiac chest pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	1 / 60 (1.67%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0	0	0	0	0	0	0
Oedema peripheral
subjects affected / exposed	0 / 7 (0.00%)	3 / 3 (100.00%)	0 / 2 (0.00%)	2 / 8 (25.00%)	2 / 2 (100.00%)	10 / 60 (16.67%)	5 / 60 (8.33%)	1 / 3 (33.33%)	1 / 4 (25.00%)	2 / 5 (40.00%)	3 / 6 (50.00%)	1 / 3 (33.33%)	4 / 12 (33.33%)	4 / 9 (44.44%)
occurrences all number	0	8	0	2	2	13	5	2	1	2	3	2	5	4
Pain
subjects affected / exposed	1 / 7 (14.29%)	1 / 3 (33.33%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	3 / 60 (5.00%)	1 / 60 (1.67%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	1	0	1	0	3	1	1	0	0	0	0	0	0
Peripheral swelling
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	1 / 2 (50.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	1 / 60 (1.67%)	2 / 60 (3.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	2 / 9 (22.22%)
occurrences all number	1	0	1	1	0	1	2	0	0	0	0	2	0	2
Pyrexia
subjects affected / exposed	7 / 7 (100.00%)	2 / 3 (66.67%)	0 / 2 (0.00%)	8 / 8 (100.00%)	0 / 2 (0.00%)	50 / 60 (83.33%)	41 / 60 (68.33%)	1 / 3 (33.33%)	2 / 4 (50.00%)	1 / 5 (20.00%)	3 / 6 (50.00%)	1 / 3 (33.33%)	7 / 12 (58.33%)	3 / 9 (33.33%)
occurrences all number	23	3	0	25	0	262	118	2	2	1	4	1	14	4
Swelling
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0	0	0	0	1	0
Temperature intolerance
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 2 (50.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	1	0
Reproductive system and breast disorders
Adnexa uteri mass
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Benign prostatic hyperplasia
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 2 (50.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	1	1	0	0	0	0	0	0	0
Erectile dysfunction
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Vaginal haemorrhage
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	4	0
Respiratory, thoracic and mediastinal disorders
Atelectasis
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0
Cough
subjects affected / exposed	3 / 7 (42.86%)	0 / 3 (0.00%)	0 / 2 (0.00%)	5 / 8 (62.50%)	1 / 2 (50.00%)	10 / 60 (16.67%)	12 / 60 (20.00%)	1 / 3 (33.33%)	2 / 4 (50.00%)	1 / 5 (20.00%)	3 / 6 (50.00%)	1 / 3 (33.33%)	4 / 12 (33.33%)	1 / 9 (11.11%)
occurrences all number	3	0	0	6	1	17	12	2	2	1	3	1	6	1
Dysphonia
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	1	0	0	0	0
Dyspnoea
subjects affected / exposed	0 / 7 (0.00%)	2 / 3 (66.67%)	1 / 2 (50.00%)	1 / 8 (12.50%)	1 / 2 (50.00%)	9 / 60 (15.00%)	4 / 60 (6.67%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 9 (11.11%)
occurrences all number	0	3	1	2	1	11	4	0	1	0	1	0	2	1
Dyspnoea exertional
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	1	1	0	0	0	1	0	0	1
Epistaxis
subjects affected / exposed	1 / 7 (14.29%)	1 / 3 (33.33%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	2 / 60 (3.33%)	0 / 60 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 9 (0.00%)
occurrences all number	1	2	0	2	0	3	0	1	0	0	0	0	2	0
Haemoptysis
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0
Laryngeal inflammation
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Lung consolidation
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Nasal congestion
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	2 / 8 (25.00%)	0 / 2 (0.00%)	2 / 60 (3.33%)	0 / 60 (0.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	2	0	2	0	1	1	0	1	0	0	0
Nasal ulcer
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Oropharyngeal pain
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	1 / 2 (50.00%)	2 / 8 (25.00%)	0 / 2 (0.00%)	5 / 60 (8.33%)	8 / 60 (13.33%)	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	2	0	1	3	0	5	12	1	0	1	0	0	1	0
Painful respiration
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	1
Pleural effusion
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	2	1	0
Pneumonitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 2 (50.00%)	4 / 60 (6.67%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	1	6	1	0	0	0	0	0	1	0
Productive cough
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	2 / 60 (3.33%)	0 / 60 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	2 / 3 (66.67%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	1	1	0	2	0	0
Pulmonary embolism
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	0 / 60 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0	1	0	0	0	1	0	0
Rales
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	2	0	0	0	0
Respiratory distress
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0
Rhinalgia
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Rhinitis allergic
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	1	0
Rhinitis atrophic
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0
Rhinorrhoea
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	2 / 60 (3.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	2	0	0	0	0	0	0	0
Sinus pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0
Throat irritation
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0	0	0	0	0	0	0
Wheezing
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0	0	1	0	0	0	0
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	1 / 60 (1.67%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0	0	0	0	0	0	0
Confusional state
subjects affected / exposed	2 / 7 (28.57%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	3 / 60 (5.00%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	2	0	0	0	0	3	1	0	0	1	1	0	0	0
Depression
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0
Insomnia
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	2 / 2 (100.00%)	2 / 8 (25.00%)	0 / 2 (0.00%)	2 / 60 (3.33%)	2 / 60 (3.33%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	2 / 6 (33.33%)	1 / 3 (33.33%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	2	0	2	2	0	3	2	0	1	0	2	1	0	1
Investigations
Activated partial thromboplastin time prolonged
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0
Alanine aminotransferase increased
subjects affected / exposed	3 / 7 (42.86%)	2 / 3 (66.67%)	0 / 2 (0.00%)	2 / 8 (25.00%)	1 / 2 (50.00%)	11 / 60 (18.33%)	11 / 60 (18.33%)	0 / 3 (0.00%)	2 / 4 (50.00%)	2 / 5 (40.00%)	3 / 6 (50.00%)	0 / 3 (0.00%)	6 / 12 (50.00%)	3 / 9 (33.33%)
occurrences all number	5	2	0	2	1	15	12	0	2	2	3	0	8	5
Amylase abnormal
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0
Amylase increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	4 / 60 (6.67%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	5	0	0	0	2	2	0	0	1
Aspartate aminotransferase increased
subjects affected / exposed	3 / 7 (42.86%)	3 / 3 (100.00%)	0 / 2 (0.00%)	2 / 8 (25.00%)	1 / 2 (50.00%)	12 / 60 (20.00%)	12 / 60 (20.00%)	0 / 3 (0.00%)	3 / 4 (75.00%)	2 / 5 (40.00%)	3 / 6 (50.00%)	0 / 3 (0.00%)	6 / 12 (50.00%)	5 / 9 (55.56%)
occurrences all number	5	3	0	3	1	17	14	0	3	4	4	0	10	8
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	2 / 8 (25.00%)	0 / 2 (0.00%)	10 / 60 (16.67%)	12 / 60 (20.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	2 / 12 (16.67%)	3 / 9 (33.33%)
occurrences all number	2	0	0	2	0	18	16	0	0	0	2	0	2	3
Blood bilirubin increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	1 / 60 (1.67%)	0 / 60 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	2	0	0	1	0	1	0	1	0
Blood cholesterol increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	3 / 60 (5.00%)	2 / 60 (3.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	2 / 9 (22.22%)
occurrences all number	0	0	0	0	0	5	2	0	0	0	0	0	0	2
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 2 (50.00%)	5 / 60 (8.33%)	6 / 60 (10.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	2 / 5 (40.00%)	3 / 6 (50.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	9	9	1	0	2	3	0	1	0
Blood creatinine increased
subjects affected / exposed	2 / 7 (28.57%)	0 / 3 (0.00%)	1 / 2 (50.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	5 / 60 (8.33%)	5 / 60 (8.33%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 9 (0.00%)
occurrences all number	4	0	2	0	0	8	6	0	1	0	0	0	2	0
Blood glucose increased
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	1	0	0	0	0	0	0	0	0
Blood iron decreased
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 60 (0.00%)	2 / 60 (3.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	3	0	0	0	0	0	0	0
Blood potassium increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0
Blood uric acid increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	1
Body temperature increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0
C-reactive protein abnormal
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0
C-reactive protein increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	1	0
Ejection fraction decreased
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 2 (50.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	2 / 60 (3.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	2	0	0	1	2	0	0	0	0	0	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	7 / 60 (11.67%)	10 / 60 (16.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	1 / 9 (11.11%)
occurrences all number	0	0	0	1	0	8	14	0	0	0	0	0	3	1
International normalised ratio increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 2 (50.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	1	0
Lipase increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	5 / 60 (8.33%)	2 / 60 (3.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 12 (8.33%)	2 / 9 (22.22%)
occurrences all number	0	0	0	0	0	7	3	0	0	2	1	0	1	3
Liver function test abnormal
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	0
Neutrophil count decreased
subjects affected / exposed	2 / 7 (28.57%)	0 / 3 (0.00%)	0 / 2 (0.00%)	3 / 8 (37.50%)	0 / 2 (0.00%)	2 / 60 (3.33%)	2 / 60 (3.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	7	0	0	4	0	7	2	0	0	0	0	0	1	0
Neutrophil count increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0
Platelet count decreased
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	2 / 8 (25.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	1	0	0	4	0	1	0	0	0	0	1	0	1	0
Procalcitonin increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0
Transaminases increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	2 / 60 (3.33%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	2	0	2	1	0	0	0	0	0	0	1
Troponin I increased
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Troponin increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Urobilinogen urine increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0
Weight decreased
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 2 (50.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	6 / 60 (10.00%)	7 / 60 (11.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	1	0	6	8	0	0	0	1	0	0	0
Weight increased
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	2 / 60 (3.33%)	2 / 60 (3.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	2	2	0	0	1	0	0	0	0
White blood cell count decreased
subjects affected / exposed	2 / 7 (28.57%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	1 / 60 (1.67%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	2	0	0	2	0	2	1	0	0	0	0	0	0	0
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	2 / 60 (3.33%)	8 / 60 (13.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	4	11	0	0	0	1	0	0	0
Back injury
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Bone contusion
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Fall
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	2	0	0	0	0	0	3	0	0	0	0	0	0	0
Meniscus injury
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Mouth injury
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Procedural pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 2 (50.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	1	1	0	0	1	0	0	0	0
Rib fracture
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Skin abrasion
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0
Skin laceration
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Sunburn
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 60 (0.00%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	1	0	0	0	0	0	0	0
Wound haemorrhage
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0
Wound secretion
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	2	0	0
Cardiac disorders
Atrioventricular block
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Left ventricular dysfunction
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Myocardial ischaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Palpitations
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Sinus bradycardia
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0
Sinus tachycardia
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	1	0	0	0	0	0	0	0	0
Tachycardia
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	2 / 60 (3.33%)	2 / 60 (3.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	2	2	0	0	0	0	0	1	0
Nervous system disorders
Dizziness
subjects affected / exposed	3 / 7 (42.86%)	0 / 3 (0.00%)	1 / 2 (50.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	7 / 60 (11.67%)	8 / 60 (13.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	3	0	1	1	0	8	10	0	0	2	2	2	0	0
Dizziness postural
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0
Dysgeusia
subjects affected / exposed	1 / 7 (14.29%)	1 / 3 (33.33%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 2 (50.00%)	2 / 60 (3.33%)	3 / 60 (5.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	2 / 3 (66.67%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	1	0	0	1	3	3	0	0	0	0	2	0	0
External compression headache
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Head discomfort
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Headache
subjects affected / exposed	5 / 7 (71.43%)	2 / 3 (66.67%)	0 / 2 (0.00%)	4 / 8 (50.00%)	0 / 2 (0.00%)	18 / 60 (30.00%)	13 / 60 (21.67%)	1 / 3 (33.33%)	1 / 4 (25.00%)	1 / 5 (20.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	4 / 12 (33.33%)	0 / 9 (0.00%)
occurrences all number	7	4	0	6	0	29	23	1	1	1	4	0	4	0
Hyperaesthesia
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 60 (0.00%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	1	0	0	0	1	0	0	0
Hypoaesthesia
subjects affected / exposed	1 / 7 (14.29%)	1 / 3 (33.33%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	2 / 60 (3.33%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	2	0	0	0	3	0	0	0	1	1	0	0	0
Hyposmia
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	0
Migraine
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	3 / 60 (5.00%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	4	1	0	0	0	0	0	0	0
Neuralgia
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Neuropathy peripheral
subjects affected / exposed	1 / 7 (14.29%)	1 / 3 (33.33%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	1	0	0	0	1	1	0	0	0	0	0	0	0
Paraesthesia
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	1 / 60 (1.67%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	2	2	0	0	0	0	0	0	0
Peroneal nerve palsy
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0
Seizure
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	1	0	0	0	0	0	0	0
Syncope
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 2 (50.00%)	2 / 60 (3.33%)	2 / 60 (3.33%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	1	2	3	0	1	0	0	0	0	0
Taste disorder
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Tremor
subjects affected / exposed	2 / 7 (28.57%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	2 / 60 (3.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	2	0	0	0	0	1	2	0	0	0	0	0	0	0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 7 (28.57%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	8 / 60 (13.33%)	3 / 60 (5.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	3 / 6 (50.00%)	1 / 3 (33.33%)	6 / 12 (50.00%)	1 / 9 (11.11%)
occurrences all number	2	0	0	1	0	13	3	0	0	0	3	1	6	1
Leukocytosis
subjects affected / exposed	0 / 7 (0.00%)	2 / 3 (66.67%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	2	0	0	0	0	1	0	0	0	0	0	0	0
Leukopenia
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	1	0	0	0	0	0	1	0	0	0	0	0	0	1
Lymphadenopathy
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	2 / 60 (3.33%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	3	0	0	0	0	0	0	0	0
Neutropenia
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	6 / 60 (10.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 9 (11.11%)
occurrences all number	2	0	0	0	0	2	9	0	0	0	0	0	1	1
Thrombocytopenia
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	2 / 60 (3.33%)	0 / 60 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	1 / 9 (11.11%)
occurrences all number	1	0	0	0	0	3	0	1	0	0	0	0	2	1
Thrombocytosis
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Ear and labyrinth disorders
Cerumen impaction
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0
Deafness unilateral
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Ear discomfort
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Ear pain
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	1	0	0	0	1	0	0	0	0
Middle ear effusion
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Tympanic membrane disorder
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0
Vertigo
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	4 / 60 (6.67%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	4	1	0	0	0	0	0	0	0
Eye disorders
Cataract
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	1	0	0
Chorioretinal disorder
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0
Chorioretinopathy
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Dry eye
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	3 / 60 (5.00%)	2 / 60 (3.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	1	0	0	1	0	4	2	0	0	0	0	0	1	0
Eyelid rash
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Iridocyclitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0
Keratitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	1	0	0	0
Ocular hyperaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Papilloedema
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Periorbital oedema
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	1	0	0	0	0	1	0	0	0
Periorbital swelling
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Photophobia
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	1	0	0	0
Retinopathy
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	1	0	0	0	0
Uveitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	3 / 60 (5.00%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	3	1	0	0	0	0	0	0	0
Vision blurred
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	2 / 8 (25.00%)	0 / 2 (0.00%)	3 / 60 (5.00%)	1 / 60 (1.67%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	2 / 3 (66.67%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	3	0	3	7	0	1	0	1	2	0	0
Visual field defect
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	2 / 60 (3.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	1	2	0	0	0	0	0	0	0
Visual impairment
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	2 / 60 (3.33%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0	0	0	1	0	0
Vitreous adhesions
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Vitreous detachment
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	1
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	1 / 7 (14.29%)	2 / 3 (66.67%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	2 / 60 (3.33%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	2	0	0	0	2	1	0	0	0	0	0	0	0
Abdominal distension
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	1	0	0	0
Abdominal pain
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 2 (0.00%)	2 / 8 (25.00%)	0 / 2 (0.00%)	3 / 60 (5.00%)	4 / 60 (6.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 12 (8.33%)	3 / 9 (33.33%)
occurrences all number	0	1	0	2	0	7	4	0	0	1	4	0	1	4
Abdominal pain lower
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	2 / 60 (3.33%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	1	0	0	1	0	2	2	0	0	0	0	0	0	1
Abdominal pain upper
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	9 / 60 (15.00%)	3 / 60 (5.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	9	3	1	0	1	0	0	0	1
Angular cheilitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0
Ascites
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	2 / 9 (22.22%)
occurrences all number	0	0	0	0	0	0	0	0	1	1	0	0	0	2
Change of bowel habit
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Colitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	2	1	0	0	0	0	0	0	3
Constipation
subjects affected / exposed	1 / 7 (14.29%)	1 / 3 (33.33%)	2 / 2 (100.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	5 / 60 (8.33%)	7 / 60 (11.67%)	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 5 (20.00%)	3 / 6 (50.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	3 / 9 (33.33%)
occurrences all number	1	3	2	1	0	7	7	1	0	2	3	0	2	3
Diarrhoea
subjects affected / exposed	5 / 7 (71.43%)	2 / 3 (66.67%)	2 / 2 (100.00%)	6 / 8 (75.00%)	0 / 2 (0.00%)	28 / 60 (46.67%)	17 / 60 (28.33%)	3 / 3 (100.00%)	2 / 4 (50.00%)	2 / 5 (40.00%)	5 / 6 (83.33%)	1 / 3 (33.33%)	5 / 12 (41.67%)	5 / 9 (55.56%)
occurrences all number	9	6	5	8	0	90	29	4	3	5	15	1	12	11
Dry mouth
subjects affected / exposed	2 / 7 (28.57%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	8 / 60 (13.33%)	2 / 60 (3.33%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	2 / 12 (16.67%)	1 / 9 (11.11%)
occurrences all number	2	0	0	0	0	10	2	0	1	0	0	1	2	1
Dyspepsia
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	3 / 60 (5.00%)	2 / 60 (3.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	5	2	0	0	0	0	0	2	0
Dysphagia
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	1	0	0	0	0	0	0	0
Frequent bowel movements
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	2 / 60 (3.33%)	4 / 60 (6.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	2	5	0	0	0	0	0	0	0
Glossodynia
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Haematemesis
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0
Haematochezia
subjects affected / exposed	1 / 7 (14.29%)	1 / 3 (33.33%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	1	0	0	0	1	0	0	0	0	1	0	0	0
Haemorrhoids
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	1	0	1	0	0	0	0
Intestinal obstruction
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Large intestine perforation
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Lip blister
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0
Lip disorder
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 2 (50.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Lip oedema
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	1	0
Lip pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	1	0	0	0
Lip ulceration
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0
Mouth ulceration
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	3 / 60 (5.00%)	0 / 60 (0.00%)	2 / 3 (66.67%)	1 / 4 (25.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	2	0	3	0	2	1	1	0	1	1	0
Nausea
subjects affected / exposed	3 / 7 (42.86%)	3 / 3 (100.00%)	1 / 2 (50.00%)	5 / 8 (62.50%)	0 / 2 (0.00%)	23 / 60 (38.33%)	28 / 60 (46.67%)	0 / 3 (0.00%)	1 / 4 (25.00%)	3 / 5 (60.00%)	3 / 6 (50.00%)	2 / 3 (66.67%)	3 / 12 (25.00%)	2 / 9 (22.22%)
occurrences all number	3	7	2	9	0	46	47	0	1	3	5	2	4	2
Oral disorder
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Oral pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Proctalgia
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	1	0
Rectal haemorrhage
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	1	0	0
Rectal tenesmus
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0
Stomatitis
subjects affected / exposed	0 / 7 (0.00%)	2 / 3 (66.67%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 2 (50.00%)	5 / 60 (8.33%)	3 / 60 (5.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	3	0	0	1	5	3	0	0	0	0	0	1	0
Tongue disorder
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Tongue oedema
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0
Toothache
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	3 / 60 (5.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	3	0	0	0	0	0	0	0	0
Vomiting
subjects affected / exposed	2 / 7 (28.57%)	1 / 3 (33.33%)	2 / 2 (100.00%)	5 / 8 (62.50%)	0 / 2 (0.00%)	22 / 60 (36.67%)	17 / 60 (28.33%)	0 / 3 (0.00%)	1 / 4 (25.00%)	2 / 5 (40.00%)	3 / 6 (50.00%)	1 / 3 (33.33%)	2 / 12 (16.67%)	2 / 9 (22.22%)
occurrences all number	2	1	2	7	0	55	29	0	1	3	8	1	2	3
Hepatobiliary disorders
Autoimmune hepatitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	1	0	0	0	0	0	0	0	0
Hepatitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0	0	1	0	0	0
Hypertransaminasaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	2 / 60 (3.33%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	2	2	0	0	0	0	0	1	0
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	2 / 60 (3.33%)	3 / 60 (5.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	1	0	2	3	0	0	0	0	0	0	1
Alopecia
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	5 / 60 (8.33%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 9 (11.11%)
occurrences all number	0	1	0	1	0	5	1	0	0	1	1	0	1	1
Dermatitis
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	2 / 60 (3.33%)	3 / 60 (5.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	6	3	0	0	0	0	0	1	0
Dermatitis acneiform
subjects affected / exposed	2 / 7 (28.57%)	3 / 3 (100.00%)	0 / 2 (0.00%)	4 / 8 (50.00%)	0 / 2 (0.00%)	9 / 60 (15.00%)	4 / 60 (6.67%)	3 / 3 (100.00%)	3 / 4 (75.00%)	2 / 5 (40.00%)	5 / 6 (83.33%)	1 / 3 (33.33%)	3 / 12 (25.00%)	6 / 9 (66.67%)
occurrences all number	2	4	0	5	0	9	4	4	7	5	6	1	4	7
Drug eruption
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Dry skin
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 2 (0.00%)	2 / 8 (25.00%)	0 / 2 (0.00%)	7 / 60 (11.67%)	4 / 60 (6.67%)	1 / 3 (33.33%)	0 / 4 (0.00%)	2 / 5 (40.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	1 / 12 (8.33%)	1 / 9 (11.11%)
occurrences all number	0	1	0	2	0	10	4	1	0	2	2	1	1	1
Eczema
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 60 (0.00%)	2 / 60 (3.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	2	0	0	0	0	0	0	0
Erythema
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	1 / 2 (50.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	7 / 60 (11.67%)	4 / 60 (6.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	2	1	1	0	12	4	0	0	1	2	0	0	0
Erythema multiforme
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0
Erythema nodosum
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	3 / 60 (5.00%)	2 / 60 (3.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	4	2	0	0	0	0	0	0	0
Hyperhidrosis
subjects affected / exposed	3 / 7 (42.86%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	4 / 60 (6.67%)	6 / 60 (10.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	10	0	0	0	0	7	10	0	0	1	0	0	0	0
Macule
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	2 / 60 (3.33%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	3	0	0	0	1	0	0	0	0
Nail disorder
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0
Night sweats
subjects affected / exposed	3 / 7 (42.86%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	3 / 60 (5.00%)	1 / 60 (1.67%)	0 / 3 (0.00%)	1 / 4 (25.00%)	2 / 5 (40.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	7	0	0	1	0	3	1	0	1	2	0	0	0	0
Pain of skin
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Palmar erythema
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	2 / 60 (3.33%)	3 / 60 (5.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	1	0	2	3	0	0	0	0	0	0	1
Pruritus
subjects affected / exposed	2 / 7 (28.57%)	3 / 3 (100.00%)	1 / 2 (50.00%)	2 / 8 (25.00%)	1 / 2 (50.00%)	10 / 60 (16.67%)	9 / 60 (15.00%)	1 / 3 (33.33%)	1 / 4 (25.00%)	2 / 5 (40.00%)	2 / 6 (33.33%)	2 / 3 (66.67%)	6 / 12 (50.00%)	3 / 9 (33.33%)
occurrences all number	6	5	1	2	2	17	12	1	1	3	2	3	10	3
Psoriasis
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0
Purpura
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0
Rash
subjects affected / exposed	3 / 7 (42.86%)	2 / 3 (66.67%)	1 / 2 (50.00%)	4 / 8 (50.00%)	1 / 2 (50.00%)	27 / 60 (45.00%)	18 / 60 (30.00%)	0 / 3 (0.00%)	2 / 4 (50.00%)	2 / 5 (40.00%)	2 / 6 (33.33%)	3 / 3 (100.00%)	6 / 12 (50.00%)	3 / 9 (33.33%)
occurrences all number	8	5	3	5	1	50	24	0	2	3	2	5	11	6
Rash erythematous
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	1 / 60 (1.67%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0	0	0	0	0	0	0
Rash follicular
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Rash macular
subjects affected / exposed	1 / 7 (14.29%)	1 / 3 (33.33%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 2 (50.00%)	2 / 60 (3.33%)	3 / 60 (5.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	1	0	0	1	2	3	0	0	0	0	0	0	0
Rash maculo-papular
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	1 / 2 (50.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	6 / 60 (10.00%)	3 / 60 (5.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	1	0	1	1	0	9	5	0	1	1	0	0	1	0
Rash pruritic
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	2 / 60 (3.33%)	1 / 60 (1.67%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 9 (11.11%)
occurrences all number	0	0	0	1	0	4	1	0	1	0	0	0	1	1
Scab
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	4	0	0	0	0	0	0	0	0	0	0	0	0
Skin exfoliation
subjects affected / exposed	0 / 7 (0.00%)	2 / 3 (66.67%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	3 / 60 (5.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	3	0	0	0	3	0	0	0	1	2	0	0	0
Skin fissures
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	0 / 60 (0.00%)	1 / 3 (33.33%)	2 / 4 (50.00%)	1 / 5 (20.00%)	3 / 6 (50.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	1	0	1	2	2	4	0	2	1
Skin haemorrhage
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	1	0	0	0
Vitiligo
subjects affected / exposed	1 / 7 (14.29%)	1 / 3 (33.33%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	12 / 60 (20.00%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	1	1	0	0	0	18	1	0	0	0	0	0	0	1
Xeroderma
subjects affected / exposed	1 / 7 (14.29%)	1 / 3 (33.33%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	1	0	0	0	0	0	0	0	0	0	0	0	0
Renal and urinary disorders
Bladder spasm
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0
Dysuria
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	2 / 60 (3.33%)	2 / 60 (3.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	2 / 12 (16.67%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	2	2	0	0	0	0	0	2	0
Haematuria
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	2 / 60 (3.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	0	0	1	0	0
Hydronephrosis
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 2 (50.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Pollakiuria
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	1 / 60 (1.67%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 5 (40.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	1	1	0	0	2	0	0	0	0
Renal failure
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Urinary retention
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	1	0	0	0	0
Urinary tract pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	0
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	3 / 8 (37.50%)	0 / 2 (0.00%)	3 / 60 (5.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	3	0	3	0	0	0	0	0	0	0	1
Hypopituitarism
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Hypothyroidism
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	3 / 8 (37.50%)	0 / 2 (0.00%)	5 / 60 (8.33%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 5 (40.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	1	0	0	3	0	6	1	0	0	2	1	0	0	1
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	3 / 7 (42.86%)	2 / 3 (66.67%)	1 / 2 (50.00%)	4 / 8 (50.00%)	0 / 2 (0.00%)	24 / 60 (40.00%)	17 / 60 (28.33%)	0 / 3 (0.00%)	2 / 4 (50.00%)	1 / 5 (20.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	2 / 9 (22.22%)
occurrences all number	6	2	1	12	0	54	34	0	2	1	2	0	0	2
Arthritis
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 60 (0.00%)	2 / 60 (3.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	2	0	0	0	0	0	0	0
Back pain
subjects affected / exposed	2 / 7 (28.57%)	0 / 3 (0.00%)	1 / 2 (50.00%)	1 / 8 (12.50%)	1 / 2 (50.00%)	8 / 60 (13.33%)	3 / 60 (5.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 5 (20.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	3	0	1	1	1	9	3	1	0	1	2	0	0	0
Bone pain
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Bursitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	1	0	0	0
Flank pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	1 / 60 (1.67%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	1	0	0	0	0	0
Joint instability
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0
Limb discomfort
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Limb mass
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Muscle spasms
subjects affected / exposed	1 / 7 (14.29%)	1 / 3 (33.33%)	0 / 2 (0.00%)	3 / 8 (37.50%)	0 / 2 (0.00%)	4 / 60 (6.67%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	3	1	0	5	0	8	0	0	0	0	2	0	0	0
Muscular weakness
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	2	1	0	0	0	0	0	0	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	2 / 60 (3.33%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	2	0	0	0	0	0	0	0	0
Musculoskeletal stiffness
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	1	1	0	0	0	0	0	0	0
Myalgia
subjects affected / exposed	2 / 7 (28.57%)	1 / 3 (33.33%)	0 / 2 (0.00%)	3 / 8 (37.50%)	0 / 2 (0.00%)	16 / 60 (26.67%)	10 / 60 (16.67%)	0 / 3 (0.00%)	2 / 4 (50.00%)	1 / 5 (20.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	2	1	0	12	0	23	17	0	3	1	2	0	1	0
Neck mass
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	1	0	0	0	0	0	0	0	0
Neck pain
subjects affected / exposed	2 / 7 (28.57%)	1 / 3 (33.33%)	0 / 2 (0.00%)	2 / 8 (25.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	2 / 60 (3.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	2	1	0	2	0	1	2	0	0	1	2	0	0	0
Osteopenia
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	0	0	1
Pain in extremity
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	1 / 2 (50.00%)	7 / 60 (11.67%)	3 / 60 (5.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	2	1	11	7	0	0	0	0	0	1	0
Rotator cuff syndrome
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0
Winged scapula
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0
Infections and infestations
Catheter site infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Cellulitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	2 / 60 (3.33%)	0 / 60 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	3	0	1	0	2	0	0	0	0
Conjunctivitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	5 / 60 (8.33%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	5	1	0	0	1	0	0	0	0
Cystitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	4 / 60 (6.67%)	4 / 60 (6.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	6	7	0	0	0	0	0	0	0
Ear infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 2 (50.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	1	0	0	1	0	0	0	0
Fungal infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0
Fungal skin infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	3 / 60 (5.00%)	1 / 60 (1.67%)	1 / 3 (33.33%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	3	1	1	0	1	0	0	0	0
Gastroenteritis
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	1
Genital herpes
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	0
Gingivitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0
Herpes virus infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	0	0	0	1	0
Herpes zoster
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0
Influenza
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	3 / 60 (5.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	4	0	0	0	0	0	1	0
Nasopharyngitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	4 / 60 (6.67%)	6 / 60 (10.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	5	6	0	0	2	0	0	0	0
Oral candidiasis
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	2 / 60 (3.33%)	3 / 60 (5.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	2	3	0	0	1	0	0	0	0
Oral fungal infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	1 / 3 (33.33%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	0
Oral herpes
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	2 / 8 (25.00%)	0 / 2 (0.00%)	3 / 60 (5.00%)	3 / 60 (5.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	2	0	4	4	0	0	1	0	0	0	0
Paronychia
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Pharyngitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	1	0	0	0	0
Pneumonia
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	4 / 60 (6.67%)	1 / 60 (1.67%)	0 / 3 (0.00%)	1 / 4 (25.00%)	2 / 5 (40.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	4	2	0	1	2	0	0	1	0
Pneumonia klebsiella
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	0	0	0
Pustule
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 2 (50.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Rash pustular
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	1	0	0	0	0
Sinusitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	2 / 60 (3.33%)	3 / 60 (5.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	2	3	0	0	1	0	0	1	0
Staphylococcal bacteraemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0
Tonsillitis
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	1	0
Upper respiratory tract infection
subjects affected / exposed	0 / 7 (0.00%)	1 / 3 (33.33%)	0 / 2 (0.00%)	3 / 8 (37.50%)	0 / 2 (0.00%)	3 / 60 (5.00%)	2 / 60 (3.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	1	0	3	0	4	2	0	0	1	0	0	0	0
Urinary tract infection
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 2 (50.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	6 / 60 (10.00%)	5 / 60 (8.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 9 (11.11%)
occurrences all number	0	0	1	2	0	9	7	0	0	2	1	0	1	1
Metabolism and nutrition disorders
Cachexia
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	0
Decreased appetite
subjects affected / exposed	3 / 7 (42.86%)	2 / 3 (66.67%)	0 / 2 (0.00%)	2 / 8 (25.00%)	0 / 2 (0.00%)	13 / 60 (21.67%)	11 / 60 (18.33%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	2 / 12 (16.67%)	0 / 9 (0.00%)
occurrences all number	4	2	0	2	0	17	11	0	0	1	1	1	2	0
Dehydration
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	1 / 2 (50.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	2 / 60 (3.33%)	3 / 60 (5.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	2 / 5 (40.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	1	0	0	2	3	0	0	3	1	0	1	0
Hypercalcaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	3 / 60 (5.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	4	0	0	0	0	0	0	1	0
Hyperglycaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	3 / 60 (5.00%)	3 / 60 (5.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	3	3	0	0	1	0	0	0	0
Hyperkalaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	1 / 60 (1.67%)	0 / 3 (0.00%)	1 / 4 (25.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	1 / 12 (8.33%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	1	0	0	0	3	0
Hyperphosphataemia
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	1	0	0	0	0	0	0	0	0
Hypertriglyceridaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	3 / 60 (5.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	1 / 12 (8.33%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	3	0	0	0	0	1	0	1	1
Hyperuricaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	1 / 9 (11.11%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Hypoalbuminaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	2 / 60 (3.33%)	4 / 60 (6.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	0	0	5	4	0	0	0	0	0	0	0
Hypocalcaemia
subjects affected / exposed	0 / 7 (0.00%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	2 / 60 (3.33%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	0	0	0	1	0	3	0	0	0	0	0	0	0	0
Hypokalaemia
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	1 / 2 (50.00%)	6 / 60 (10.00%)	3 / 60 (5.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	1	1	8	3	0	0	0	0	0	0	0
Hypomagnesaemia
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	1 / 60 (1.67%)	1 / 60 (1.67%)	0 / 3 (0.00%)	0 / 4 (0.00%)	1 / 5 (20.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)	3 / 12 (25.00%)	1 / 9 (11.11%)
occurrences all number	1	0	0	0	0	1	1	0	0	1	2	0	3	1
Hyponatraemia
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	1 / 2 (50.00%)	1 / 60 (1.67%)	4 / 60 (6.67%)	0 / 3 (0.00%)	2 / 4 (50.00%)	0 / 5 (0.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	1	1	5	0	4	0	1	1	0	0
Hypophagia
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Hypophosphataemia
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	1 / 8 (12.50%)	0 / 2 (0.00%)	2 / 60 (3.33%)	0 / 60 (0.00%)	1 / 3 (33.33%)	2 / 4 (50.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	1	0	2	0	1	3	0	0	0	0	0
Polydipsia
subjects affected / exposed	1 / 7 (14.29%)	0 / 3 (0.00%)	0 / 2 (0.00%)	0 / 8 (0.00%)	0 / 2 (0.00%)	0 / 60 (0.00%)	0 / 60 (0.00%)	0 / 3 (0.00%)	0 / 4 (0.00%)	0 / 5 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)	0 / 12 (0.00%)	0 / 9 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

20 Jan 2015

Amendment 01 removed the MK-3475 10 mg/kg administered on Day 1 of each 2-week cycle (Q2W) dose/schedule and all associated combination treatment arms using the 10 mg/kg Q2W dose/schedule and implemented the monotherapy dose/schedule for MK-3475 at 2 mg/kg administered on Day 1 of each 3-week cycle (Q3W).

19 Oct 2016

Amendment 02 incorporated study Parts 4 and 5 that included additional dosing regimens to identify, confirm, and expand a tolerable dose level of pembrolizumab and trametinib in BRAF wild-type melanoma and solid tumor participants.

22 Jan 2018

Amendment 03 implemented a safety update regarding myocarditis, updated the protocol for compliance with the latest dose modification guidance, and clarified the collection of survivor information throughout and following study participation regardless of discontinuation of treatment.

26 Jul 2018

Amendment 04 unblinded participants in Part 3 as a result of final analysis. The option for entering the second course phase of treatment was discontinued and language was added to transition participants to an extension study to continue protocol-defined assessments and treatment. The collection of data for pharmacokinetics, anti-drug antibodies, and patient reported outcomes questionnaires was discontinued since sufficient data were collected to complete the planned analysis.

13 May 2019

Amendment 05 removed enrollment for the Part 5 dose expansion phase from the protocol and updated language for contraception requirements and rash management.

19 Jan 2020

Amendment 06 added dose modification requirements for cases of severe cutaneous adverse reactions (SCARs) that have been reported during treatment with dabrafenib in combination with trametinib.

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 I/II Study to Assess the Safety and Efficacy of MK-3475 in Combination with Trametinib and Dabrafenib in Subjects with Advanced Melanoma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Parts 1, 2, 4, and 5: Number of Participants Who Experienced Dose-limiting Toxicities (DLTs)

Primary: Parts 1, 2, 4, and 5: Number of Participants Who Experienced Dose-limiting Toxicities (DLTs)

Primary: Part 2: Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator in Participants Without BRAF V600 E or K Mutations

Primary: Part 2: Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as Assessed by Investigator in Participants Without BRAF V600 E or K Mutations

Primary: Part 5: ORR per RECIST 1.1 as Assessed by Investigator in Participants Without BRAF V600 E or K Mutations or With Solid Tumors Irrespective of BRAF Status

Primary: Part 5: ORR per RECIST 1.1 as Assessed by Investigator in Participants Without BRAF V600 E or K Mutations or With Solid Tumors Irrespective of BRAF Status

Primary: Part 3: Progression-Free Survival (PFS) Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations

Primary: Part 3: Progression-Free Survival (PFS) Per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations

Primary: Parts 1, 2, 4, and 5: Number of Participants Who Experienced an Adverse Event (AE)

Primary: Parts 1, 2, 4, and 5: Number of Participants Who Experienced an Adverse Event (AE)

Primary: Parts 1, 2, 4, and 5: Number of Participants Who Discontinued Study Treatment Due to an AE

Primary: Parts 1, 2, 4, and 5: Number of Participants Who Discontinued Study Treatment Due to an AE

Secondary: Part 1: ORR per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations

Secondary: Part 1: ORR per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations

Secondary: Part 2: ORR per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations

Secondary: Part 2: ORR per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations

Secondary: Part 3: ORR per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations

Secondary: Part 3: ORR per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations

Secondary: Part 3: Duration of Response (DOR) per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations

Secondary: Part 3: Duration of Response (DOR) per RECIST 1.1 as Assessed by Investigator in Participants With BRAF V600 E or K Mutations

Secondary: Part 3: Overall Survival (OS) in Participants With BRAF V600 E or K Mutations

Secondary: Part 3: Overall Survival (OS) in Participants With BRAF V600 E or K Mutations

Secondary: Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination with Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2

Secondary: Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination with Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2

Secondary: Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination with Dabrafenib and Trametinib in Participants From Part 3

Secondary: Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination with Dabrafenib and Trametinib in Participants From Part 3

Secondary: Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination with Trametinib in Participants From Part 4

Secondary: Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination with Trametinib in Participants From Part 4

Secondary: Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination with Trametinib in Participants From Part 5

Secondary: Maximum Concentration (Cmax) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination with Trametinib in Participants From Part 5

Secondary: Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination with Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2

Secondary: Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination with Dabrafenib and/or Trametinib in Participants Pooled From Parts 1 and 2

Secondary: Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination with Dabrafenib and Trametinib in Participants From Part 3

Secondary: Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 2 mg/kg Pembrolizumab in Combination with Dabrafenib and Trametinib in Participants From Part 3

Secondary: Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination with Trametinib in Participants From Part 4

Secondary: Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination with Trametinib in Participants From Part 4

Secondary: Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination with Trametinib in Participants From Part 5

Secondary: Trough Concentration (Ctrough) of Pembrolizumab Following Administration of 200 mg Pembrolizumab in Combination with Trametinib in Participants From Part 5

Secondary: Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2

Secondary: Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2

Secondary: Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3

Secondary: Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3

Secondary: Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with Placebo and 2 mg Trametinib in Participants From Part 3

Secondary: Maximum Concentration (Cmax) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with Placebo and 2 mg Trametinib in Participants From Part 3

Secondary: Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2

Secondary: Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants Pooled From Parts 1 and 2

Secondary: Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3

Secondary: Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with 2 mg/kg Pembrolizumab and 2 mg Trametinib in Participants From Part 3

Secondary: Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with Placebo and 2 mg Trametinib in Participants From Part 3

Secondary: Trough Concentration (Ctrough) of Dabrafenib Following Administration of 150 mg Dabrafenib in Combination with Placebo and 2 mg Trametinib in Participants From Part 3

Secondary: Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination with 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2

Secondary: Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination with 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2

Secondary: Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg Trametinib in Combination with 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2

Secondary: Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg Trametinib in Combination with 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2

Secondary: Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination with 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3

Secondary: Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination with 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants From Part 3

Secondary: Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination with Placebo and 150 mg Dabrafenib in Participants From Part 3

Secondary: Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination with Placebo and 150 mg Dabrafenib in Participants From Part 3

Secondary: Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 4

Secondary: Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 4

Secondary: Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 4

Secondary: Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 4

Secondary: Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg of Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 5

Secondary: Maximum Concentration (Cmax) of Trametinib Following Administration of 2 mg of Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 5

Secondary: Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 5

Secondary: Maximum Concentration (Cmax) of Trametinib Following Administration of 1.5 mg of Trametinib in Combination with 200 mg Pembrolizumab in Participants From Part 5

Secondary: Trough Concentration (Ctrough) of Trametinib Following Administration of 1.5 mg Trametinib in Combination with 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2

Secondary: Trough Concentration (Ctrough) of Trametinib Following Administration of 1.5 mg Trametinib in Combination with 2 mg/kg Pembrolizumab in Participants Pooled From Parts 1 and 2

Secondary: Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination with 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2

Secondary: Trough Concentration (Ctrough) of Trametinib Following Administration of 2 mg Trametinib in Combination with 2 mg/kg Pembrolizumab and 150 mg Dabrafenib in Participants Pooled From Parts 1 and 2

Clinical Trial Results:
A Phase I/II Study to Assess the Safety and Efficacy of MK-3475 in Combination with Trametinib and Dabrafenib in Subjects with Advanced Melanoma