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Clinical Trial Results:
An Exploratory Study of the Biologic Effects of Nivolumab and Nivolumab in Combination with Ipilimumab Treatment in Subjects with Advanced Melanoma (Unresectable or Metastatic)

Summary
EudraCT number	2012-001840-23
Trial protocol	Outside EU/EEA
Global end of trial date	25 Oct 2018

Results information
Results version number	v1(current)
This version publication date	25 Jun 2022
First version publication date	25 Jun 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

CA209-038

ISRCTN number

US NCT number

NCT01621490

WHO universal trial number (UTN)

Sponsor organisation name

Bristol-Myers Squibb

Sponsor organisation address

Chaussee de la Hulpe 18, Brussels, Belgium, 1170

Public contact

EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, Clinical.Trials@bms.com

Scientific contact

Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, Clinical.Trials@bms.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

21 Mar 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

25 Oct 2018

Was the trial ended prematurely?

Main objective of the trial

To investigate the pharmacodynamic activity of nivolumab, and nivolumab in combination with ipilimumab in the tumor environment and the periphery on biomarker measures such as circulating T cell subsets (activated and memory T cell populations by flow cytometry), interferon, interferon inducible factors and T cell (CD4 and CD8) infiltration in tumor biopsy sections from subjects with advanced melanoma.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial participants were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

27 Sep 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Netherlands: 20

Country: Number of subjects enrolled

Spain: 26

Country: Number of subjects enrolled

United States: 124

Worldwide total number of subjects

170

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)

122

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

227 participants were enrolled; 55 did not enter the treatment period: 41 did not meet study criteria; 6 other; 5 withdrew consent; 1 adverse events; 2 deaths. 172 entered the treatment period.2 were not treated;1 received ipilimumab monotherapy prior to the closure of Arm C; 1 received an unplanned treatment;168 were treated

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

N3 60 M Naive

Arm description

Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; Naive = Anti-CTLA4 Naive

Arm type

Experimental

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nivolumab 3 mg/kg administered intravenously (IV) in 60 minute infusion

N3 60M Prog

Arm description

Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; PROG = Anti-CTLA4 Progressed

Arm type

Experimental

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nivolumab 3 mg/kg administered intravenously (IV) in 60 minute infusion

N1 60M + I3 90M, W2

Arm description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; W2 = Week 2 Biopsy

Arm type

Experimental

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Ipilimumab 3 mg/kg administered intravenously (IV) in 90 minute infusion

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nivolumab 1 mg/kg administered intravenously (IV) in 60 minute infusion

N1 60M + I3 90M, W4

Arm description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; W4 = Week 4 Biopsy

Arm type

Experimental

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Ipilimumab 3 mg/kg administered intravenously (IV) in 90 minute infusion

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nivolumab 1 mg/kg administered intravenously (IV) in 60 minute infusion

N1 60M +I3 90M, WU

Arm description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; WU = Unknown Week Biopsy

Arm type

Experimental

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Ipilimumab 3 mg/kg administered intravenously (IV) in 90 minute infusion

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nivolumab 1 mg/kg administered intravenously (IV) in 60 minute infusion

N1 30M + I3 30M non-BM

Arm description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases

Arm type

Experimental

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Ipilimumab 3 mg/kg administered intravenously (IV) in 30 minute infusion

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nivolumab 1 mg/kg administered intravenously (IV) in 30 minute infusion

N3 30M non-BM

Arm description

Treatment Group: N3 = Nivolumab 3mg/kg;30M = 30 minute infusion; BM = Brain metastases

Arm type

Experimental

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nivolumab 3 mg/kg administered intravenously (IV) in 30 minute infusion

N1 30M +I3 30M BM

Arm description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases

Arm type

Experimental

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nivolumab 1 mg/kg administered intravenously (IV) in 30 minute infusion

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Ipilimumab 3 mg/kg administered intravenously (IV) in 30 minute infusion

N3 30M BM

Arm description

Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases

Arm type

Experimental

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nivolumab 3 mg/kg administered intravenously (IV) in 30 minute infusion

I3 Monotherapy

Arm description

Treatment Group: I3 = Ipilimumab 3 mg/kg infusion. Participant was enrolled prior to the closure of this arm via amendment

Arm type

Experimental

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Ipilimumab 3 mg/kg administered intravenously (IV)

Unplanned Treatment

Arm description

Unplanned treatment of nivolumab 1 mg/kg x 4 then nivolumab 3 mg/kg

Arm type

Experimental

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nivolumab 1 mg/kg administered intravenously (IV) for 4 doses followed by Nivolumab 3 mg/kg

Number of subjects in period 1	N3 60 M Naive	N3 60M Prog	N1 60M + I3 90M, W2	N1 60M + I3 90M, W4	N1 60M +I3 90M, WU	N1 30M + I3 30M non-BM	N3 30M non-BM	N1 30M +I3 30M BM	N3 30M BM	I3 Monotherapy	Unplanned Treatment
Started	41	44	11	10	6	25	11	10	10	1	1
Completed	0	0	0	0	0	0	0	0	0	0	0
Not completed	41	44	11	10	6	25	11	10	10	1	1
Adverse event, serious fatal	-	-	-	-	-	-	-	-	1	-	-
Consent withdrawn by subject	1	-	-	-	-	1	-	-	-	-	-
Disease progression	27	28	1	5	3	8	7	1	4	1	1
Completed	-	-	-	-	-	1	-	-	-	-	-
Study drug toxicity	1	4	5	3	1	10	1	4	1	-	-
Subject request to discontinue study	1	3	1	1	-	2	1	-	1	-	-
Maximum clinical benefit	3	2	-	-	-	-	1	2	2	-	-
Adverse event unrelated to study drug	1	1	-	-	-	-	-	2	-	-	-
Other reasons	7	6	4	1	1	3	1	1	1	-	-
Subject no longer meets study criteria	-	-	-	-	1	-	-	-	-	-	-

Baseline characteristics

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Reporting group title

N3 60 M Naive

Reporting group description

Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; Naive = Anti-CTLA4 Naive

Reporting group title

N3 60M Prog

Reporting group description

Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; PROG = Anti-CTLA4 Progressed

Reporting group title

N1 60M + I3 90M, W2

Reporting group description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; W2 = Week 2 Biopsy

Reporting group title

N1 60M + I3 90M, W4

Reporting group description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; W4 = Week 4 Biopsy

Reporting group title

N1 60M +I3 90M, WU

Reporting group description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; WU = Unknown Week Biopsy

Reporting group title

N1 30M + I3 30M non-BM

Reporting group description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases

Reporting group title

N3 30M non-BM

Reporting group description

Treatment Group: N3 = Nivolumab 3mg/kg;30M = 30 minute infusion; BM = Brain metastases

Reporting group title

N1 30M +I3 30M BM

Reporting group description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases

Reporting group title

N3 30M BM

Reporting group description

Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases

Reporting group title

I3 Monotherapy

Reporting group description

Treatment Group: I3 = Ipilimumab 3 mg/kg infusion. Participant was enrolled prior to the closure of this arm via amendment

Reporting group title

Unplanned Treatment

Reporting group description

Unplanned treatment of nivolumab 1 mg/kg x 4 then nivolumab 3 mg/kg

Reporting group values	N3 60 M Naive	N3 60M Prog	N1 60M + I3 90M, W2	N1 60M + I3 90M, W4	N1 60M +I3 90M, WU	N1 30M + I3 30M non-BM	N3 30M non-BM	N1 30M +I3 30M BM	N3 30M BM	I3 Monotherapy	Unplanned Treatment	Total
Number of subjects	41	44	11	10	6	25	11	10	10	1	1	170
Age categorical
Units: Subjects
Adults (18-64 years)	34	34	5	7	4	16	8	8	5	1	0	122
From 65-84 years	6	10	6	3	2	9	3	2	5	0	1	47
85 years and over	1	0	0	0	0	0	0	0	0	0	0	1
Age Continuous
"999"=N/A
Units: years
arithmetic mean (standard deviation)	55.5 ± 12.49	53.7 ± 15.10	61.0 ± 11.82	58.5 ± 13.29	56.8 ± 9.64	56.9 ± 13.52	51.5 ± 15.55	56.9 ± 9.37	58.9 ± 13.46	52.0 ± 999	66.0 ± 999	-
Sex: Female, Male
Units:
Female	19	18	3	4	3	8	4	4	5	1	0	69
Male	22	26	8	6	3	17	7	6	5	0	1	101
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0	0	0	0	0	0	0
Asian	0	1	0	0	0	0	0	0	0	0	0	1
Native Hawaiian or Other Pacific Islander	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
White	41	43	11	10	6	25	11	10	10	1	1	169
More than one race	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
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	2	0	2	0	0	0	1	1	0	0	0	6
Not Hispanic or Latino	34	41	6	10	5	15	5	3	7	1	1	128
Unknown or Not Reported	5	3	3	0	1	10	5	6	3	0	0	36

Subject analysis set title

N3 60M Naive

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: Part 1: Nivolumab 3 mg/kg 60 Minute Infusion Anti-CTLA4 Naive

Subject analysis set title

N3 60M PROG

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; PROG = Anti-CTLA4 Progressed

Subject analysis set title

N1 60M + I3 90M

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: Part 2: Nivolumab 1 mg/kg 60 Minute Infusion + Ipilimumab 3 mg/kg 90 Minute

Subject analysis set title

N1 30M + I3 30M BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases

Subject analysis set title

N1+ I3 Non-BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: Part 2+3: Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg Non-Brain Metastases

Subject analysis set title

Naive Nivo Mono

Subject analysis set type

Sub-group analysis

Subject analysis set description

Nivolumab Monotherapy CTLA-4 Naive

Subject analysis set title

All Nivo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: All Nivolumab Monotherapy

Subject analysis set title

All Combo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: All Combination Therapy

Subject analysis set title

Total

Subject analysis set type

Sub-group analysis

Subject analysis set description

All treatments

Subject analysis set title

N3 60M Naive

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: Part 1: Nivolumab 3 mg/kg 60 Minute Infusion Anti-CTLA4 Naive

Subject analysis set title

N3 60M PROG

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; PROG = Anti-CTLA4 Progressed

Subject analysis set title

N1 60M + I3 90M W2

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: Part 2: Nivolumab 1 mg/kg 60 Minute Infusion + Ipilimumab 3 mg/kg 90 Minute Infusion Week 2 Biopsy

Subject analysis set title

N1 60M + I3 90M W4

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: Part 2: Nivolumab 1 mg/kg 60 Minute Infusion + Ipilimumab 3 mg/kg 90 Minute Infusion Week 4 Biopsy

Subject analysis set title

N3 30M + I3 30M BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: Part 4: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Brain Metastases

Subject analysis set title

Nivo Mono

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: Part 1: Regular Infusion Nivolumab Mono

Subject analysis set title

Nivo Mono Reduced Infusion

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: Reduced Infusion Nivolumab Monotherapy

Subject analysis set title

Week 2 Biopsy Combo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: Week 2 Biopsy Combo

Subject analysis set title

Week 2 Biopsy non-BM Combo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: Week 2 Biopsy Non-Brain Metastases Combo

Subject analysis set title

Naive Nivo Mono non-BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: Naive Nivolumab Mono Non-Brain Metastases

Subject analysis set title

N1 + I3 non-BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: Part 2+3: Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg Non-Brain Metastases

Subject analysis set title

N3 60M Naive

Subject analysis set type

Sub-group analysis

Subject analysis set description

N3 = Nivolumab 3mg/kg;60M = 60 minute infusion; NAIVE = Anti-CTLA4 Naive

Subject analysis set title

N3 60M PROG

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; PROG = Anti-CTLA4 Progressed

Subject analysis set title

N1 60M + I3 90M

Subject analysis set type

Sub-group analysis

Subject analysis set description

N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion

Subject analysis set title

N1 30M + I3 30M BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases

Subject analysis set title

N3 60M Naive

Subject analysis set type

Sub-group analysis

Subject analysis set description

Part 1: Nivolumab 3 mg/kg 60 Minute Infusion Anti-CTLA4 Naive

Subject analysis set title

N1 60M + I3 90M

Subject analysis set type

Sub-group analysis

Subject analysis set description

Part 2: Nivolumab 1 mg/kg 60 Minute Infusion + Ipilimumab 3 mg/kg 90 Minute Infusion

Subject analysis set title

N1 30M + I3 30M Non-BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

Part 3: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Non-Brain Metastases

Subject analysis set title

N3 30M Non-BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

Part 3: Nivolumab 3 mg/kg 30 Minute Infusion Non-Brain Metastases

Subject analysis set title

N1 30M I3 30M BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

Part 4: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Brain Metastases

Subject analysis set title

N3 60M NAIVE

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; Naive = Anti-CTLA4 Naive

Subject analysis set title

N1 60M +I3 90M

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion

Subject analysis set title

N3 60M NAIVE

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; Naive = Anti-CTLA4 Naive

Subject analysis set title

N3 60M PROG

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; PROG = Anti-CTLA4 Progressed

Subject analysis set title

N1 60M +I3 90M

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion

Subject analysis set title

N1 60M+I3 90M

Subject analysis set type

Sub-group analysis

Subject analysis set description

N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion

Subject analysis set title

N1 30M + I3 30M BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

N3 = Nivolumab 3mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases

Subject analysis set title

N1 30M + I3 30M NON-BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases

Subject analysis set title

N3 30M NON-BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases

Subject analysis set title

N3 60M NAIVE

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; Naive = Anti-CTLA4 Naive

Subject analysis set title

N3 60M PROG

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; PROG = Anti-CTLA4 Progressed

Subject analysis set title

N1 60M + I3 (Nivo ADA

Subject analysis set type

Sub-group analysis

Subject analysis set description

Part 2: Nivolumab 1 mg/kg 60 Minute Infusion + Ipilimumab 3 mg/kg 90 Minute

Subject analysis set title

N1 60M + I3 90M (Ipi ADA)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Part 2: Nivolumab 1 mg/kg 60 Minute Infusion + Ipilimumab 3 mg/kg 90 Minute

Subject analysis set title

N1 30M + I3 30M Non-BM (Nivo ADA)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Part 3: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Non-Brain Metastases

Subject analysis set title

N1 30M + I3 30M Non-BM (Ipi ADA)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Part 3: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Non-Brain Metastases

Subject analysis set title

N1 30M + I3 30M (Nivo ADA)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Part 4: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Brain Metastases

Subject analysis set title

N1 30M + I3 30M (Ipi ADA)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Part 4: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Brain Metastases

Subject analysis set title

Total (Nivo ADA)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Total (All Nivolumab or Nivolumab + Ipilimumab Treated Subjects with Baseline and at Least One Post-Baseline Assessment)

Subject analysis set title

Total (Ipi ADA)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Total (All Nivolumab or Nivolumab + Ipilimumab Treated Subjects with Baseline and at Least One Post-Baseline Assessment)

Subject analysis set title

N3 60M NAIVE, W4

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; NAIVE = Anti-CTLA4 Naive

Subject analysis set title

N3 60M PROG, W4

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; PROG = Anti-CTLA4 Progressed;

Subject analysis set title

N1 60M + I3 90M, WU

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; WU = Unknown Week Biopsy

Subject analysis set title

N1 30M + I3 30M NON-BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases

Subject analysis set title

N3 30M NON-BM, W2

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy

Subject analysis set title

N1 30M + I3 30M BM, W2

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy

Subject analysis set title

N3 30M BM, W2

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy

Subject analysis set title

N3 60M, W4

Subject analysis set type

Sub-group analysis

Subject analysis set description

N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; W4 = Week 4 Biopsy

Subject analysis set title

N3 30M, W2

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy

Subject analysis set title

N1 + I3, W2

Subject analysis set type

Sub-group analysis

Subject analysis set description

N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; W2 = Week 2 Biopsy

Subject analysis set title

N1 + I3 W2, NON-BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; W2 = Week 2 Biopsy; BM = Brain metastases

Subject analysis set title

N3 NAIVE, NON-BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

N3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive; BM = Brain metastases

Subject analysis set title

N1 + I3 NON-BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases

Subject analysis set title

Total

Subject analysis set type

Sub-group analysis

Subject analysis set description

All treatments

Subject analysis set title

N1 + I3 NON-BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases

Subject analysis set title

N3 NAIVE

Subject analysis set type

Sub-group analysis

Subject analysis set description

N3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive

Subject analysis set title

All N3

Subject analysis set type

Sub-group analysis

Subject analysis set description

N3 = Nivolumab 3mg/kg

Subject analysis set title

N1 + I3

Subject analysis set type

Sub-group analysis

Subject analysis set description

All combination

Subject analysis set title

Total

Subject analysis set type

Sub-group analysis

Subject analysis set description

All treatments

N3 60M Naive

N3 60M PROG

N1 60M + I3 90M

N1 30M + I3 30M BM

N1+ I3 Non-BM

Naive Nivo Mono

All Nivo

All Combo

Total

N3 60M Naive

N3 60M PROG

N1 60M + I3 90M W2

N1 60M + I3 90M W4

N3 30M + I3 30M BM

Nivo Mono

Nivo Mono Reduced Infusion

Week 2 Biopsy Combo

Week 2 Biopsy non-BM Combo

Naive Nivo Mono non-BM

N1 + I3 non-BM

N3 60M Naive

N3 60M PROG

N1 60M + I3 90M

N1 30M + I3 30M BM

N3 60M Naive

N1 60M + I3 90M

N1 30M + I3 30M Non-BM

N3 30M Non-BM

N1 30M I3 30M BM

N3 60M NAIVE

N1 60M +I3 90M

N3 60M NAIVE

N3 60M PROG

N1 60M +I3 90M

N1 60M+I3 90M

N1 30M + I3 30M BM

N1 30M + I3 30M NON-BM

N3 30M NON-BM

N3 60M NAIVE

N3 60M PROG

N1 60M + I3 (Nivo ADA

N1 60M + I3 90M (Ipi ADA)

N1 30M + I3 30M Non-BM (Nivo ADA)

N1 30M + I3 30M Non-BM (Ipi ADA)

N1 30M + I3 30M (Nivo ADA)

N1 30M + I3 30M (Ipi ADA)

Total (Nivo ADA)

Total (Ipi ADA)

N3 60M NAIVE, W4

N3 60M PROG, W4

N1 60M + I3 90M, WU

N1 30M + I3 30M NON-BM

N3 30M NON-BM, W2

N1 30M + I3 30M BM, W2

N3 30M BM, W2

N3 60M, W4

N3 30M, W2

N1 + I3, W2

N1 + I3 W2, NON-BM

N3 NAIVE, NON-BM

N1 + I3 NON-BM

Total

N1 + I3 NON-BM

N3 NAIVE

All N3

N1 + I3

Total

Number of subjects

156

154

140

106

168

Units: Subjects

Adults (18-64 years)

From 65-84 years

85 years and over

"999"=N/A

Units: years

arithmetic mean (standard deviation)

44.4 ±

70.0 ±

26.25 ±

Units:

Female

Male

Units: Subjects

American Indian or Alaska Native

Asian

Native Hawaiian or Other Pacific Islander

Black or African American

White

More than one race

Unknown or Not Reported

Units: Subjects

Hispanic or Latino

Not Hispanic or Latino

Unknown or Not Reported

End points

Top of page

Reporting group title

N3 60 M Naive

Reporting group description

Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; Naive = Anti-CTLA4 Naive

Reporting group title

N3 60M Prog

Reporting group description

Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; PROG = Anti-CTLA4 Progressed

Reporting group title

N1 60M + I3 90M, W2

Reporting group description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; W2 = Week 2 Biopsy

Reporting group title

N1 60M + I3 90M, W4

Reporting group description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; W4 = Week 4 Biopsy

Reporting group title

N1 60M +I3 90M, WU

Reporting group description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; WU = Unknown Week Biopsy

Reporting group title

N1 30M + I3 30M non-BM

Reporting group description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases

Reporting group title

N3 30M non-BM

Reporting group description

Treatment Group: N3 = Nivolumab 3mg/kg;30M = 30 minute infusion; BM = Brain metastases

Reporting group title

N1 30M +I3 30M BM

Reporting group description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases

Reporting group title

N3 30M BM

Reporting group description

Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases

Reporting group title

I3 Monotherapy

Reporting group description

Treatment Group: I3 = Ipilimumab 3 mg/kg infusion. Participant was enrolled prior to the closure of this arm via amendment

Reporting group title

Unplanned Treatment

Reporting group description

Unplanned treatment of nivolumab 1 mg/kg x 4 then nivolumab 3 mg/kg

Subject analysis set title

N3 60M Naive

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: Part 1: Nivolumab 3 mg/kg 60 Minute Infusion Anti-CTLA4 Naive

Subject analysis set title

N3 60M PROG

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; PROG = Anti-CTLA4 Progressed

Subject analysis set title

N1 60M + I3 90M

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: Part 2: Nivolumab 1 mg/kg 60 Minute Infusion + Ipilimumab 3 mg/kg 90 Minute

Subject analysis set title

N1 30M + I3 30M BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases

Subject analysis set title

N1+ I3 Non-BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: Part 2+3: Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg Non-Brain Metastases

Subject analysis set title

Naive Nivo Mono

Subject analysis set type

Sub-group analysis

Subject analysis set description

Nivolumab Monotherapy CTLA-4 Naive

Subject analysis set title

All Nivo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: All Nivolumab Monotherapy

Subject analysis set title

All Combo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: All Combination Therapy

Subject analysis set title

Total

Subject analysis set type

Sub-group analysis

Subject analysis set description

All treatments

Subject analysis set title

N3 60M Naive

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: Part 1: Nivolumab 3 mg/kg 60 Minute Infusion Anti-CTLA4 Naive

Subject analysis set title

N3 60M PROG

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; PROG = Anti-CTLA4 Progressed

Subject analysis set title

N1 60M + I3 90M W2

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: Part 2: Nivolumab 1 mg/kg 60 Minute Infusion + Ipilimumab 3 mg/kg 90 Minute Infusion Week 2 Biopsy

Subject analysis set title

N1 60M + I3 90M W4

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: Part 2: Nivolumab 1 mg/kg 60 Minute Infusion + Ipilimumab 3 mg/kg 90 Minute Infusion Week 4 Biopsy

Subject analysis set title

N3 30M + I3 30M BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: Part 4: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Brain Metastases

Subject analysis set title

Nivo Mono

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: Part 1: Regular Infusion Nivolumab Mono

Subject analysis set title

Nivo Mono Reduced Infusion

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: Reduced Infusion Nivolumab Monotherapy

Subject analysis set title

Week 2 Biopsy Combo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: Week 2 Biopsy Combo

Subject analysis set title

Week 2 Biopsy non-BM Combo

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: Week 2 Biopsy Non-Brain Metastases Combo

Subject analysis set title

Naive Nivo Mono non-BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: Naive Nivolumab Mono Non-Brain Metastases

Subject analysis set title

N1 + I3 non-BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: Part 2+3: Nivolumab 1 mg/kg + Ipilimumab 3 mg/kg Non-Brain Metastases

Subject analysis set title

N3 60M Naive

Subject analysis set type

Sub-group analysis

Subject analysis set description

N3 = Nivolumab 3mg/kg;60M = 60 minute infusion; NAIVE = Anti-CTLA4 Naive

Subject analysis set title

N3 60M PROG

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; PROG = Anti-CTLA4 Progressed

Subject analysis set title

N1 60M + I3 90M

Subject analysis set type

Sub-group analysis

Subject analysis set description

N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion

Subject analysis set title

N1 30M + I3 30M BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases

Subject analysis set title

N3 60M Naive

Subject analysis set type

Sub-group analysis

Subject analysis set description

Part 1: Nivolumab 3 mg/kg 60 Minute Infusion Anti-CTLA4 Naive

Subject analysis set title

N1 60M + I3 90M

Subject analysis set type

Sub-group analysis

Subject analysis set description

Part 2: Nivolumab 1 mg/kg 60 Minute Infusion + Ipilimumab 3 mg/kg 90 Minute Infusion

Subject analysis set title

N1 30M + I3 30M Non-BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

Part 3: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Non-Brain Metastases

Subject analysis set title

N3 30M Non-BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

Part 3: Nivolumab 3 mg/kg 30 Minute Infusion Non-Brain Metastases

Subject analysis set title

N1 30M I3 30M BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

Part 4: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Brain Metastases

Subject analysis set title

N3 60M NAIVE

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; Naive = Anti-CTLA4 Naive

Subject analysis set title

N1 60M +I3 90M

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion

Subject analysis set title

N3 60M NAIVE

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; Naive = Anti-CTLA4 Naive

Subject analysis set title

N3 60M PROG

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; PROG = Anti-CTLA4 Progressed

Subject analysis set title

N1 60M +I3 90M

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion

Subject analysis set title

N1 60M+I3 90M

Subject analysis set type

Sub-group analysis

Subject analysis set description

N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion

Subject analysis set title

N1 30M + I3 30M BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

N3 = Nivolumab 3mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases

Subject analysis set title

N1 30M + I3 30M NON-BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases

Subject analysis set title

N3 30M NON-BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases

Subject analysis set title

N3 60M NAIVE

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; Naive = Anti-CTLA4 Naive

Subject analysis set title

N3 60M PROG

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; PROG = Anti-CTLA4 Progressed

Subject analysis set title

N1 60M + I3 (Nivo ADA

Subject analysis set type

Sub-group analysis

Subject analysis set description

Part 2: Nivolumab 1 mg/kg 60 Minute Infusion + Ipilimumab 3 mg/kg 90 Minute

Subject analysis set title

N1 60M + I3 90M (Ipi ADA)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Part 2: Nivolumab 1 mg/kg 60 Minute Infusion + Ipilimumab 3 mg/kg 90 Minute

Subject analysis set title

N1 30M + I3 30M Non-BM (Nivo ADA)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Part 3: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Non-Brain Metastases

Subject analysis set title

N1 30M + I3 30M Non-BM (Ipi ADA)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Part 3: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Non-Brain Metastases

Subject analysis set title

N1 30M + I3 30M (Nivo ADA)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Part 4: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Brain Metastases

Subject analysis set title

N1 30M + I3 30M (Ipi ADA)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Part 4: Nivolumab 1 mg/kg 30 Minute Infusion + Ipilimumab 3 mg/kg 30 Minute Infusion Brain Metastases

Subject analysis set title

Total (Nivo ADA)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Total (All Nivolumab or Nivolumab + Ipilimumab Treated Subjects with Baseline and at Least One Post-Baseline Assessment)

Subject analysis set title

Total (Ipi ADA)

Subject analysis set type

Sub-group analysis

Subject analysis set description

Total (All Nivolumab or Nivolumab + Ipilimumab Treated Subjects with Baseline and at Least One Post-Baseline Assessment)

Subject analysis set title

N3 60M NAIVE, W4

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; NAIVE = Anti-CTLA4 Naive

Subject analysis set title

N3 60M PROG, W4

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; PROG = Anti-CTLA4 Progressed;

Subject analysis set title

N1 60M + I3 90M, WU

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; WU = Unknown Week Biopsy

Subject analysis set title

N1 30M + I3 30M NON-BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases

Subject analysis set title

N3 30M NON-BM, W2

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy

Subject analysis set title

N1 30M + I3 30M BM, W2

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy

Subject analysis set title

N3 30M BM, W2

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy

Subject analysis set title

N3 60M, W4

Subject analysis set type

Sub-group analysis

Subject analysis set description

N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; W4 = Week 4 Biopsy

Subject analysis set title

N3 30M, W2

Subject analysis set type

Sub-group analysis

Subject analysis set description

Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; W2 = Week 2 Biopsy

Subject analysis set title

N1 + I3, W2

Subject analysis set type

Sub-group analysis

Subject analysis set description

N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; W2 = Week 2 Biopsy

Subject analysis set title

N1 + I3 W2, NON-BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; W2 = Week 2 Biopsy; BM = Brain metastases

Subject analysis set title

N3 NAIVE, NON-BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

N3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive; BM = Brain metastases

Subject analysis set title

N1 + I3 NON-BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases

Subject analysis set title

Total

Subject analysis set type

Sub-group analysis

Subject analysis set description

All treatments

Subject analysis set title

N1 + I3 NON-BM

Subject analysis set type

Sub-group analysis

Subject analysis set description

N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; BM = Brain metastases

Subject analysis set title

N3 NAIVE

Subject analysis set type

Sub-group analysis

Subject analysis set description

N3 = Nivolumab 3mg/kg; NAIVE = Anti-CTLA4 Naive

Subject analysis set title

All N3

Subject analysis set type

Sub-group analysis

Subject analysis set description

N3 = Nivolumab 3mg/kg

Subject analysis set title

N1 + I3

Subject analysis set type

Sub-group analysis

Subject analysis set description

All combination

Subject analysis set title

Total

Subject analysis set type

Sub-group analysis

Subject analysis set description

All treatments

Primary: Median change from baseline to week 7, of Interferon (IFN) and interferon gamma (IFN-gamma) inducible factors

Top of page

End point title

Median change from baseline to week 7, of Interferon (IFN) and interferon gamma (IFN-gamma) inducible factors ^[1] ^[2]

End point description

Baseline and post-treatment modulation of serum levels of chemokines, cytokines and other immune mediators were assessed by techniques that included ELISA or other multiplex-based assay methods. Primary analysis included IFN-gamma and IFN-gamma inducible factors, including chemokine [C-X-C motif] ligand 9 (CXCL9) and CXCL10

End point type

Primary

End point timeframe

From last non-missing value prior to first dose to week 7 day 1

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: All participants listed in the baseline period who received treatment per the protocol are reported in the subject analysis sets which are subsets of the full population.
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: All participants listed in the baseline period who received treatment per the protocol are reported in the subject analysis sets which are subsets of the full population.

N1 30M + I3 30M non-BM

N3 30M non-BM

N3 30M BM

N3 60M Naive

N3 60M PROG

N1 60M + I3 90M

N1 30M + I3 30M BM

N1+ I3 Non-BM

Naive Nivo Mono

All Nivo

All Combo

Total

Number of subjects analysed

156

Units: pg/mL

median (standard deviation)

IFN-gamma Simoa

0.1600 ± 1.2047

0.0520 ± 0.1207

0.0375 ± 0.1868

0.0130 ± 0.1740

0.0320 ± 0.0817

0.2310 ± 0.4528

0.0950 ± 1.5082

0.2200 ± 0.8198

0.0130 ± 0.1674

0.0240 ± 0.1373

0.1520 ± 1.0023

0.0515 ± 0.5944

CXL9 (aka MIG)

3542.0 ± 12133.1

-29.0 ± 1684.2

3610.0 ± 2197.4

1105.0 ± 10467.4

1890.0 ± 8706.0

4680.0 ± 18096.9

5692.0 ± 6796.0

458.5 ± 1651.0

1056.5 ± 9167.8

1235.0 ± 8984.2

4680.0 ± 14792.5

2027.0 ± 11491.9

CXL10 (aka IP10)

934.5 ± 2842.0

26.0 ± 172.7

318.0 ± 354.0

184.0 ± 514.1

160.0 ± 539.9

684.0 ± 2563.1

514.0 ± 612.3

695.0 ± 2627.7

185.0 ± 474.6

184.0 ± 500.7

684.0 ± 2450.6

234.5 ± 1566.3

No statistical analyses for this end point

Primary: Tumor infiltrating lymphocytes (TILs) as measured by medians in percent positive CD8 and positive CD4 at baseline and on-treatment biopsy, both using the Mosaic Singleplex IHC assay

Top of page

End point title

Tumor infiltrating lymphocytes (TILs) as measured by medians in percent positive CD8 and positive CD4 at baseline and on-treatment biopsy, both using the Mosaic Singleplex IHC assay ^[3] ^[4]

End point description

Biomarkers examined were percent positive CD8 and percent positive CD4, both using the Mosaic Singleplex IHC assay. Analyses are presented with the medians at baseline and on-treatment, rather than the median change because the baseline values differed across groups. Baseline was defined as the last non-missing value on or prior to the first dose of study therapy. Biopsies were also collected on treatment. "999"=N/A

End point type

Primary

End point timeframe

From last non-missing value prior to first dose to week 4 day 1

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: All participants listed in the baseline period who received treatment per the protocol are reported in the subject analysis sets which are subsets of the full population.
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: All participants listed in the baseline period who received treatment per the protocol are reported in the subject analysis sets which are subsets of the full population.

N1 30M + I3 30M non-BM

N3 30M non-BM

N3 30M BM

N3 60M Naive

N3 60M PROG

N1 60M + I3 90M W2

N1 60M + I3 90M W4

N3 30M + I3 30M BM

Nivo Mono

Nivo Mono Reduced Infusion

Week 2 Biopsy Combo

Week 2 Biopsy non-BM Combo

Naive Nivo Mono non-BM

N1 + I3 non-BM

Number of subjects analysed

Units: Percentage of positive cells

median (standard deviation)

Percent CD8 Baseline

4.700 ± 9.810

5.615 ± 12.475

6.135 ± 5.664

3.73 ± 10.994

7.230 ± 10.712

3.260 ± 9.259

11.105 ± 9.524

18.590 ± 8.132

6.360 ± 10.727

5.615 ± 11.472

4.700 ± 9.292

4.230 ± 9.401

5.210 ± 11.288

4.230 ± 9.844

Percent positive CD8 Week 2

7.970 ± 15.132

10.100 ± 10.909

29.735 ± 5.254

999 ± 999

11.345 ± 21.316

999 ± 999

8.470 ± 7.740

999 ± 999

10.910 ± 12.387

9.080 ± 17.510

9.125 ± 18.654

10.100 ± 10.909

9.125 ± 18.654

Percent positive CD8 Week 4

37.465 ± 5.706

999 ± 999

18.435 ± 17.108

7.140 ± 25.204

999 ± 999

32.455 ± 15.967

999 ± 999

15.150 ± 21.475

999 ± 999

37.465 ± 5.706

18.435 ± 17.108

34.785 ± 13.856

Percent CD4 Baseline

4.155 ± 6.624

4.950 ± 4.992

2.780 ± 999

0.360 ± 1.844

0.600 ± 2.268

0.840 ± 1.852

0.470 ± 3.833

6.500 ± 8.108

0.375 ± 2.057

4.600 ± 4.807

2.750 ± 5.833

2.610 ± 5.607

0.870 ± 3.727

1.510 ± 6.023

Percent positive CD4 Week 2

6.260 ± 8.518

4.210 ± 5.029

20.830 ± 999

999 ± 999

4.500 ± 10.741

999 ± 999

6.420 ± 14.778

999 ± 999

6.155 ± 6.585

6.125 ± 10.222

5.990 ± 9.602

4.210 ± 5.029

5.990 ± 9.602

Percent positive CD4 Week 4

24.520 ± 2.659

999 ± 999

1.585 ± 3.071

1.260 ± 4.641

999 ± 999

9.005 ± 13.324

999 ± 999

1.275 ± 3.921

999 ± 999

24.520 ± 2.659

1.585 ± 3.071

10.155 ± 12.707

No statistical analyses for this end point

Secondary: Safety and tolerability of Nivolumab, Ipilimumab and Nivolumab in combination with Ipilimumab as measured by the number of deaths and AEs

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End point title

Safety and tolerability of Nivolumab, Ipilimumab and Nivolumab in combination with Ipilimumab as measured by the number of deaths and AEs ^[5]

End point description

The assessment of safety was based on frequency of deaths and adverse events (AEs). AEs were graded for severity according to the NCI CTCAE version 4.0.

End point type

Secondary

End point timeframe

Includes events reported between first dose and up to 100 days after last dose of study medication (up to approximately 2 years).

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: All participants listed in the baseline period who received treatment per the protocol are reported in the subject analysis sets which are subsets of the full population.

End point values	N1 30M + I3 30M non-BM	N3 30M non-BM	N3 30M BM	N1 60M + I3 90M	N3 60M Naive	N3 60M PROG	N1 30M + I3 30M BM
Number of subjects analysed	25	11	10	27	41	44	10
Units: Events
Participants who died	14	4	4	11	26	25	2
Participants who died within 30 days of last dose	0	0	0	4	3	2	1
Participants who died within 100 days of last dose	0	1	2	5	5	8	2
Participants with an AE	25	11	10	27	41	44	10

No statistical analyses for this end point

Secondary: Number of Laboratory Abnormalities in Specific Liver Tests

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End point title

Number of Laboratory Abnormalities in Specific Liver Tests ^[6]

End point description

Abnormalities in hepatic parameters measured included those in aspartate aminotransferase (AST), alanine aminotransferase (ALT)and total bilirubin, with respect to upper limit of normal (ULN)

End point type

Secondary

End point timeframe

101-120 days after last dose.

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: All participants listed in the baseline period who received treatment per the protocol are reported in the subject analysis sets which are subsets of the full population.

End point values	N1 30M + I3 30M non-BM	N3 30M non-BM	N3 30M BM	N3 60M PROG	N1 30M + I3 30M BM	N3 60M NAIVE	N1 60M +I3 90M
Number of subjects analysed	25	11	10	44	10	41	27
Units: Events
ALT OR AST > 3XULN	5	0	0	4	3	2	8
ALT OR AST> 5XULN	4	0	0	2	1	1	6
ALT OR AST> 10XULN	2	0	0	0	1	1	3
ALT OR AST > 20XULN	0	0	0	0	1	0	1
TOTAL BILIRUBIN > 2XULN	1	0	0	0	2	0	2
ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 1 DAY	1	0	0	0	1	0	2
ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 30 DAY	1	0	0	0	1	0	2

No statistical analyses for this end point

Secondary: Number of Laboratory Abnormalities in Specific Thyroid Tests

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End point title

Number of Laboratory Abnormalities in Specific Thyroid Tests ^[7]

End point description

Abnormalities in thyroid parameters measured included those in thyroid stimulating hormone (TSH) levels with respect to upper limit of normal (ULN) and lower limit of normal (LLN)

End point type

Secondary

End point timeframe

101-120 days after last dose.

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: All participants listed in the baseline period who received treatment per the protocol are reported in the subject analysis sets which are subsets of the full population.

End point values	N1 30M + I3 30M non-BM	N3 30M non-BM	N3 30M BM	N1 30M + I3 30M BM	N3 60M NAIVE	N3 60M PROG	N1 60M +I3 90M
Number of subjects analysed	25	11	8	10	29	33	21
Units: Events
TSH > ULN	7	1	4	3	9	16	7
TSH > ULN WITH TSH <= ULN AT BASELINE	4	1	2	3	4	9	7
TSH >ULN WITH ATLEAST ONE FT3/FT4 TEST VALUE <LLN	3	0	2	2	0	0	3
TSH >ULN WITH ALL OTHER FT3/FT4 TEST VALUES >= LLN	0	0	0	0	0	0	0
TSH > ULN WITH FT3/FT4 TEST MISSING	4	1	2	1	9	16	4
TSH < LLN	12	2	5	6	3	4	11
TSH <LLN WITH TSH >= LLN AT BASELINE	12	2	5	6	3	4	11
TSH <LLN WITH ATLEAST ONE FT3/FT4 TEST VALUE > ULN	4	0	2	2	0	0	5
TSH <LLN WITH ALL OTHER FT3/FT4 TEST VALUES <= ULN	1	0	1	0	0	0	3
TSH < LLN WITH FT3/FT4 TEST MISSING	7	2	2	4	3	4	3

No statistical analyses for this end point

Secondary: Antitumor Activity of Nivolumab and Nivolumab in combination with Ipilimumab as measured by the objective response rate (ORR)

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End point title

Antitumor Activity of Nivolumab and Nivolumab in combination with Ipilimumab as measured by the objective response rate (ORR) ^[8]

End point description

The objective response rate (ORR) was defined as the number of subjects with a best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized subjects in the population of interest (eg, all treated subjects or response-evaluable subjects). The BOR was defined as the subject’s best response designation, over the study as a whole, recorded between the date of first study drug administration and the date of objectively documented progression per RECIST 1.1, with subsequent confirmation, or date of subsequent anti-cancer therapy, whichever occurred first in the study.

End point type

Secondary

End point timeframe

Approximately every 8 weeks until disease progression and in follow-up if no progression (up to approximately 2 years)

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: All participants listed in the baseline period who received treatment per the protocol are reported in the subject analysis sets which are subsets of the full population.

End point values	N3 60M Prog	N1 30M + I3 30M non-BM	N3 30M non-BM	N3 30M BM	N3 60M Naive	N1 30M + I3 30M BM	N1 60M+I3 90M
Number of subjects analysed	44	25	11	10	41	10	27
Units: Percentage of participants
number (confidence interval 95%)	22.7 (11.5 to 37.8)	40.0 (21.1 to 61.3)	27.3 (6.0 to 61.0)	60.0 (26.2 to 87.8)	31.7 (18.1 to 48.1)	70.0 (34.8 to 93.3)	44.4 (25.5 to 64.7)

No statistical analyses for this end point

Secondary: Antitumor Activity of Nivolumab and Nivolumab in combination with Ipilimumab as measured by the median duration of response (mDOR)

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End point title

Antitumor Activity of Nivolumab and Nivolumab in combination with Ipilimumab as measured by the median duration of response (mDOR) ^[9]

End point description

Median duration of response (mDOR) was calculated for subjects with BOR of CR or PR only, and is defined as time between the date of first documented objective response and the date of the first subsequent disease progression or death, whichever occurred first, if death occurred within 100 days after last dose of study medication. "999"=N/A

End point type

Secondary

End point timeframe

2 years from the first dose of treatment

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: All participants listed in the baseline period who received treatment per the protocol are reported in the subject analysis sets which are subsets of the full population.

End point values	N3 30M BM	N1 60M + I3 90M	N3 60M Naive	N3 60M PROG	N1 30M + I3 30M BM	N1 30M + I3 30M NON-BM	N3 30M NON-BM
Number of subjects analysed	10	27	41	44	10	25	11
Units: Months
median (confidence interval 95%)	20.27 (13.57 to 999)	999 (5.85 to 999)	16.59 (7.29 to 999)	999 (5.55 to 999)	999 (22.01 to 999)	26.25 (7.85 to 999)	999 (3.71 to 999)

No statistical analyses for this end point

Secondary: Antitumor Activity of Nivolumab and Nivolumab in combination with Ipilimumab as measured by the median time to response (mTTR)

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End point title

Antitumor Activity of Nivolumab and Nivolumab in combination with Ipilimumab as measured by the median time to response (mTTR) ^[10]

End point description

Median time to response (mTTR) for a participant with a BOR of CR or PR is defined as the time from the first dosing date to the date of the first documented objective response (CR or PR).

End point type

Secondary

End point timeframe

2 years from the first dose of treatment

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: All participants listed in the baseline period who received treatment per the protocol are reported in the subject analysis sets which are subsets of the full population.

End point values	N3 30M BM	N1 60M + I3 90M	N3 60M Naive	N3 60M PROG	N1 30M + I3 30M BM	N1 30M + I3 30M NON-BM	N3 30M NON-BM
Number of subjects analysed	10	27	41	44	10	25	11
Units: Months
median (confidence interval 95%)	2.14 (1.25 to 4.99)	1.41 (1.28 to 1.87)	1.87 (1.77 to 3.71)	2.78 (1.84 to 14.59)	1.71 (1.38 to 7.43)	2.51 (1.28 to 2.86)	1.41 (1.41 to 6.90)

No statistical analyses for this end point

Secondary: Antitumor Activity of Nivolumab and Nivolumab in combination with Ipilimumab as measured by the progression free survival rate (PFSR)

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End point title

Antitumor Activity of Nivolumab and Nivolumab in combination with Ipilimumab as measured by the progression free survival rate (PFSR) ^[11]

End point description

The progression free survival rate (PFSR) for a subject was defined as the time from the date of first dose of study medication to the date of the first documented disease progression, or death due to any cause, whichever occurred first, if death occurred within 100 days after last dose of study medication. "999"=N/A

End point type

Secondary

End point timeframe

2 years from the first dose of treatment

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: All participants listed in the baseline period who received treatment per the protocol are reported in the subject analysis sets which are subsets of the full population.

End point values	N3 30M BM	N1 60M + I3 90M	N3 60M Naive	N3 60M PROG	N1 30M + I3 30M BM	N1 30M + I3 30M NON-BM	N3 30M NON-BM
Number of subjects analysed	10	27	41	44	10	25	11
Units: Percentage
median (confidence interval 95%)	23.00 (0.85 to 999)	7.00 (1.41 to 999)	3.68 (1.84 to 7.36)	5.62 (1.87 to 9.66)	999 (1.18 to 999)	9.69 (1.94 to 29.01)	4.93 (1.41 to 999)

No statistical analyses for this end point

Secondary: Immunogenicity of Nivolumab and Nivolumab in combination with Ipilimumab as measured by the number of serum anti-drug antibody (ADA) positive participants and the number of neutralizing ADA positive participants

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End point title

Immunogenicity of Nivolumab and Nivolumab in combination with Ipilimumab as measured by the number of serum anti-drug antibody (ADA) positive participants and the number of neutralizing ADA positive participants ^[12]

End point description

Time Frame: Part 1: Day 1, Day 15, Day 43 of cycle 1, Day 1 of cycle 2, Day 15 of cycle 3, every 16 weeks after cycle 3 up to 2 years, follow-up visit 1 (40-60 days after last treatment), and follow-up visit 2 (101-120 days since last treatment) Part 2, 3 and 4: Weeks 1, 3, 4, 7, 9, 10, 13, 25, 53, 79, 95 follow-up visit 1 (40-60 days after last treatment), and follow-up visit 2 (101-120 days since last treatment). "999"=N/A

End point type

Secondary

End point timeframe

Up to follow-up visit 2 (101-120 days since last treatment)

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: All participants listed in the baseline period who received treatment per the protocol are reported in the subject analysis sets which are subsets of the full population.

End point values	N3 30M non-BM	N3 30M BM	N3 60M NAIVE	N3 60M PROG	N1 60M + I3 (Nivo ADA	N1 60M + I3 90M (Ipi ADA)	N1 30M + I3 30M Non-BM (Nivo ADA)	N1 30M + I3 30M Non-BM (Ipi ADA)	N1 30M + I3 30M (Nivo ADA)	N1 30M + I3 30M (Ipi ADA)	Total (Nivo ADA)	Total (Ipi ADA)
Number of subjects analysed	11	7	38	42	22	22	24	23	10	9	154	54
Units: Participants
ADA positive	1	1	2	5	10	1	16	4	7	0	42	5
Neutralizing ADA positive	0	0	0	0	0	0	1	0	2	999	3	0

No statistical analyses for this end point

Secondary: Association between Programmed cell death ligand 1 (PD-L1) and clinical efficacy measures such as Objective Response Rate (PD-L1 ORR)

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End point title

Association between Programmed cell death ligand 1 (PD-L1) and clinical efficacy measures such as Objective Response Rate (PD-L1 ORR) ^[13]

End point description

For immunohistochemistry (IHC) measurements, to explore the PD-L1 expression as a potential predictive marker of clinical activity, PD-L1 expression status were derived from percent of tumor cells exhibiting cell surface staining for PD-L1 at baseline and/or in archived biopsy samples using verified and/or validated assays. In the case of multiple specimens, a subject would be identified as PD-L1 expression levels >= x%, where x% can be 10%, 5%, and/or 1% in any of the baseline and/or archived specimens. The association between PD-L1 expression status and/or level and clinical efficacy measures was assessed. The objective response rate (ORR) was defined as the number of subjects with a best overall response (BOR) of a complete response (CR) or partial response (PR) divided by the number of randomized subjects in the population of interest (all response-evaluable participants).

End point type

Secondary

End point timeframe

2 years from first dose of treatment; Assessed up to September 2017

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: All participants listed in the baseline period who received treatment per the protocol are reported in the subject analysis sets which are subsets of the full population.

N1 60M + I3 90M, W2

N1 60M + I3 90M, W4

N3 60M NAIVE, W4

N3 60M PROG, W4

N1 60M + I3 90M, WU

N1 30M + I3 30M NON-BM

N3 30M NON-BM, W2

N1 30M + I3 30M BM, W2

N3 30M BM, W2

N3 60M, W4

N3 30M, W2

N1 + I3, W2

N1 + I3 W2, NON-BM

N3 NAIVE, NON-BM

N1 + I3 NON-BM

Total

Number of subjects analysed

140

Units: Percentage

number (confidence interval 95%)

STTU 1 - 1% Level PD-L1 Status: Met criteria

85.7 (42.1 to 99.6)

50.0 (11.8 to 88.2)

40.0 (19.1 to 63.9)

35.3 (14.2 to 61.7)

50.0 (1.3 to 98.7)

63.6 (30.8 to 89.1)

40.0 (5.3 to 85.3)

100.0 (15.8 to 100.0)

100.0 (2.5 to 100.0)

37.8 (22.5 to 55.2)

50.0 (11.8 to 88.2)

75.0 (50.9 to 91.3)

72.2 (46.5 to 90.3)

40.0 (21.1 to 61.3)

65.4 (44.3 to 82.8)

50.7 (38.6 to 62.8)

STTU 1 - 5% Level PD-L1 Status: Met criteria

80.0 (28.4 to 99.5)

60.0 (14.7 to 94.7)

40.0 (12.2 to 73.8)

33.3 (7.5 to 70.1)

100.0 (2.5 to 100.0)

71.4 (29.0 to 96.3)

50.0 (1.3 to 98.7)

100.0 (15.8 to 100.0)

100.0 (2.5 to 100.0)

36.8 (16.3 to 61.6)

66.7 (9.4 to 99.2)

78.6 (49.2 to 95.3)

75.0 (42.8 to 94.5)

41.7 (15.2 to 72.3)

72.2 (46.5 to 90.3)

57.1 (41.0 to 72.3)

STTU 1 - 10% Level PD-L1 Status: Met criteria

100.0 (29.2 to 100.0)

75.0 (19.4 to 99.4)

42.9 (9.9 to 81.6)

20.0 (0.5 to 71.6)

100.0 (2.5 to 100.0)

66.7 (9.4 to 99.2)

100.0 (2.5 to 100.0)

100.0 (15.8 to 100.0)

100.0 (2.5 to 100.0)

33.3 (9.9 to 65.1)

100.0 (15.8 to 100.0)

87.5 (47.3 to 99.7)

83.3 (35.9 to 99.6)

50.0 (15.7 to 84.3)

81.8 (48.2 to 97.7)

63.0 (42.4 to 80.6)

No statistical analyses for this end point

Secondary: Association between Programmed cell death ligand 1 (PD-L1) and clinical efficacy measures such as the Duration of Response (PD-L1 DOR)

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End point title

Association between Programmed cell death ligand 1 (PD-L1) and clinical efficacy measures such as the Duration of Response (PD-L1 DOR) ^[14]

End point description

For immunohistochemistry (IHC) measurements, to explore the PD-L1 expression as a potential predictive marker of clinical activity, PD-L1 expression status were derived from percent of tumor cells exhibiting cell surface staining for PD-L1 at baseline and/or in archived biopsy samples using verified and/or validated assays. In the case of multiple specimens, a subject would be identified as PD-L1 expression levels >= x%, where x% can be 10%, 5%, and/or 1% in any of the baseline and/or archived specimens. Median duration of response (mDOR) was calculated for all response-evaluable participants with best overall response of CR or PR only, and is defined as time between the date of first documented objective response and the date of the first subsequent disease progression or death, whichever occurred first, if death occurred within 100 days after last dose of study medication. "999"=N/A

End point type

Secondary

End point timeframe

2 years from first dose of treatment; Assessed up to September 2017

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: All participants listed in the baseline period who received treatment per the protocol are reported in the subject analysis sets which are subsets of the full population.

N1 60M + I3 90M, W2

N1 60M + I3 90M, W4

N3 60M NAIVE, W4

N3 60M PROG, W4

N1 60M + I3 90M, WU

N1 30M + I3 30M NON-BM

N3 30M NON-BM, W2

N1 30M + I3 30M BM, W2

N3 30M BM, W2

N3 60M, W4

N3 30M, W2

N1 + I3, W2

N1 + I3 W2, NON-BM

N3 NAIVE, NON-BM

N1 + I3 NON-BM

Total

Number of subjects analysed

140

Units: Months

median (confidence interval 95%)

STTU 1 - 1% Level PD-L1 Status: Met criteria

999 (2.96 to 999)

999 (999 to 999)

15.21 (4.60 to 18.20)

999 (15.57 to 999)

999 (999 to 999)

26.25 (8.31 to 999)

999 (3.71 to 999)

22.01 (-999 to 999)

999 (999 to 999)

16.59 (11.50 to 999)

999 (3.71 to 999)

26.25 (22.01 to 999)

999 (8.31 to 999)

15.21 (3.71 to 999)

999 (26.25 to 999)

26.25 (16.59 to 999)

STTU 1 - 5% Level PD-L1 Status: Met criteria

999 (2.96 to 999)

999 (999 to 999)

15.21 (11.50 to 16.59)

999 (15.57 to 999)

999 (999 to 999)

26.25 (8.31 to 999)

999 (3.71 to 999)

22.01 (-999 to 999)

999 (999 to 999)

16.59 (11.50 to 999)

999 (999 to 999)

26.25 (8.31 to 999)

999 (2.96 to 999)

16.59 (11.50 to 999)

999 (8.31 to 999)

26.25 (15.57 to 999)

STTU 1 - 10% Level PD-L1 Status: Met criteria

999 (2.96 to 999)

999 (999 to 999)

15.90 (15.21 to 16.59)

15.57 (-999 to 999)

999 (999 to 999)

22.01 (-999 to 999)

999 (999 to 999)

15.57 (15.21 to 16.59)

999 (999 to 999)

999 (2.96 to 999)

16.59 (15.21 to 999)

999 (2.96 to 999)

999 (15.57 to 999)

No statistical analyses for this end point

Secondary: Association between Programmed cell death ligand 1 (PD-L1) and clinical efficacy measures such as Progression Free Survival (PD-L1 PFS)

Top of page

End point title

Association between Programmed cell death ligand 1 (PD-L1) and clinical efficacy measures such as Progression Free Survival (PD-L1 PFS) ^[15]

End point description

For immunohistochemistry (IHC) measurements, to explore the PD-L1 expression as a potential predictive marker of clinical activity, PD-L1 expression status were derived from percent of tumor cells exhibiting cell surface staining for PD-L1 at baseline and/or in archived biopsy samples using verified and/or validated assays. In the case of multiple specimens, a subject would be identified as PD-L1 expression levels >= x%, where x% can be 10%, 5%, and/or 1% in any of the baseline and/or archived specimens. The association between PD-L1 expression status and/or level and clinical efficacy measures was assessed. The progression free survival rate (PFSR) for a subject was defined as the time from the date of first dose of study medication to the date of the first documented disease progression, or death due to any cause, whichever occurred first, if death occurred within 100 days after last dose of study medication. "999"=N/A

End point type

Secondary

End point timeframe

2 years from first dose of treatment; Assessed up to September 2017

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: All participants listed in the baseline period who received treatment per the protocol are reported in the subject analysis sets which are subsets of the full population.

N1 60M + I3 90M, W2

N1 60M + I3 90M, W4

N3 60M NAIVE, W4

N3 60M PROG, W4

N1 60M + I3 90M, WU

N1 30M + I3 30M NON-BM

N3 30M NON-BM, W2

N1 30M + I3 30M BM, W2

N3 30M BM, W2

N3 60M, W4

N3 30M, W2

N1 + I3, W2

N1 + I3 W2, NON-BM

N3 NAIVE, NON-BM

N1 + I3 NON-BM

Total

Number of subjects analysed

140

Units: Months

median (confidence interval 95%)

STTU 1 - 1% Level PD-L1 Status: Met criteria

999 (1.22 to 999)

999 (0.85 to 999)

4.50 (1.84 to 15.18)

9.66 (3.71 to 999)

999 (0.76 to 999)

29.01 (1.94 to 29.01)

8.77 (1.22 to 999)

999 (23.95 to 999)

999 (999 to 999)

6.24 (3.65 to 17.05)

8.77 (1.22 to 999)

29.01 (4.17 to 999)

29.01 (3.02 to 999)

5.36 (1.94 to 10.94)

29.01 (3.02 to 999)

10.58 (5.62 to 19.81)

STTU 1 - 5% Level PD-L1 Status: Met criteria

999 (1.22 to 999)

999 (0.85 to 999)

6.28 (0.33 to 17.05)

19.29 (1.77 to 999)

999 (999 to 999)

29.01 (1.94 to 29.01)

999 (1.22 to 999)

999 (23.95 to 999)

999 (999 to 999)

7.20 (1.87 to 18.40)

999 (1.22 to 999)

29.01 (3.02 to 999)

29.01 (1.94 to 999)

6.28 (1.22 to 17.05)

29.01 (3.02 to 999)

17.05 (5.36 to 29.01)

STTU 1 - 10% Level PD-L1 Status: Met criteria

999 (4.17 to 999)

999 (1.64 to 999)

5.36 (0.33 to 18.40)

19.29 (1.77 to 19.29)

999 (999 to 999)

999 (1.94 to 999)

999 (999 to 999)

999 (23.95 to 999)

999 (999 to 999)

6.24 (1.71 to 18.40)

999 (999 to 999)

999 (1.94 to 999)

11.20 (0.33 to 999)

999 (1.94 to 999)

19.29 (5.36 to 999)

No statistical analyses for this end point

Secondary: Antitumor Activity of Nivolumab and Nivolumab in combination with Ipilimumab as measured by the Overall Survival Rate (OSR)

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End point title

Antitumor Activity of Nivolumab and Nivolumab in combination with Ipilimumab as measured by the Overall Survival Rate (OSR) ^[16]

End point description

The proportion of subjects surviving to time t, where t is a specific length of time, eg, 12 months, which was determined by the available data for final analysis and was documented in the DPP. The proportion was calculated by the product-limit method (Kaplan-Meier estimate), which takes into account censored data. The overall survival rate (OSR) for a subject was defined as the time from the date of first dose of study medication to the date of death for any cause. A subject who had not died was censored at last known date alive

End point type

Secondary

End point timeframe

2 years from first dose of treatment; Assessed up to September 2017

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: All participants listed in the baseline period who received treatment per the protocol are reported in the subject analysis sets which are subsets of the full population.

N3 30M BM

N1 60M + I3 90M

N3 60M Naive

N3 60M PROG

N1 30M + I3 30M BM

N1 30M + I3 30M NON-BM

N3 30M NON-BM

N1 + I3 NON-BM

N3 NAIVE

All N3

N1 + I3

Total

Number of subjects analysed

106

168

Units: Percentage of participants

median (confidence interval 95%)

3 months

80.0 (40.9 to 94.6)

85.2 (65.2 to 94.2)

92.7 (79.0 to 97.6)

90.8 (77.3 to 96.4)

90.0 (47.3 to 98.5)

100.0 (100.0 to 100.0)

90.0 (47.3 to 98.5)

92.3 (80.8 to 97.0)

90.2 (79.6 to 95.5)

90.5 (83.0 to 94.8)

91.9 (81.7 to 96.6)

91.0 (85.5 to 94.5)

6 months

80.0 (40.9 to 94.6)

81.5 (61.1 to 91.8)

85.3 (70.2 to 93.1)

78.9 (63.3 to 88.4)

90.0 (47.3 to 98.5)

100.0 (100.0 to 100.0)

90.0 (47.3 to 98.5)

90.4 (78.4 to 95.9)

85.3 (73.6 to 92.0)

82.6 (73.8 to 88.6)

90.3 (79.7 to 95.5)

85.5 (79.2 to 90.1)

9 months

68.6 (30.5 to 88.7)

81.5 (61.1 to 91.8)

75.0 (58.5 to 85.7)

71.7 (55.5 to 82.8)

90.0 (47.3 to 98.5)

88.0 (67.3 to 96.0)

90.0 (47.3 to 98.5)

84.6 (71.6 to 92.0)

76.6 (63.7 to 85.4)

74.6 (64.9 to 81.9)

85.5 (74.0 to 92.2)

78.7 (71.6 to 84.2)

12 months

68.6 (30.5 to 88.7)

77.6 (56.8 to 89.3)

72.4 (55.7 to 83.7)

64.5 (48.2 to 76.9)

90.0 (47.3 to 98.5)

88.0 (67.3 to 96.0)

80.0 (40.9 to 94.6)

82.6 (69.3 to 90.6)

73.1 (59.8 to 82.6)

69.5 (59.5 to 77.5)

83.8 (72.0 to 91.0)

74.9 (67.5 to 80.9)

24 months

57.1 (21.7 to 81.5)

69.6 (48.3 to 83.5)

51.0 (34.3 to 65.4)

46.8 (31.1 to 61.1)

80.0 (40.9 to 94.6)

58.1 (36.0 to 75.0)

58.3 (23.0 to 82.1)

64.3 (49.3 to 75.8)

53.3 (39.6 to 65.2)

50.6 (40.3 to 60.0)

66.8 (53.3 to 77.2)

56.8 (48.7 to 64.1)

No statistical analyses for this end point

Secondary: Safety and tolerability of Nivolumab, Ipilimumab and Nivolumab in combination with Ipilimumab as measured by SAEs and AEs leading to discontinuation of study drug

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End point title

Safety and tolerability of Nivolumab, Ipilimumab and Nivolumab in combination with Ipilimumab as measured by SAEs and AEs leading to discontinuation of study drug ^[17]

End point description

The assessment of safety was based on frequency of serious adverse events (SAEs) and AEs leading to discontinuation of study drug. AEs were graded for severity according to the NCI CTCAE version 4.0.

End point type

Secondary

End point timeframe

From enrollment to 100 days after the last dose date (up to approximately 2 years)

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: All participants listed in the baseline period who received treatment per the protocol are reported in the subject analysis sets which are subsets of the full population.

End point values	N3 60M Prog	N3 30M BM	N1 60M + I3 90M	N3 60M Naive	N1 30M + I3 30M Non-BM	N3 30M Non-BM	N1 30M I3 30M BM
Number of subjects analysed	44	10	27	41	25	11	10
Units: Events
SAEs	22	4	20	20	14	2	7
AEs Leading to Discontinuation	6	2	12	2	9	1	4

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose up to 100 days after last dose of study drug, approximately 75 months

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

MedDRA21.1

Reporting group title

N3 60M NAIVE

Reporting group description

Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; Naive = Anti-CTLA4 Naive

Reporting group title

N1 60M + I3 90M, W2

Reporting group description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; W2 = Week 2 Biopsy

Reporting group title

N1 60M + I3 90M, W4

Reporting group description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; W4 = Week 4 Biopsy

Reporting group title

N1 60M + I3 90M, WU

Reporting group description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 90M = 90 minute infusion; 60M = 60 minute infusion; WU = Unknown Week Biopsy

Reporting group title

N3 60M PROG

Reporting group description

Treatment Group: N3 = Nivolumab 3mg/kg; 60M = 60 minute infusion; PROG = Anti-CTLA4 Progressed

Reporting group title

N1 30M + I3 30M non-BM

Reporting group description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases

Reporting group title

N1 30M + I3 30M BM

Reporting group description

Treatment Group: N1 = Nivolumab 1mg/kg; I3 = Ipilimumab 3 mg/kg; 30M = 30 minute infusion; BM = Brain metastases

Reporting group title

N3 30M non-BM

Reporting group description

Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases

Reporting group title

I3 Monotherapy

Reporting group description

Treatment Group: I3 = Ipilimumab 3 mg/kg infusion. Participant was enrolled prior to the closure of this arm via amendment

Reporting group title

N3 30M BM

Reporting group description

Treatment Group: N3 = Nivolumab 3mg/kg; 30M = 30 minute infusion; BM = Brain metastases

Reporting group title

Unplanned Treatment

Reporting group description

Treatment Group: Unplanned treatment of Nivolumab 1 mg/kg x 4 then Nivolumab 3 mg/kg

Serious adverse events	N3 60M NAIVE	N1 60M + I3 90M, W2	N1 60M + I3 90M, W4	N1 60M + I3 90M, WU	N3 60M PROG	N1 30M + I3 30M non-BM	N1 30M + I3 30M BM	N3 30M non-BM	I3 Monotherapy	N3 30M BM	Unplanned Treatment
Total subjects affected by serious adverse events
subjects affected / exposed	20 / 41 (48.78%)	8 / 11 (72.73%)	6 / 10 (60.00%)	6 / 6 (100.00%)	22 / 44 (50.00%)	14 / 25 (56.00%)	7 / 10 (70.00%)	2 / 11 (18.18%)	1 / 1 (100.00%)	4 / 10 (40.00%)	1 / 1 (100.00%)
number of deaths (all causes)	26	4	3	4	25	14	2	4	1	4	1
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malignant neoplasm progression
subjects affected / exposed	3 / 41 (7.32%)	0 / 11 (0.00%)	2 / 10 (20.00%)	3 / 6 (50.00%)	8 / 44 (18.18%)	4 / 25 (16.00%)	1 / 10 (10.00%)	1 / 11 (9.09%)	0 / 1 (0.00%)	2 / 10 (20.00%)	1 / 1 (100.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 2	0 / 3	0 / 8	0 / 4	0 / 1	0 / 1	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 2	0 / 0	0 / 2	0 / 3	0 / 7	0 / 1	0 / 1	0 / 1	0 / 0	0 / 2	0 / 1
Metastases to central nervous system
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastatic neoplasm
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tumour pain
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	1 / 1 (100.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypotension
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malaise
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	1 / 41 (2.44%)	1 / 11 (9.09%)	1 / 10 (10.00%)	1 / 6 (16.67%)	1 / 44 (2.27%)	3 / 25 (12.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	1 / 1	0 / 1	0 / 1	3 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Pelvic pain
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	1 / 41 (2.44%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0	1 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 41 (2.44%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 1 (100.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 1 (100.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mental status changes
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 1 (100.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	2 / 41 (4.88%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic enzyme increased
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lipase increased
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Brain herniation
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 1 (100.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Aphasia
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arachnoiditis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysaesthesia
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Guillain-Barre syndrome
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Monoplegia
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorder
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nystagmus
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Paraesthesia
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Autoimmune haemolytic anaemia
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune thrombocytopenic purpura
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Iridocyclitis
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	1 / 1	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Autoimmune colitis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	3 / 41 (7.32%)	1 / 11 (9.09%)	0 / 10 (0.00%)	2 / 6 (33.33%)	0 / 44 (0.00%)	2 / 25 (8.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	3 / 3	1 / 1	0 / 0	2 / 2	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 41 (0.00%)	2 / 11 (18.18%)	0 / 10 (0.00%)	2 / 6 (33.33%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	2 / 2	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Enterocolitis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal ischaemia
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intra-abdominal fluid collection
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Necrotising oesophagitis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Volvulus
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 1 (100.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 1 (100.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Autoimmune hepatitis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bile duct obstruction
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatotoxicity
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune-mediated hepatitis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Liver disorder
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Drug reaction with eosinophilia and systemic symptoms
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rash
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperthyroidism
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypophysitis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthritis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bone disorder
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Flank pain
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Clostridium difficile infection
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Encephalitis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Liver abscess
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal infection
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	0 / 10 (0.00%)	2 / 6 (33.33%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 1 (100.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Failure to thrive
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	1 / 10 (10.00%)	1 / 6 (16.67%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 1 (100.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	1 / 41 (2.44%)	1 / 11 (9.09%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	N3 60M NAIVE	N1 60M + I3 90M, W2	N1 60M + I3 90M, W4	N1 60M + I3 90M, WU	N3 60M PROG	N1 30M + I3 30M non-BM	N1 30M + I3 30M BM	N3 30M non-BM	I3 Monotherapy	N3 30M BM	Unplanned Treatment
Total subjects affected by non serious adverse events
subjects affected / exposed	41 / 41 (100.00%)	11 / 11 (100.00%)	10 / 10 (100.00%)	6 / 6 (100.00%)	44 / 44 (100.00%)	25 / 25 (100.00%)	10 / 10 (100.00%)	10 / 11 (90.91%)	1 / 1 (100.00%)	9 / 10 (90.00%)	1 / 1 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	1	0
Tumour pain
subjects affected / exposed	3 / 41 (7.32%)	1 / 11 (9.09%)	2 / 10 (20.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	2 / 25 (8.00%)	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	3	1	2	0	2	2	0	1	0	0	0
Tumour embolism
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Oncologic complication
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 1 (100.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
Vascular disorders
Embolism
subjects affected / exposed	2 / 41 (4.88%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	2	0	0	1	0	0	1	0	0	0	0
Flushing
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0	0	2	0	1	0	0	1	0
Hypertension
subjects affected / exposed	6 / 41 (14.63%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	1 / 25 (4.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 1 (100.00%)
occurrences all number	8	0	1	0	1	1	1	0	0	0	1
Hypotension
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	1 / 10 (10.00%)	1 / 6 (16.67%)	0 / 44 (0.00%)	2 / 25 (8.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	1	2	0	2	0	0	0	0	0
Lymphoedema
subjects affected / exposed	2 / 41 (4.88%)	1 / 11 (9.09%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 1 (100.00%)
occurrences all number	2	1	1	0	0	0	0	0	0	0	1
Hot flush
subjects affected / exposed	1 / 41 (2.44%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	1	0	0	0	1	0	0	0	0	0
Orthostatic hypotension
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 1 (100.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
General disorders and administration site conditions
Asthenia
subjects affected / exposed	3 / 41 (7.32%)	3 / 11 (27.27%)	2 / 10 (20.00%)	1 / 6 (16.67%)	1 / 44 (2.27%)	3 / 25 (12.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	3	3	2	1	1	3	1	0	0	0	0
Chest pain
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	2 / 10 (20.00%)	1 / 1 (100.00%)
occurrences all number	2	0	0	0	1	1	0	0	0	2	1
Chills
subjects affected / exposed	3 / 41 (7.32%)	3 / 11 (27.27%)	4 / 10 (40.00%)	1 / 6 (16.67%)	4 / 44 (9.09%)	3 / 25 (12.00%)	2 / 10 (20.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	2 / 10 (20.00%)	0 / 1 (0.00%)
occurrences all number	3	3	5	2	5	4	2	0	0	2	0
Fatigue
subjects affected / exposed	21 / 41 (51.22%)	7 / 11 (63.64%)	4 / 10 (40.00%)	4 / 6 (66.67%)	29 / 44 (65.91%)	13 / 25 (52.00%)	6 / 10 (60.00%)	5 / 11 (45.45%)	1 / 1 (100.00%)	6 / 10 (60.00%)	1 / 1 (100.00%)
occurrences all number	32	7	5	5	38	19	8	5	1	6	2
Hernia pain
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Influenza like illness
subjects affected / exposed	4 / 41 (9.76%)	2 / 11 (18.18%)	1 / 10 (10.00%)	1 / 6 (16.67%)	3 / 44 (6.82%)	3 / 25 (12.00%)	3 / 10 (30.00%)	1 / 11 (9.09%)	0 / 1 (0.00%)	3 / 10 (30.00%)	0 / 1 (0.00%)
occurrences all number	6	3	1	1	3	3	4	1	0	3	0
Localised oedema
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	0	0	1	0	0	0
Malaise
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	2 / 6 (33.33%)	1 / 44 (2.27%)	2 / 25 (8.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	2	1	2	1	0	0	0	0
Mucosal inflammation
subjects affected / exposed	3 / 41 (7.32%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	2 / 25 (8.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	3	0	0	0	0	2	0	0	0	0	0
Non-cardiac chest pain
subjects affected / exposed	2 / 41 (4.88%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	3	0	1	0	0	0	0	0	0	1	0
Oedema peripheral
subjects affected / exposed	9 / 41 (21.95%)	1 / 11 (9.09%)	3 / 10 (30.00%)	2 / 6 (33.33%)	6 / 44 (13.64%)	6 / 25 (24.00%)	4 / 10 (40.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	10	1	4	2	6	8	4	0	0	2	0
Pain
subjects affected / exposed	3 / 41 (7.32%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	11 / 44 (25.00%)	1 / 25 (4.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	5	0	0	1	11	1	1	0	0	1	0
Peripheral swelling
subjects affected / exposed	1 / 41 (2.44%)	1 / 11 (9.09%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	1	1	0	0	0	1	0	0	0	0
Pyrexia
subjects affected / exposed	11 / 41 (26.83%)	6 / 11 (54.55%)	6 / 10 (60.00%)	3 / 6 (50.00%)	9 / 44 (20.45%)	9 / 25 (36.00%)	5 / 10 (50.00%)	3 / 11 (27.27%)	0 / 1 (0.00%)	3 / 10 (30.00%)	0 / 1 (0.00%)
occurrences all number	12	7	7	6	17	10	8	3	0	3	0
Temperature intolerance
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Decreased activity
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Feeling cold
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Gait disturbance
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Feeling of body temperature change
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Inflammation
subjects affected / exposed	1 / 41 (2.44%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	1	0	0	0	0	0	0	0	0	0
Physical deconditioning
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0	0	0	0
Axillary pain
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 1 (100.00%)
occurrences all number	1	0	0	0	1	0	0	0	0	0	1
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Hypersensitivity
subjects affected / exposed	1 / 41 (2.44%)	2 / 11 (18.18%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	1	2	0	0	1	0	0	1	0	1	0
Reproductive system and breast disorders
Nipple pain
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Spermatic cord haemorrhage
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0
Genital rash
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	1	0	0	0	0	0	0	0	0
Scrotal swelling
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Bronchial obstruction
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Cough
subjects affected / exposed	10 / 41 (24.39%)	4 / 11 (36.36%)	3 / 10 (30.00%)	2 / 6 (33.33%)	13 / 44 (29.55%)	4 / 25 (16.00%)	3 / 10 (30.00%)	1 / 11 (9.09%)	0 / 1 (0.00%)	3 / 10 (30.00%)	1 / 1 (100.00%)
occurrences all number	12	4	3	2	20	6	3	1	0	4	1
Dyspnoea
subjects affected / exposed	3 / 41 (7.32%)	3 / 11 (27.27%)	3 / 10 (30.00%)	3 / 6 (50.00%)	7 / 44 (15.91%)	5 / 25 (20.00%)	2 / 10 (20.00%)	1 / 11 (9.09%)	0 / 1 (0.00%)	2 / 10 (20.00%)	1 / 1 (100.00%)
occurrences all number	3	3	3	3	9	6	3	1	0	2	1
Hypoxia
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0	0	0	0
Oropharyngeal pain
subjects affected / exposed	4 / 41 (9.76%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	2 / 44 (4.55%)	1 / 25 (4.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	4	0	0	1	2	1	1	0	0	1	0
Nasal congestion
subjects affected / exposed	6 / 41 (14.63%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 6 (16.67%)	1 / 44 (2.27%)	2 / 25 (8.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	7	0	1	1	1	2	0	0	0	0	0
Pleural effusion
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	3 / 10 (30.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	3	0	1	0	0	0	0	0	0
Pneumonitis
subjects affected / exposed	1 / 41 (2.44%)	1 / 11 (9.09%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	3 / 25 (12.00%)	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	1	1	0	0	3	0	1	0	0	0
Productive cough
subjects affected / exposed	2 / 41 (4.88%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	2	0	0	0	0	1	1	0	0	0	0
Rhinitis allergic
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	0	1	0	0	0
Rhinorrhoea
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	2 / 10 (20.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	2	0	1	0	0	1	0	0	0
Upper-airway cough syndrome
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	4 / 44 (9.09%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	4	0	0	0	0	0	0
Dysphonia
subjects affected / exposed	1 / 41 (2.44%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	1	0	0	1	1	0	0	0	0	0
Dyspnoea exertional
subjects affected / exposed	1 / 41 (2.44%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	1	0	0	2	1	0	0	0	0	0
Epistaxis
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Haemoptysis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	2	0	0	0	0	0	0
Hiccups
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	2 / 44 (4.55%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	2	0	0	0	0	0	0
Pulmonary embolism
subjects affected / exposed	2 / 41 (4.88%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	2	1	0	0	0	1	0	0	0	0	0
Respiratory failure
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0
Respiratory tract congestion
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	3	0	1	0	0	0	0	0	0	0	0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	1	0	0	1	0	0	0	0	0
Anxiety
subjects affected / exposed	2 / 41 (4.88%)	0 / 11 (0.00%)	2 / 10 (20.00%)	0 / 6 (0.00%)	4 / 44 (9.09%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	1 / 1 (100.00%)	1 / 10 (10.00%)	1 / 1 (100.00%)
occurrences all number	2	0	2	0	5	0	0	0	1	1	1
Depression
subjects affected / exposed	2 / 41 (4.88%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 1 (100.00%)
occurrences all number	2	1	0	0	1	0	0	0	0	0	1
Insomnia
subjects affected / exposed	6 / 41 (14.63%)	1 / 11 (9.09%)	3 / 10 (30.00%)	2 / 6 (33.33%)	5 / 44 (11.36%)	2 / 25 (8.00%)	3 / 10 (30.00%)	1 / 11 (9.09%)	0 / 1 (0.00%)	1 / 10 (10.00%)	1 / 1 (100.00%)
occurrences all number	6	1	3	2	6	2	3	1	0	1	1
Sleep disorder
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	1	0	0	0	0
Depressed mood
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Disorientation
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Irritability
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Hallucination
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Mental status changes
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 1 (100.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
Investigations
Activated partial thromboplastin time prolonged
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Alanine aminotransferase increased
subjects affected / exposed	6 / 41 (14.63%)	5 / 11 (45.45%)	3 / 10 (30.00%)	2 / 6 (33.33%)	2 / 44 (4.55%)	5 / 25 (20.00%)	2 / 10 (20.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	8	7	3	2	2	6	6	0	0	0	0
Amylase increased
subjects affected / exposed	2 / 41 (4.88%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 6 (16.67%)	0 / 44 (0.00%)	2 / 25 (8.00%)	3 / 10 (30.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	2	0	1	1	0	2	7	0	0	4	0
Aspartate aminotransferase increased
subjects affected / exposed	6 / 41 (14.63%)	6 / 11 (54.55%)	3 / 10 (30.00%)	2 / 6 (33.33%)	2 / 44 (4.55%)	6 / 25 (24.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	11	9	3	2	2	7	1	0	0	1	0
Blood alkaline phosphatase increased
subjects affected / exposed	5 / 41 (12.20%)	0 / 11 (0.00%)	1 / 10 (10.00%)	2 / 6 (33.33%)	4 / 44 (9.09%)	3 / 25 (12.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	1 / 1 (100.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	10	0	1	2	5	3	0	0	1	0	0
Blood bilirubin increased
subjects affected / exposed	2 / 41 (4.88%)	1 / 11 (9.09%)	2 / 10 (20.00%)	1 / 6 (16.67%)	0 / 44 (0.00%)	1 / 25 (4.00%)	1 / 10 (10.00%)	1 / 11 (9.09%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	4	3	2	1	0	1	2	1	0	0	0
Blood creatinine increased
subjects affected / exposed	1 / 41 (2.44%)	1 / 11 (9.09%)	1 / 10 (10.00%)	1 / 6 (16.67%)	2 / 44 (4.55%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	2	1	1	1	2	1	0	0	0	4	0
Blood thyroid stimulating hormone decreased
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	2 / 10 (20.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	2	0
Blood thyroid stimulating hormone increased
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	2 / 10 (20.00%)	0 / 1 (0.00%)
occurrences all number	1	0	1	0	1	1	0	0	0	2	0
Cortisol increased
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Hepatic enzyme increased
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
International normalised ratio increased
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Lipase increased
subjects affected / exposed	8 / 41 (19.51%)	2 / 11 (18.18%)	2 / 10 (20.00%)	2 / 6 (33.33%)	8 / 44 (18.18%)	3 / 25 (12.00%)	3 / 10 (30.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	15	3	4	2	13	4	11	0	0	8	0
Lymphocyte count decreased
subjects affected / exposed	4 / 41 (9.76%)	1 / 11 (9.09%)	0 / 10 (0.00%)	1 / 6 (16.67%)	1 / 44 (2.27%)	1 / 25 (4.00%)	0 / 10 (0.00%)	1 / 11 (9.09%)	1 / 1 (100.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	8	1	0	1	2	1	0	1	1	0	0
Platelet count decreased
subjects affected / exposed	1 / 41 (2.44%)	2 / 11 (18.18%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	2 / 25 (8.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	1	3	0	0	0	2	0	0	0	1	0
Norovirus test positive
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Transaminases increased
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	2 / 25 (8.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	2	0	0	0	0	0
Weight decreased
subjects affected / exposed	8 / 41 (19.51%)	2 / 11 (18.18%)	2 / 10 (20.00%)	2 / 6 (33.33%)	5 / 44 (11.36%)	3 / 25 (12.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	1 / 1 (100.00%)	1 / 10 (10.00%)	1 / 1 (100.00%)
occurrences all number	8	2	2	3	6	4	0	0	1	1	1
Weight increased
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	2 / 10 (20.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0	0	1	0	3	0	0	0	0
Blood urea increased
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Heart rate increased
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	5 / 41 (12.20%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	5	0	0	0	2	0	0	0	0	0	0
Infusion related reaction
subjects affected / exposed	2 / 41 (4.88%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	2	0	1	0	2	0	0	0	0	1	0
Limb injury
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Procedural pain
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	2	0	0	0	0	1	0
Bone fissure
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Radiation pneumonitis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Fall
subjects affected / exposed	2 / 41 (4.88%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 1 (100.00%)
occurrences all number	2	0	0	0	1	0	0	0	0	0	2
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Angina pectoris
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Palpitations
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 6 (16.67%)	1 / 44 (2.27%)	2 / 25 (8.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	1	1	3	2	0	0	0	0	0
Tachycardia
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	2 / 10 (20.00%)	2 / 6 (33.33%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	2	3	0	1	0	0	0	0	0
Cardiac failure congestive
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Atrioventricular block second degree
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Nervous system disorders
Autonomic nervous system imbalance
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0	0	0
Cerebrovascular accident
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Disturbance in attention
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	1	0
Dizziness
subjects affected / exposed	5 / 41 (12.20%)	1 / 11 (9.09%)	1 / 10 (10.00%)	2 / 6 (33.33%)	8 / 44 (18.18%)	1 / 25 (4.00%)	2 / 10 (20.00%)	3 / 11 (27.27%)	0 / 1 (0.00%)	2 / 10 (20.00%)	0 / 1 (0.00%)
occurrences all number	5	1	1	5	9	1	2	3	0	3	0
Dysaesthesia
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	4 / 10 (40.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	4	0
Dysarthria
subjects affected / exposed	1 / 41 (2.44%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	1	0	0	0	0	1	0	0	0	0
Dysgeusia
subjects affected / exposed	0 / 41 (0.00%)	2 / 11 (18.18%)	2 / 10 (20.00%)	1 / 6 (16.67%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	0	2	2	1	0	1	0	0	0	1	0
Headache
subjects affected / exposed	10 / 41 (24.39%)	0 / 11 (0.00%)	3 / 10 (30.00%)	3 / 6 (50.00%)	9 / 44 (20.45%)	9 / 25 (36.00%)	5 / 10 (50.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	2 / 10 (20.00%)	0 / 1 (0.00%)
occurrences all number	13	0	3	6	11	10	6	0	0	2	0
Hemiparesis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Lethargy
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 1 (100.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	1
Neuropathy peripheral
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	1 / 10 (10.00%)	0 / 6 (0.00%)	3 / 44 (6.82%)	1 / 25 (4.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	1	0	3	1	1	0	0	0	0
Paraesthesia
subjects affected / exposed	2 / 41 (4.88%)	1 / 11 (9.09%)	1 / 10 (10.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	2	1	2	0	1	0	0	0	0	1	0
Presyncope
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0	0	0
Restless legs syndrome
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	1	0	0	0	0
Seizure
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	0	1	0	0	0	0
Aphasia
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	1	0	0	0	0	0	0	0	0
Amnesia
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Fine motor delay
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Encephalopathy
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0	0	0
Hypersomnia
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Hypoaesthesia
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	3	1	0	0	0	0	0
Mental impairment
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Muscle spasticity
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Neurotoxicity
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Somnolence
subjects affected / exposed	1 / 41 (2.44%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	1	0	0	1	0	0	0	0	0	0
Syncope
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Spinal cord compression
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Tremor
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Balance disorder
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 1 (100.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	1
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	9 / 41 (21.95%)	0 / 11 (0.00%)	2 / 10 (20.00%)	2 / 6 (33.33%)	8 / 44 (18.18%)	5 / 25 (20.00%)	2 / 10 (20.00%)	0 / 11 (0.00%)	1 / 1 (100.00%)	2 / 10 (20.00%)	0 / 1 (0.00%)
occurrences all number	10	0	3	2	9	7	4	0	1	3	0
Haemolytic anaemia
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Thrombocytopenia
subjects affected / exposed	2 / 41 (4.88%)	0 / 11 (0.00%)	2 / 10 (20.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	1 / 25 (4.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	2	0	4	0	3	2	1	0	0	0	0
Coagulopathy
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Lymphadenopathy
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Microcytic anaemia
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Ear and labyrinth disorders
Hypoacusis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	1 / 25 (4.00%)	2 / 10 (20.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	1	2	0	0	0	0
Cerumen impaction
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Eye disorders
Dry eye
subjects affected / exposed	2 / 41 (4.88%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	2 / 10 (20.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	2	1	0	0	1	0	2	0	0	1	0
Eye disorder
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Eye pain
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	1 / 44 (2.27%)	2 / 25 (8.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	1	2	0	0	0	0	0
Uveitis
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0	1	0	0	1	0
Vision blurred
subjects affected / exposed	2 / 41 (4.88%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	3 / 44 (6.82%)	3 / 25 (12.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	2 / 10 (20.00%)	0 / 1 (0.00%)
occurrences all number	3	0	0	0	3	3	0	0	0	2	0
Visual impairment
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0	1	0
Eye pruritus
subjects affected / exposed	1 / 41 (2.44%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	1	0	0	1	0	0	0	0	0	0
Eye swelling
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Iridocyclitis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Lacrimation increased
subjects affected / exposed	1 / 41 (2.44%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	1	0	0	1	0	0	0	0	0	0
Ocular hyperaemia
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Conjunctival oedema
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 1 (100.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	1	0	0	0	0
Abdominal distension
subjects affected / exposed	2 / 41 (4.88%)	1 / 11 (9.09%)	1 / 10 (10.00%)	0 / 6 (0.00%)	3 / 44 (6.82%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	2	1	1	0	3	1	0	0	0	0	0
Abdominal pain
subjects affected / exposed	11 / 41 (26.83%)	3 / 11 (27.27%)	1 / 10 (10.00%)	3 / 6 (50.00%)	5 / 44 (11.36%)	4 / 25 (16.00%)	0 / 10 (0.00%)	3 / 11 (27.27%)	1 / 1 (100.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	14	3	1	4	5	4	0	3	1	1	0
Abdominal pain upper
subjects affected / exposed	2 / 41 (4.88%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	3 / 25 (12.00%)	2 / 10 (20.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	2	1	0	0	2	4	2	0	0	0	0
Anal pruritus
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Colitis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	2 / 6 (33.33%)	1 / 44 (2.27%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	2	1	0	1	0	0	0	0
Constipation
subjects affected / exposed	11 / 41 (26.83%)	4 / 11 (36.36%)	2 / 10 (20.00%)	1 / 6 (16.67%)	14 / 44 (31.82%)	1 / 25 (4.00%)	1 / 10 (10.00%)	1 / 11 (9.09%)	0 / 1 (0.00%)	2 / 10 (20.00%)	1 / 1 (100.00%)
occurrences all number	13	4	3	2	18	1	2	1	0	3	2
Diarrhoea
subjects affected / exposed	15 / 41 (36.59%)	5 / 11 (45.45%)	5 / 10 (50.00%)	2 / 6 (33.33%)	14 / 44 (31.82%)	9 / 25 (36.00%)	6 / 10 (60.00%)	4 / 11 (36.36%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	23	5	6	7	30	15	8	4	0	2	0
Dry mouth
subjects affected / exposed	3 / 41 (7.32%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	6 / 44 (13.64%)	2 / 25 (8.00%)	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	3	0	0	1	6	2	0	2	0	0	0
Dyspepsia
subjects affected / exposed	2 / 41 (4.88%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	4 / 44 (9.09%)	2 / 25 (8.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	2	0	1	0	5	5	1	0	0	0	0
Dysphagia
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0
Gastritis
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	1	0	1	0	0	0
Flatulence
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 6 (16.67%)	2 / 44 (4.55%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	1	2	0	0	0	0	0	0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Haemorrhoids
subjects affected / exposed	1 / 41 (2.44%)	1 / 11 (9.09%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	1	0	1	0	0	0	0	0	0	0
Nausea
subjects affected / exposed	9 / 41 (21.95%)	3 / 11 (27.27%)	2 / 10 (20.00%)	3 / 6 (50.00%)	12 / 44 (27.27%)	13 / 25 (52.00%)	7 / 10 (70.00%)	4 / 11 (36.36%)	0 / 1 (0.00%)	2 / 10 (20.00%)	1 / 1 (100.00%)
occurrences all number	16	4	2	4	14	22	8	5	0	2	2
Oral pain
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	1	0	0	0	0
Stomatitis
subjects affected / exposed	4 / 41 (9.76%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	2 / 44 (4.55%)	2 / 25 (8.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	4	0	0	1	2	2	0	0	0	1	0
Vomiting
subjects affected / exposed	6 / 41 (14.63%)	2 / 11 (18.18%)	2 / 10 (20.00%)	2 / 6 (33.33%)	4 / 44 (9.09%)	9 / 25 (36.00%)	3 / 10 (30.00%)	1 / 11 (9.09%)	0 / 1 (0.00%)	1 / 10 (10.00%)	1 / 1 (100.00%)
occurrences all number	10	3	2	2	5	19	3	1	0	1	2
Abdominal tenderness
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Aphthous ulcer
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Autoimmune colitis
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Ascites
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0	2	0	0	0	0	0	0	0
Chronic gastritis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Faecaloma
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	2 / 41 (4.88%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	2	1	0	0	3	1	0	0	0	0	0
Hepatobiliary disorders
Hepatic pain
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	3 / 44 (6.82%)	0 / 25 (0.00%)	0 / 10 (0.00%)	2 / 11 (18.18%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	5	0	0	2	0	0	0
Hypertransaminasaemia
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0	0	0	0
Bile duct obstruction
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Cholelithiasis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	1 / 10 (10.00%)	2 / 6 (33.33%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	0	1	1	2	0	0	1	0	0	1	0
Actinic keratosis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Dermatitis acneiform
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	1	2	0	0	0	0
Dry skin
subjects affected / exposed	7 / 41 (17.07%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	4 / 44 (9.09%)	0 / 25 (0.00%)	1 / 10 (10.00%)	2 / 11 (18.18%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	7	1	0	0	6	0	1	2	0	0	0
Dermatitis exfoliative generalised
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Hyperhidrosis
subjects affected / exposed	3 / 41 (7.32%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 1 (100.00%)
occurrences all number	3	0	0	1	1	0	0	0	0	0	1
Eczema nummular
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Lichenoid keratosis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0
Livedo reticularis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Pruritus
subjects affected / exposed	11 / 41 (26.83%)	8 / 11 (72.73%)	3 / 10 (30.00%)	2 / 6 (33.33%)	12 / 44 (27.27%)	8 / 25 (32.00%)	4 / 10 (40.00%)	1 / 11 (9.09%)	0 / 1 (0.00%)	6 / 10 (60.00%)	1 / 1 (100.00%)
occurrences all number	16	8	3	2	17	8	4	1	0	6	1
Rash
subjects affected / exposed	11 / 41 (26.83%)	5 / 11 (45.45%)	3 / 10 (30.00%)	1 / 6 (16.67%)	11 / 44 (25.00%)	6 / 25 (24.00%)	1 / 10 (10.00%)	1 / 11 (9.09%)	0 / 1 (0.00%)	3 / 10 (30.00%)	0 / 1 (0.00%)
occurrences all number	11	6	6	1	13	8	1	1	0	3	0
Rash erythematous
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0
Rash maculo-papular
subjects affected / exposed	5 / 41 (12.20%)	2 / 11 (18.18%)	4 / 10 (40.00%)	0 / 6 (0.00%)	5 / 44 (11.36%)	4 / 25 (16.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	6	2	5	0	9	4	1	0	0	1	0
Rash papular
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	1 / 11 (9.09%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0	0	0	0	1	1	0	0	0
Rash pruritic
subjects affected / exposed	1 / 41 (2.44%)	1 / 11 (9.09%)	1 / 10 (10.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	3 / 25 (12.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	2	3	1	0	2	3	0	0	0	0	0
Scab
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Skin hypopigmentation
subjects affected / exposed	1 / 41 (2.44%)	1 / 11 (9.09%)	1 / 10 (10.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	1 / 25 (4.00%)	2 / 10 (20.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	2 / 10 (20.00%)	0 / 1 (0.00%)
occurrences all number	1	1	1	0	1	1	2	0	0	2	0
Vitiligo
subjects affected / exposed	4 / 41 (9.76%)	2 / 11 (18.18%)	1 / 10 (10.00%)	0 / 6 (0.00%)	6 / 44 (13.64%)	0 / 25 (0.00%)	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	4	2	1	0	6	0	0	1	0	0	0
Erythema
subjects affected / exposed	2 / 41 (4.88%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	2	1	0	0	1	0	0	0	0	0	0
Night sweats
subjects affected / exposed	2 / 41 (4.88%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	2	1	0	0	2	0	0	0	0	0	0
Scar pain
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Skin ulcer
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	1	0	0	0	0	0	0
Facial wasting
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 1 (100.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
Renal and urinary disorders
Chromaturia
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	0
Acute kidney injury
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 6 (16.67%)	1 / 44 (2.27%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	1	1	1	0	0	0	0	0
Dysuria
subjects affected / exposed	3 / 41 (7.32%)	1 / 11 (9.09%)	2 / 10 (20.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	4	1	2	0	2	1	0	0	0	0	0
Pollakiuria
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	1	0
Haematuria
subjects affected / exposed	2 / 41 (4.88%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	3	1	0	0	0	0	0	0	0	0	0
Nocturia
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Polyuria
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Urinary hesitation
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0
Urinary incontinence
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	0 / 41 (0.00%)	2 / 11 (18.18%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 44 (0.00%)	4 / 25 (16.00%)	3 / 10 (30.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	2	0	1	0	4	3	0	0	0	0
Endocrine disorder
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0
Hyperthyroidism
subjects affected / exposed	1 / 41 (2.44%)	3 / 11 (27.27%)	3 / 10 (30.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	4 / 25 (16.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	1	3	3	0	2	4	1	0	0	1	0
Hypophysitis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	2 / 25 (8.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	2	0	0	0	0	0
Hypothyroidism
subjects affected / exposed	5 / 41 (12.20%)	1 / 11 (9.09%)	3 / 10 (30.00%)	2 / 6 (33.33%)	5 / 44 (11.36%)	5 / 25 (20.00%)	3 / 10 (30.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	1 / 1 (100.00%)
occurrences all number	6	1	3	2	7	6	3	0	0	1	1
Thyroiditis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	8 / 41 (19.51%)	2 / 11 (18.18%)	3 / 10 (30.00%)	2 / 6 (33.33%)	13 / 44 (29.55%)	5 / 25 (20.00%)	3 / 10 (30.00%)	1 / 11 (9.09%)	0 / 1 (0.00%)	2 / 10 (20.00%)	0 / 1 (0.00%)
occurrences all number	13	2	4	2	18	5	3	1	0	3	0
Arthritis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0	0	0
Back pain
subjects affected / exposed	11 / 41 (26.83%)	1 / 11 (9.09%)	1 / 10 (10.00%)	1 / 6 (16.67%)	8 / 44 (18.18%)	1 / 25 (4.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	2 / 10 (20.00%)	0 / 1 (0.00%)
occurrences all number	13	1	1	1	9	1	1	0	0	3	0
Bone pain
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0	0	0
Flank pain
subjects affected / exposed	2 / 41 (4.88%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 1 (100.00%)
occurrences all number	3	0	0	0	0	0	1	0	0	0	1
Joint range of motion decreased
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Muscle spasms
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	3 / 44 (6.82%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	3	0	0	0	0	1	0
Musculoskeletal pain
subjects affected / exposed	4 / 41 (9.76%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	6 / 44 (13.64%)	1 / 25 (4.00%)	2 / 10 (20.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	4	0	1	0	6	1	3	0	0	2	0
Muscular weakness
subjects affected / exposed	3 / 41 (7.32%)	1 / 11 (9.09%)	1 / 10 (10.00%)	1 / 6 (16.67%)	3 / 44 (6.82%)	1 / 25 (4.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	3	1	1	1	3	1	1	0	0	0	0
Neck pain
subjects affected / exposed	1 / 41 (2.44%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	5 / 44 (11.36%)	2 / 25 (8.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	1	1	0	0	5	2	0	0	0	1	0
Myalgia
subjects affected / exposed	2 / 41 (4.88%)	2 / 11 (18.18%)	1 / 10 (10.00%)	1 / 6 (16.67%)	7 / 44 (15.91%)	3 / 25 (12.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	2	2	1	2	7	3	1	0	0	1	0
Pain in extremity
subjects affected / exposed	7 / 41 (17.07%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	5 / 44 (11.36%)	1 / 25 (4.00%)	2 / 10 (20.00%)	3 / 11 (27.27%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	8	0	1	0	6	1	3	3	0	2	0
Pain in jaw
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0	0	0
Musculoskeletal stiffness
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	1	0	0	0	0	0
Infections and infestations
Candida infection
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	2 / 10 (20.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	2	0	0	1	0	0	0	0	0
Cellulitis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	1	0	1	0	0	0
Conjunctivitis
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 6 (16.67%)	0 / 44 (0.00%)	2 / 25 (8.00%)	2 / 10 (20.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	1	1	0	3	2	0	0	0	0
Influenza
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	1	0	1	0	0	0	0
Cytomegalovirus infection
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0
Pneumonia
subjects affected / exposed	2 / 41 (4.88%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	2	1	0	0	0	1	1	0	0	0	0
Nasopharyngitis
subjects affected / exposed	3 / 41 (7.32%)	1 / 11 (9.09%)	2 / 10 (20.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	1 / 1 (100.00%)
occurrences all number	4	1	3	0	0	1	0	0	0	1	1
Rash pustular
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	2 / 10 (20.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	0	0
Respiratory tract infection
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	1 / 11 (9.09%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	1	0	1	0	0	0
Rhinitis
subjects affected / exposed	1 / 41 (2.44%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	0 / 25 (0.00%)	2 / 10 (20.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	0	0	0	2	0	2	0	0	0	0
Sepsis
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	1 / 10 (10.00%)	2 / 6 (33.33%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	1	2	0	0	0	0	0	0	0
Sinusitis
subjects affected / exposed	2 / 41 (4.88%)	0 / 11 (0.00%)	2 / 10 (20.00%)	1 / 6 (16.67%)	3 / 44 (6.82%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	5	0	2	1	3	1	0	0	0	0	0
Skin infection
subjects affected / exposed	3 / 41 (7.32%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	3	0	0	0	2	1	0	0	0	0	0
Upper respiratory tract infection
subjects affected / exposed	4 / 41 (9.76%)	1 / 11 (9.09%)	2 / 10 (20.00%)	2 / 6 (33.33%)	4 / 44 (9.09%)	2 / 25 (8.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	4	1	2	2	4	2	2	0	0	1	0
Urinary tract infection
subjects affected / exposed	2 / 41 (4.88%)	1 / 11 (9.09%)	1 / 10 (10.00%)	2 / 6 (33.33%)	3 / 44 (6.82%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	3	1	1	2	3	0	1	0	0	0	0
Fungal skin infection
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Hordeolum
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Infected skin ulcer
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0
Laryngitis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0
Onychomycosis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Oral candidiasis
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Oral herpes
subjects affected / exposed	2 / 41 (4.88%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	2 / 44 (4.55%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	2	0	1	0	2	0	0	0	0	0	0
Pyuria
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Staphylococcal infection
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0
Herpes zoster
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	1 / 1 (100.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	10 / 41 (24.39%)	5 / 11 (45.45%)	3 / 10 (30.00%)	2 / 6 (33.33%)	15 / 44 (34.09%)	4 / 25 (16.00%)	4 / 10 (40.00%)	1 / 11 (9.09%)	1 / 1 (100.00%)	1 / 10 (10.00%)	1 / 1 (100.00%)
occurrences all number	11	6	3	2	16	5	4	1	1	2	1
Dehydration
subjects affected / exposed	2 / 41 (4.88%)	3 / 11 (27.27%)	1 / 10 (10.00%)	3 / 6 (50.00%)	0 / 44 (0.00%)	2 / 25 (8.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	1 / 1 (100.00%)
occurrences all number	2	3	2	3	0	2	1	0	0	2	3
Hypercalcaemia
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	1	0
Hyperglycaemia
subjects affected / exposed	4 / 41 (9.76%)	2 / 11 (18.18%)	0 / 10 (0.00%)	1 / 6 (16.67%)	4 / 44 (9.09%)	2 / 25 (8.00%)	1 / 10 (10.00%)	1 / 11 (9.09%)	0 / 1 (0.00%)	2 / 10 (20.00%)	0 / 1 (0.00%)
occurrences all number	7	2	0	1	7	2	2	1	0	8	0
Hyperuricaemia
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	1 / 44 (2.27%)	0 / 25 (0.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	1	0	1	0	0	0	0
Hypoalbuminaemia
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	2 / 6 (33.33%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	2	1	0	0	0	0	1	0
Hypoglycaemia
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	0 / 6 (0.00%)	1 / 44 (2.27%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	2 / 10 (20.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	2	0
Hypokalaemia
subjects affected / exposed	1 / 41 (2.44%)	2 / 11 (18.18%)	2 / 10 (20.00%)	3 / 6 (50.00%)	1 / 44 (2.27%)	2 / 25 (8.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	1	2	3	4	1	3	0	0	0	0	0
Hypomagnesaemia
subjects affected / exposed	2 / 41 (4.88%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 6 (16.67%)	1 / 44 (2.27%)	2 / 25 (8.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	3	0	1	1	1	2	0	0	0	1	0
Hyponatraemia
subjects affected / exposed	3 / 41 (7.32%)	2 / 11 (18.18%)	2 / 10 (20.00%)	4 / 6 (66.67%)	3 / 44 (6.82%)	2 / 25 (8.00%)	1 / 10 (10.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	3	2	2	4	3	3	1	0	0	1	0
Hypophosphataemia
subjects affected / exposed	3 / 41 (7.32%)	0 / 11 (0.00%)	2 / 10 (20.00%)	2 / 6 (33.33%)	2 / 44 (4.55%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	1 / 10 (10.00%)	0 / 1 (0.00%)
occurrences all number	4	0	2	3	3	0	0	0	0	1	0
Lactic acidosis
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	2 / 6 (33.33%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	2	0	0	0	0	0	0	0
Malnutrition
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	1 / 6 (16.67%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0	0	0	0
Diabetes mellitus
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	0	0	0
Fluid retention
subjects affected / exposed	0 / 41 (0.00%)	1 / 11 (9.09%)	0 / 10 (0.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	2	0	0	0	1	0	0	0	0	0
Hyperkalaemia
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0	0	0	0
Hypocalcaemia
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	1 / 10 (10.00%)	0 / 6 (0.00%)	0 / 44 (0.00%)	1 / 25 (4.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	0	0	0
Hypophagia
subjects affected / exposed	0 / 41 (0.00%)	0 / 11 (0.00%)	0 / 10 (0.00%)	1 / 6 (16.67%)	0 / 44 (0.00%)	0 / 25 (0.00%)	0 / 10 (0.00%)	0 / 11 (0.00%)	0 / 1 (0.00%)	0 / 10 (0.00%)	0 / 1 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0

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Were there any global substantial amendments to the protocol? No

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: An Exploratory Study of the Biologic Effects of Nivolumab and Nivolumab in Combination with Ipilimumab Treatment in Subjects with Advanced Melanoma (Unresectable or Metastatic)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Median change from baseline to week 7, of Interferon (IFN) and interferon gamma (IFN-gamma) inducible factors

Primary: Median change from baseline to week 7, of Interferon (IFN) and interferon gamma (IFN-gamma) inducible factors

Primary: Tumor infiltrating lymphocytes (TILs) as measured by medians in percent positive CD8 and positive CD4 at baseline and on-treatment biopsy, both using the Mosaic Singleplex IHC assay

Primary: Tumor infiltrating lymphocytes (TILs) as measured by medians in percent positive CD8 and positive CD4 at baseline and on-treatment biopsy, both using the Mosaic Singleplex IHC assay

Secondary: Safety and tolerability of Nivolumab, Ipilimumab and Nivolumab in combination with Ipilimumab as measured by the number of deaths and AEs

Secondary: Safety and tolerability of Nivolumab, Ipilimumab and Nivolumab in combination with Ipilimumab as measured by the number of deaths and AEs

Secondary: Number of Laboratory Abnormalities in Specific Liver Tests

Secondary: Number of Laboratory Abnormalities in Specific Liver Tests

Secondary: Number of Laboratory Abnormalities in Specific Thyroid Tests

Secondary: Number of Laboratory Abnormalities in Specific Thyroid Tests

Secondary: Antitumor Activity of Nivolumab and Nivolumab in combination with Ipilimumab as measured by the objective response rate (ORR)

Secondary: Antitumor Activity of Nivolumab and Nivolumab in combination with Ipilimumab as measured by the objective response rate (ORR)

Secondary: Antitumor Activity of Nivolumab and Nivolumab in combination with Ipilimumab as measured by the median duration of response (mDOR)

Secondary: Antitumor Activity of Nivolumab and Nivolumab in combination with Ipilimumab as measured by the median duration of response (mDOR)

Secondary: Antitumor Activity of Nivolumab and Nivolumab in combination with Ipilimumab as measured by the median time to response (mTTR)

Secondary: Antitumor Activity of Nivolumab and Nivolumab in combination with Ipilimumab as measured by the median time to response (mTTR)

Secondary: Antitumor Activity of Nivolumab and Nivolumab in combination with Ipilimumab as measured by the progression free survival rate (PFSR)

Secondary: Antitumor Activity of Nivolumab and Nivolumab in combination with Ipilimumab as measured by the progression free survival rate (PFSR)

Secondary: Immunogenicity of Nivolumab and Nivolumab in combination with Ipilimumab as measured by the number of serum anti-drug antibody (ADA) positive participants and the number of neutralizing ADA positive participants

Secondary: Immunogenicity of Nivolumab and Nivolumab in combination with Ipilimumab as measured by the number of serum anti-drug antibody (ADA) positive participants and the number of neutralizing ADA positive participants

Secondary: Association between Programmed cell death ligand 1 (PD-L1) and clinical efficacy measures such as Objective Response Rate (PD-L1 ORR)

Secondary: Association between Programmed cell death ligand 1 (PD-L1) and clinical efficacy measures such as Objective Response Rate (PD-L1 ORR)

Secondary: Association between Programmed cell death ligand 1 (PD-L1) and clinical efficacy measures such as the Duration of Response (PD-L1 DOR)

Secondary: Association between Programmed cell death ligand 1 (PD-L1) and clinical efficacy measures such as the Duration of Response (PD-L1 DOR)

Secondary: Association between Programmed cell death ligand 1 (PD-L1) and clinical efficacy measures such as Progression Free Survival (PD-L1 PFS)

Secondary: Association between Programmed cell death ligand 1 (PD-L1) and clinical efficacy measures such as Progression Free Survival (PD-L1 PFS)

Secondary: Antitumor Activity of Nivolumab and Nivolumab in combination with Ipilimumab as measured by the Overall Survival Rate (OSR)

Secondary: Antitumor Activity of Nivolumab and Nivolumab in combination with Ipilimumab as measured by the Overall Survival Rate (OSR)

Secondary: Safety and tolerability of Nivolumab, Ipilimumab and Nivolumab in combination with Ipilimumab as measured by SAEs and AEs leading to discontinuation of study drug

Secondary: Safety and tolerability of Nivolumab, Ipilimumab and Nivolumab in combination with Ipilimumab as measured by SAEs and AEs leading to discontinuation of study drug

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
An Exploratory Study of the Biologic Effects of Nivolumab and Nivolumab in Combination with Ipilimumab Treatment in Subjects with Advanced Melanoma (Unresectable or Metastatic)