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Clinical Trial Results:
A Study Of Nivolumab In Combination With Trametinib With Or Without Ipilimumab In Participants With Previously Treated Metastatic Colorectal Cancers

Summary
EudraCT number	2017-001830-24
Trial protocol	CZ IT ES
Global end of trial date	04 Nov 2024

Results information
Results version number	v1(current)
This version publication date	20 Nov 2025
First version publication date	20 Nov 2025
Other versions

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

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Trial information

Top of page

Sponsor protocol code

CA209-9N9

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Bristol-Myers Squibb

Sponsor organisation address

Chaussée de la Hulpe 185, Brussels, Belgium, 1170

Public contact

Global Submission Management, Clinical Trials, Bristol-Myers Squibb International Corporation, mg-gsm-ct@bms.com

Scientific contact

Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, mg-gsm-ct@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

04 Nov 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

04 Nov 2024

Was the trial ended prematurely?

Main objective of the trial

To characterize the safety and tolerability of combination therapies

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 subjects were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

31 Jan 2018

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 21

Country: Number of subjects enrolled

Australia: 39

Country: Number of subjects enrolled

Canada: 28

Country: Number of subjects enrolled

Chile: 35

Country: Number of subjects enrolled

Czechia: 18

Country: Number of subjects enrolled

Italy: 24

Country: Number of subjects enrolled

Spain: 60

Country: Number of subjects enrolled

United States: 74

Worldwide total number of subjects

299

EEA total number of subjects

102

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)

223

From 65 to 84 years

85 years and over

Subject disposition

Top of page

Recruitment details

Screening details

292 subjects Randomized and Treated

Period 1 title

Pre-Treatment

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Part 1 Cohort 1

Arm description

Trame 1.5mg Cont

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Trame

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

0.5 mg and various strengths

Part 1 Cohort 1B

Arm description

Trame 2 mg Int

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Trame

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

0.5 mg and various strengths

Part 1 Cohort 1D

Arm description

Trame 2mg Cont

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Trame

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

0.5 mg and various strengths

Part 1A Cohort 2

Arm description

Trame 1.5mg Cont

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Trame

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

0.5 mg and various strengths

Part 1A Cohort 2A

Arm description

Trame 1mg Cont

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Trame

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

0.5 mg and various strengths

Part 1A Cohort 3

Arm description

Trame 1.5mg Int

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Trame

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

0.5 mg and various strengths

Part 1A Cohort 3B

Arm description

Trame 2mg Int

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Trame

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

0.5 mg and various strengths

Part 2 Treatment 1

Arm description

Nivo 6 + Ipi 1 + Trame 1.5

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Trame

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

0.5 mg and various strengths

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

Ipi

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

200 mg, 50 mg, (5 mg/mL)

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Nivo

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

100 mg (10 mg/mL)

Part 2 Treatment 2

Arm description

Regorafenib 80/160

Arm type

Experimental

Investigational medicinal product name

Regorafenib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

40 mg and various strengths

Part 1B

Arm description

Nivo 6 + Ipi 1 + Trame 1.5

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Trame

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

0.5 mg and various strengths

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

Ipi

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

200 mg, 50 mg, (5 mg/mL)

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Nivo

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

100 mg (10 mg/mL)

Number of subjects in period 1	Part 1 Cohort 1	Part 1 Cohort 1B	Part 1 Cohort 1D	Part 1A Cohort 2	Part 1A Cohort 2A	Part 1A Cohort 3	Part 1A Cohort 3B	Part 2 Treatment 1	Part 2 Treatment 2	Part 1B
Started	3	3	6	7	3	3	7	124	61	82
Completed	3	3	6	7	3	3	7	121	57	82
Not completed	0	0	0	0	0	0	0	3	4	0
Subject withdrew consent	-	-	-	-	-	-	-	3	1	-
Not Reported	-	-	-	-	-	-	-	-	3	-

Period 2 title

Treatment Period

Is this the baseline period?

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Part 1 Cohort 1

Arm description

Trame 1.5mg Cont

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Trame

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

0.5 mg and various strengths

Part 1 Cohort 1B

Arm description

Trame 2 mg Int

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Trame

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

0.5 mg and various strengths

Part 1 Cohort 1D

Arm description

Trame 2mg Cont

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Trame

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

0.5 mg and various strengths

Part 1A Cohort 2

Arm description

Trame 1.5mg Cont

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Trame

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

0.5 mg and various strengths

Part 1A Cohort 2A

Arm description

Trame 1mg Cont

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Trame

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

0.5 mg and various strengths

Part 1A Cohort 3

Arm description

Trame 1.5mg Int

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Trame

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

0.5 mg and various strengths

Part 1A Cohort 3B

Arm description

Trame 2mg Int

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Trame

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

0.5 mg and various strengths

Part 2 Treatment 1

Arm description

Nivo 6 + Ipi 1 + Trame 1.5

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Trame

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

0.5 mg and various strengths

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

Ipi

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

200 mg, 50 mg, (5 mg/mL)

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Nivo

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

100 mg (10 mg/mL)

Part 2 Treatment 2

Arm description

Regorafenib 80/160

Arm type

Experimental

Investigational medicinal product name

Regorafenib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

40 mg and various strengths

Part 1B

Arm description

Nivo 6 + Ipi 1 + Trame 1.5

Arm type

Experimental

Investigational medicinal product name

Trametinib

Investigational medicinal product code

Other name

Trame

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

0.5 mg and various strengths

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Nivo

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

100 mg (10 mg/mL)

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

Ipi

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

200 mg, 50 mg, (5 mg/mL)

Number of subjects in period 2	Part 1 Cohort 1	Part 1 Cohort 1B	Part 1 Cohort 1D	Part 1A Cohort 2	Part 1A Cohort 2A	Part 1A Cohort 3	Part 1A Cohort 3B	Part 2 Treatment 1	Part 2 Treatment 2	Part 1B
Started	3	3	6	7	3	3	7	121	57	82
Completed	0	0	0	0	0	0	0	1	0	1
Not completed	3	3	6	7	3	3	7	120	57	81
Adverse event, serious fatal	-	-	1	-	-	-	-	2	1	3
Subject withdrew consent	-	-	-	-	-	-	-	-	2	1
Other Reasons	-	-	-	3	-	-	-	2	-	1
Subject request to discontinue study treatment	-	-	-	-	-	-	-	-	1	1
Adverse Event Unrelated to Study Drug	-	-	-	-	-	-	1	2	3	-
No longer meets study criteria	-	1	-	-	-	-	-	1	-	-
Study Drug Toxicity	-	-	-	1	-	-	-	7	2	16
Disease Progression	3	2	5	3	3	3	6	106	48	59

Baseline characteristics

Top of page

Reporting group title

Part 1 Cohort 1

Reporting group description

Trame 1.5mg Cont

Reporting group title

Part 1 Cohort 1B

Reporting group description

Trame 2 mg Int

Reporting group title

Part 1 Cohort 1D

Reporting group description

Trame 2mg Cont

Reporting group title

Part 1A Cohort 2

Reporting group description

Trame 1.5mg Cont

Reporting group title

Part 1A Cohort 2A

Reporting group description

Trame 1mg Cont

Reporting group title

Part 1A Cohort 3

Reporting group description

Trame 1.5mg Int

Reporting group title

Part 1A Cohort 3B

Reporting group description

Trame 2mg Int

Reporting group title

Part 2 Treatment 1

Reporting group description

Nivo 6 + Ipi 1 + Trame 1.5

Reporting group title

Part 2 Treatment 2

Reporting group description

Regorafenib 80/160

Reporting group title

Part 1B

Reporting group description

Nivo 6 + Ipi 1 + Trame 1.5

Reporting group values	Part 1 Cohort 1	Part 1 Cohort 1B	Part 1 Cohort 1D	Part 1A Cohort 2	Part 1A Cohort 2A	Part 1A Cohort 3	Part 1A Cohort 3B	Part 2 Treatment 1	Part 2 Treatment 2	Part 1B	Total
Number of subjects	3	3	6	7	3	3	7	124	61	82	299
Age Categorical
Units: Participants
Between 18 and 65 years	2	3	5	6	2	3	6	89	47	60	223
Between 65 and 84 years old	1	0	1	1	1	0	1	35	14	22	76
>=85 years	0	0	0	0	0	0	0	0	0	0	0
Sex: Female, Male
Units: Participants
Female	3	1	0	4	2	1	3	48	30	37	129
Male	0	2	6	3	1	2	4	76	31	45	170
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0	0	0	0	0	0
Asian	0	0	1	1	0	0	1	2	0	5	10
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0	0	0	0	0
Black or African American	0	0	0	0	0	0	0	1	1	1	3
White	3	3	4	6	3	2	6	119	58	74	278
More than one race	0	0	0	0	0	0	0	0	0	0	0
Unknown or Not Reported	0	0	1	0	0	1	0	2	2	2	8
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	0	0	0	1	0	1	0	10	6	7	25
Not Hispanic or Latino	3	3	6	6	3	2	7	55	27	51	163
Unknown or Not Reported	0	0	0	0	0	0	0	59	28	24	111

End points

Top of page

Reporting group title

Part 1 Cohort 1

Reporting group description

Trame 1.5mg Cont

Reporting group title

Part 1 Cohort 1B

Reporting group description

Trame 2 mg Int

Reporting group title

Part 1 Cohort 1D

Reporting group description

Trame 2mg Cont

Reporting group title

Part 1A Cohort 2

Reporting group description

Trame 1.5mg Cont

Reporting group title

Part 1A Cohort 2A

Reporting group description

Trame 1mg Cont

Reporting group title

Part 1A Cohort 3

Reporting group description

Trame 1.5mg Int

Reporting group title

Part 1A Cohort 3B

Reporting group description

Trame 2mg Int

Reporting group title

Part 2 Treatment 1

Reporting group description

Nivo 6 + Ipi 1 + Trame 1.5

Reporting group title

Part 2 Treatment 2

Reporting group description

Regorafenib 80/160

Reporting group title

Part 1B

Reporting group description

Nivo 6 + Ipi 1 + Trame 1.5

Reporting group title

Part 1 Cohort 1

Reporting group description

Trame 1.5mg Cont

Reporting group title

Part 1 Cohort 1B

Reporting group description

Trame 2 mg Int

Reporting group title

Part 1 Cohort 1D

Reporting group description

Trame 2mg Cont

Reporting group title

Part 1A Cohort 2

Reporting group description

Trame 1.5mg Cont

Reporting group title

Part 1A Cohort 2A

Reporting group description

Trame 1mg Cont

Reporting group title

Part 1A Cohort 3

Reporting group description

Trame 1.5mg Int

Reporting group title

Part 1A Cohort 3B

Reporting group description

Trame 2mg Int

Reporting group title

Part 2 Treatment 1

Reporting group description

Nivo 6 + Ipi 1 + Trame 1.5

Reporting group title

Part 2 Treatment 2

Reporting group description

Regorafenib 80/160

Reporting group title

Part 1B

Reporting group description

Nivo 6 + Ipi 1 + Trame 1.5

Primary: Dose Limiting Toxicities in Part 1 and Part 1A

Top of page

End point title

Dose Limiting Toxicities in Part 1 and Part 1A ^[1] ^[2]

End point description

Dose Limiting Toxicities are defined as adverse events have to be at least possibly related to study treatment, and not to disease progression, be clinically relevant and a clinically relevant shift from baseline.

End point type

Primary

End point timeframe

4 weeks for Doublet Reginmen and 8 weeks for triplet Regimen

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No further statistical analysis done
[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: Cohort specific endpoint

End point values	Part 1 Cohort 1	Part 1 Cohort 1B	Part 1 Cohort 1D	Part 1A Cohort 2	Part 1A Cohort 2A	Part 1A Cohort 3	Part 1A Cohort 3B
Number of subjects analysed	3	3	6	7	3	3	7
Units: Participants	0	0	1	1	0	0	0

No statistical analyses for this end point

Primary: Safety Related Events in Part 1 and Part 1 A

Top of page

End point title

Safety Related Events in Part 1 and Part 1 A ^[3] ^[4]

End point description

Safety-related events in clinical trials include Adverse Events (AEs), Serious Adverse Events (SAEs), and deaths. An AE is any new or worsening medical issue in a participant receiving the study drug, regardless of its relation to the drug. This includes abnormal lab results, symptoms, or diseases. An SAE is a more severe AE that results in death, is life-threatening, requires or prolongs hospitalization, causes significant disability, involves a birth defect, or is deemed medically important—potentially jeopardizing the participant or requiring intervention, even if not immediately life-threatening. These definitions help ensure consistent reporting and evaluation of safety during clinical studies.

End point type

Primary

End point timeframe

Assessed from first dose date to 100 days after last dose of study therapy. (Approximately: Part 1: ~ 6.5 Months Part 1A: ~ 5.5 Months)

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No further statistical analysis done
[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: Cohort specific endpoint

End point values	Part 1 Cohort 1	Part 1 Cohort 1B	Part 1 Cohort 1D	Part 1A Cohort 2	Part 1A Cohort 2A	Part 1A Cohort 3	Part 1A Cohort 3B
Number of subjects analysed	3	3	6	7	3	3	7
Units: Participants
Adverse Events (AEs)	3	3	6	7	3	3	7
Drug-Related AEs	3	3	6	7	3	3	7
Serious Adverse Events (SAEs)	2	0	4	3	0	2	3
Drug-Related SAEs	0	0	2	3	0	1	1
Deaths	2	2	6	3	2	3	5

No statistical analyses for this end point

Primary: Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests

Top of page

End point title

Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests ^[5] ^[6]

End point description

Number of participants with clinical laboratory abnormalities in specific thyroid tests.

End point type

Primary

End point timeframe

Assessed from first dose date to 100 days after last dose of study therapy. (Approximately: Part 1: ~ 6.5 Months Part 1A: ~ 5.5 Months)

Notes
[5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No further statistical analysis done
[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: Cohort specific endpoint

End point values	Part 1 Cohort 1	Part 1 Cohort 1B	Part 1 Cohort 1D	Part 1A Cohort 2	Part 1A Cohort 2A	Part 1A Cohort 3	Part 1A Cohort 3B
Number of subjects analysed	3	3	6	7	3	3	7
Units: Participants
TSH > ULN	2	1	1	3	1	3	2
TSH > ULN WITH TSH ≤ ULN AT BASELINE	2	1	1	0	0	2	2
TSH >ULN WITH ATLEAST ONE FT3/FT4 TEST VALUE <LLN	2	1	1	1	0	1	1
TSH >ULN WITH ALL OTHER FT3/FT4 TEST VALUES ≥ LLN	0	0	0	2	1	2	1
TSH > ULN WITH FT3/FT4 TEST MISSING	0	0	0	0	0	0	0
TSH < LLN	2	0	2	2	2	1	2
TSH <LLN WITH TSH ≥ LLN AT BASELINE	1	0	2	1	2	1	2
TSH <LLN WITH ATLEAST ONE FT3/FT4 TEST VALUE > ULN	2	0	1	1	0	1	2
TSH <LLN WITH ALL OTHER FT3/FT4 TEST VALUES ≤ ULN	0	0	1	0	2	0	0
TSH < LLN WITH FT3/FT4 TEST MISSING	0	0	0	1	0	0	0

No statistical analyses for this end point

Primary: Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests

Top of page

End point title

Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests ^[7] ^[8]

End point description

Number of participants with clinical laboratory abnormalities in specific liver tests

End point type

Primary

End point timeframe

Assessed from first dose date to 100 days after last dose of study therapy. (Approximately: Part 1: ~ 6.5 Months Part 1A: ~ 5.5 Months)

Notes
[7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No further statistical analysis done
[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: Cohort specific endpoint

End point values	Part 1 Cohort 1	Part 1 Cohort 1B	Part 1 Cohort 1D	Part 1A Cohort 2	Part 1A Cohort 2A	Part 1A Cohort 3	Part 1A Cohort 3B
Number of subjects analysed	3	3	6	7	3	3	7
Units: Participants
ALT OR AST > 3XULN	0	0	2	1	1	0	2
ALT OR AST> 5XULN	0	0	2	1	1	0	2
ALT OR AST> 10XULN	0	0	2	1	0	0	2
ALT OR AST > 20XULN	0	0	1	1	0	0	0
TOTAL BILIRUBIN > 2XULN	0	0	2	0	0	0	1
ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 1 DAY	0	0	2	0	0	0	1
ALT/AST ELEV>3XULN;TOTAL BILI>2XULN IN 30 DAYS	0	0	2	0	0	0	1

No statistical analyses for this end point

Primary: Objective Response Rate in Part 1B and Part 2

Top of page

End point title

Objective Response Rate in Part 1B and Part 2 ^[9] ^[10]

End point description

ORR is defined as the proportion of all treated (randomized, for Part 2) participants whose BOR is either confirmed complete response (CR) or confirmed partial response (PR).

End point type

Primary

End point timeframe

Approximately up to 30 Months

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No further statistical analysis done
[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: Cohort specific endpoint

End point values	Part 2 Treatment 1	Part 2 Treatment 2	Part 1B
Number of subjects analysed	124	61	82
Units: Percentage of Participants
number (confidence interval 95%)	1.6 (0.2 to 5.7)	1.6 (0.0 to 8.8)	9.8 (4.3 to 18.3)

No statistical analyses for this end point

Secondary: Objective Response Rate in Part 1 and Part 1A

Top of page

End point title

Objective Response Rate in Part 1 and Part 1A ^[11]

End point description

ORR is defined as the percentage of all treated (randomized, for Part 2) participants whose BOR is either confirmed complete response (CR) or confirmed partial response (PR).

End point type

Secondary

End point timeframe

From the first dosing date and the date of the initial objectively documented tumor progression or subsequent therapy date (Approximately up to 21 Months)

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: Cohort specific endpoint

End point values	Part 1 Cohort 1	Part 1 Cohort 1B	Part 1 Cohort 1D	Part 1A Cohort 2	Part 1A Cohort 2A	Part 1A Cohort 3	Part 1A Cohort 3B
Number of subjects analysed	3	3	6	7	3	3	7
Units: Percentage of Participants
number (confidence interval 95%)	0 (0.0 to 70.8)	0 (0.0 to 70.8)	0 (0.0 to 45.9)	28.6 (3.7 to 71.0)	33.3 (0.8 to 90.6)	0 (0.0 to 70.8)	0 (0.0 to 41.0)

No statistical analyses for this end point

Secondary: Disease Control Rate in Part 1 and Part 1A

Top of page

End point title

Disease Control Rate in Part 1 and Part 1A ^[12]

End point description

The disease control rate (DCR) is defined as the percentage of participants whose BOR is either confirmed CR or confirmed PR or stable disease (SD)

End point type

Secondary

End point timeframe

From the first dosing date and the date of the initial objectively documented tumor progression or subsequent therapy date (Approximately up to 21 Months)

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

End point values	Part 1 Cohort 1	Part 1 Cohort 1B	Part 1 Cohort 1D	Part 1A Cohort 2	Part 1A Cohort 2A	Part 1A Cohort 3	Part 1A Cohort 3B
Number of subjects analysed	3	3	6	7	3	3	7
Units: Percentage of Participants
number (confidence interval 95%)	66.7 (9.4 to 99.2)	33.3 (0.8 to 90.6)	50.0 (11.8 to 88.2)	57.1 (18.4 to 90.1)	33.3 (0.8 to 90.6)	66.7 (9.4 to 99.2)	28.6 (3.7 to 71.0)

No statistical analyses for this end point

Secondary: Duration of Response in Part 1 and Part 1A

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End point title

Duration of Response in Part 1 and Part 1A ^[13]

End point description

DOR for a participant with a BOR of confirmed CR or PR, is defined as the time between the date of first confirmed response and the date of the first objectively documented tumor progression per RECIST 1.1 or death, whichever occurs first. Here "-99999 and 99999" = NA

End point type

Secondary

End point timeframe

Approximately up to 20 Months

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

End point values	Part 1 Cohort 1	Part 1 Cohort 1B	Part 1 Cohort 1D	Part 1A Cohort 2	Part 1A Cohort 2A	Part 1A Cohort 3	Part 1A Cohort 3B
Number of subjects analysed	0 ^[14]	0 ^[15]	0 ^[16]	2	1	0 ^[17]	0 ^[18]
Units: Months
median (confidence interval 95%)	( to )	( to )	( to )	9.46 (-99999 to 99999)	19.42 (-99999 to 99999)	( to )	( to )

Notes
[14] - Zero subjects with an event
[15] - Zero subjects with an event
[16] - Zero subjects with an event
[17] - Zero subjects with an event
[18] - Zero subjects with an event

No statistical analyses for this end point

Secondary: Time to Response in Part 1 and Part 1A

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End point title

Time to Response in Part 1 and Part 1A ^[19]

End point description

Time to response (TTR) is defined for participants who had a confirmed CR or PR as the time from the first dosing date to the date of first documented CR or PR per RECIST 1.1.

End point type

Secondary

End point timeframe

From the first dosing date to the date of first documented CR or PR per RECIST 1.1. (Approximately on average 10 months)

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

End point values	Part 1 Cohort 1	Part 1 Cohort 1B	Part 1 Cohort 1D	Part 1A Cohort 2	Part 1A Cohort 2A	Part 1A Cohort 3	Part 1A Cohort 3B
Number of subjects analysed	0 ^[20]	0 ^[21]	0 ^[22]	2	1	0 ^[23]	0 ^[24]
Units: Months
median (full range (min-max))	( to )	( to )	( to )	5.63 (1.8 to 9.5)	1.54 (1.54 to 1.54)	( to )	( to )

Notes
[20] - Zero subjects with an event
[21] - Zero subjects with an event
[22] - Zero subjects with an event
[23] - Zero subjects with an event
[24] - Zero subjects with an event

No statistical analyses for this end point

Secondary: Progression Free Survival in Part 1 and Part 1A

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End point title

Progression Free Survival in Part 1 and Part 1A ^[25]

End point description

PFS for a participant is defined as the time from the first dosing date to the date of first objectively documented disease progression per RECIST 1.1 (ie, radiologic) or death due to any cause, whichever occurs first. Here "-99999 and 99999" = NA

End point type

Secondary

End point timeframe

from the first dosing date to the date of first objectively documented disease progression or death, whichever occurs first (Approximately up to 21 months)

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

End point values	Part 1 Cohort 1	Part 1 Cohort 1B	Part 1 Cohort 1D	Part 1A Cohort 2	Part 1A Cohort 2A	Part 1A Cohort 3	Part 1A Cohort 3B
Number of subjects analysed	3	3	6	7	3	3	7
Units: Months
median (confidence interval 95%)	3.58 (1.84 to 99999)	1.91 (1.74 to 99999)	2.66 (0.79 to 99999)	7.36 (1.84 to 99999)	1.74 (1.74 to 99999)	4.14 (1.84 to 99999)	1.81 (0.92 to 99999)

No statistical analyses for this end point

Secondary: Overall Survival in Part 1 and Part 1A

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End point title

Overall Survival in Part 1 and Part 1A ^[26]

End point description

OS for a participant is defined as the time from the first dosing date to the date of death due to any cause. A participant who has not died will be censored at last known date alive. Here "99999" = NA

End point type

Secondary

End point timeframe

Approximately up to 69 Months

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

End point values	Part 1 Cohort 1	Part 1 Cohort 1B	Part 1 Cohort 1D	Part 1A Cohort 2	Part 1A Cohort 2A	Part 1A Cohort 3	Part 1A Cohort 3B
Number of subjects analysed	3	3	6	7	3	3	7
Units: Months
median (confidence interval 95%)	8.99 (8.80 to 99999)	18.50 (17.45 to 99999)	9.61 (0.89 to 99999)	42.09 (11.60 to 99999)	19.02 (8.80 to 99999)	11.33 (10.51 to 99999)	36.24 (2.23 to 99999)

No statistical analyses for this end point

Secondary: Safety Related Events in Part 1B and Part 2

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End point title

Safety Related Events in Part 1B and Part 2 ^[27]

End point description

End point type

Secondary

End point timeframe

Assessed from first dose date to 100 days after last dose of study therapy. (Approximately: 6.8 Months)

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

End point values	Part 2 Treatment 1	Part 2 Treatment 2	Part 1B
Number of subjects analysed	121	57	82
Units: Participants
Adverse Events (AEs)	121	57	82
Drug-Related AEs	116	52	80
Serious Adverse Events (SAEs)	56	19	36
Drug-Related SAEs	21	3	20
Deaths	106	53	49

No statistical analyses for this end point

Secondary: Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests

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End point title

Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests ^[28]

End point description

Number of participants with clinical laboratory abnormalities in specific thyroid tests.

End point type

Secondary

End point timeframe

Assessed from first dose date to 100 days after last dose of study therapy. (Approximately: 6.8 Months)

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

End point values	Part 2 Treatment 1	Part 2 Treatment 2	Part 1B
Number of subjects analysed	114	46	81
Units: Participants
TSH > ULN	31	21	13
TSH > ULN WITH TSH ≤ ULN AT BASELINE	18	16	9
TSH >ULN WITH ATLEAST ONE FT3/FT4 TEST VALUE <LLN	14	3	9
TSH >ULN WITH ALL OTHER FT3/FT4 TEST VALUES ≥ LLN	13	14	3
TSH > ULN WITH FT3/FT4 TEST MISSING	4	4	1
TSH < LLN	24	0	14
TSH <LLN WITH TSH ≥ LLN AT BASELINE	21	0	11
TSH <LLN WITH ATLEAST ONE FT3/FT4 TEST VALUE > ULN	12	0	5
TSH <LLN WITH ALL OTHER FT3/FT4 TEST VALUES ≤ ULN	7	0	8
TSH < LLN WITH FT3/FT4 TEST MISSING	5	0	1

No statistical analyses for this end point

Secondary: Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Liver Tests

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End point title

Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Liver Tests ^[29]

End point description

Number of participants with clinical laboratory abnormalities in specific liver tests

End point type

Secondary

End point timeframe

Assessed from first dose date to 100 days after last dose of study therapy. (Approximately: 6.8 Months)

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

End point values	Part 2 Treatment 1	Part 2 Treatment 2	Part 1B
Number of subjects analysed	118	53	82
Units: Participants
ALT OR AST > 3XULN	38	11	18
ALT OR AST> 5XULN	19	8	8
ALT OR AST> 10XULN	5	4	1
ALT OR AST > 20XULN	3	2	0
TOTAL BILIRUBIN > 2XULN	9	12	3
ALT/AST ELEV>3XULN;TOTAL BILIRUBIN>2XULN IN 1 DAY	6	7	2
ALT/AST ELEV>3XULN;TOTAL BILI>2XULN IN 30 DAYS	7	7	2

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

Part 1: Approximately 5.5 Months Part 1A: Approximately 6.5 Months Part 1B and 2: Approximately 6.8 Months

Adverse event reporting additional description

The number at Risk for All-Cause Mortality represents all Randomized Participants. The number at Risk for Serious Adverse Events and Other (Not Including Serious) Adverse Events represents all participants that received at least 1 dose of study medication

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

27.1

Reporting group title

Part 1 Cohort 1 (Trame 1.5 mg Cont)

Reporting group description

Trame 1.5mg Cont

Reporting group title

Part 1 Cohort 1B (Trame 2 mg Int)

Reporting group description

Trame 2 mg Int

Reporting group title

Part 2 Regorafenib 80/160

Reporting group description

Regorafenib 80/160

Reporting group title

Part 1A Cohort 3 (Trame 1.5 mg Int)

Reporting group description

Trame 1.5mg Int

Reporting group title

Part 1A Cohort 3B (Trame 2 mg Int)

Reporting group description

Trame 2mg Int

Reporting group title

Part 1B Nivo 6 + Ipi 1 + Trame 1.5

Reporting group description

Nivo 6 + Ipi 1 + Trame 1.5

Reporting group title

Part 2 Nivo 6 + Ipi 1 + Trame 1.5

Reporting group description

‌ Nivo 6 + Ipi 1 + Trame 1.5

Reporting group title

Part 1A Cohort 2 (Trame 1.5 mg Cont)

Reporting group description

Trame 1.5mg Cont

Reporting group title

Part 1 Cohort 1D (Trame 2 mg Cont)

Reporting group description

Trame 2mg Cont

Reporting group title

Part 1A Cohort 2A (Trame 1 mg Cont)

Reporting group description

Trame 1mg Cont

Serious adverse events	Part 1 Cohort 1 (Trame 1.5 mg Cont)	Part 1 Cohort 1B (Trame 2 mg Int)	Part 2 Regorafenib 80/160	Part 1A Cohort 3 (Trame 1.5 mg Int)	Part 1A Cohort 3B (Trame 2 mg Int)	Part 1B Nivo 6 + Ipi 1 + Trame 1.5	Part 2 Nivo 6 + Ipi 1 + Trame 1.5	Part 1A Cohort 2 (Trame 1.5 mg Cont)	Part 1 Cohort 1D (Trame 2 mg Cont)	Part 1A Cohort 2A (Trame 1 mg Cont)
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	33 / 57 (57.89%)	2 / 3 (66.67%)	3 / 7 (42.86%)	42 / 82 (51.22%)	79 / 121 (65.29%)	3 / 7 (42.86%)	5 / 6 (83.33%)	0 / 3 (0.00%)
number of deaths (all causes)	2	2	53	3	5	49	106	3	6	2
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Brain neoplasm malignant
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Colorectal cancer
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 3 (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 / 1	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 / 1	0 / 0
Malignant neoplasm progression
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	21 / 57 (36.84%)	0 / 3 (0.00%)	0 / 7 (0.00%)	11 / 82 (13.41%)	42 / 121 (34.71%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 21	0 / 0	0 / 0	0 / 12	0 / 43	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 20	0 / 0	0 / 0	0 / 10	0 / 42	0 / 0	0 / 0	0 / 0
Metastases to central nervous system
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Metastases to eye
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Neoplasm progression
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 57 (3.51%)	0 / 3 (0.00%)	1 / 7 (14.29%)	1 / 82 (1.22%)	1 / 121 (0.83%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 1	0 / 1	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 1	0 / 1	0 / 1	0 / 0	0 / 1	0 / 0
Neoplasm malignant
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 57 (3.51%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	2 / 121 (1.65%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 1	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 1	0 / 2	0 / 0	0 / 0	0 / 0
Tumour haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 3 (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
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
Extrinsic iliac vein compression
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Embolism
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 3 (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 / 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
Hypertension
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	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
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Cardiac death
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Disease progression
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Fatigue
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	2 / 121 (1.65%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 2	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
Influenza like illness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Oedema peripheral
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Non-cardiac chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 82 (2.44%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	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
Localised oedema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Pyrexia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 57 (3.51%)	0 / 3 (0.00%)	0 / 7 (0.00%)	5 / 82 (6.10%)	7 / 121 (5.79%)	2 / 7 (28.57%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	1 / 5	6 / 10	2 / 2	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
Reproductive system and breast disorders
Intermenstrual bleeding
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Pelvic pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Respiratory, thoracic and mediastinal disorders
Haemoptysis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Dyspnoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 3 (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 / 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
Immune-mediated lung disease
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	1 / 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
Pulmonary embolism
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 82 (0.00%)	2 / 121 (1.65%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 2	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
Pneumonitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 82 (2.44%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 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	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Delirium
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Mental status changes
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 82 (2.44%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	1 / 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
Amylase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Aspartate aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 82 (2.44%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	1 / 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
Blood creatinine increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Blood bilirubin increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Blood lactic acid increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Ejection fraction decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Lipase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Injury, poisoning and procedural complications
Hip fracture
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Intentional overdose
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Infusion related reaction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	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
Limb injury
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Overdose
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Cardiac disorders
Cardiac failure
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Cardiac arrest
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
deaths 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
Atrial fibrillation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 3 (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 / 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
Cardiac failure congestive
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Sinus tachycardia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Nervous system disorders
Hyponatraemic encephalopathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Hepatic encephalopathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Cerebrovascular accident
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Seizure
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Spinal cord compression
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Syncope
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 82 (2.44%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 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
Transient ischaemic attack
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	1 / 7 (14.29%)	1 / 82 (1.22%)	2 / 121 (1.65%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	1 / 1	1 / 2	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
Eye disorders
Detachment of retinal pigment epithelium
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	1 / 82 (1.22%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	1 / 1	1 / 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
Eyelid ptosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 57 (3.51%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 82 (2.44%)	2 / 121 (1.65%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 2	0 / 2	0 / 0	0 / 0	0 / 0
deaths 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
Abdominal distension
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Anal fistula
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Ascites
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
Colitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	2 / 121 (1.65%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	3 / 3	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
Enteritis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Duodenal ulcer
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 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
Diarrhoea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	5 / 82 (6.10%)	3 / 121 (2.48%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	4 / 5	3 / 3	1 / 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
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 57 (3.51%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	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
Gastrooesophageal haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Haematochezia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Ileus
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Immune-mediated enterocolitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	2 / 121 (1.65%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	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
Intestinal ischaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Intestinal pseudo-obstruction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Intestinal perforation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Intestinal obstruction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 82 (2.44%)	4 / 121 (3.31%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 3	0 / 4	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
Large intestinal obstruction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3	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
Rectal haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Pancreatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Nausea
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 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
Rectal perforation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Small intestinal obstruction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 82 (0.00%)	0 / 121 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2	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
Stomatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Vomiting
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	2 / 121 (1.65%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 3	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
Hepatobiliary disorders
Acute hepatic failure
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Acute cholecystitis necrotic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 3 (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
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
Biliary cast syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Biliary obstruction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 2	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
Hepatic function abnormal
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Hepatic failure
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	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	1 / 1	0 / 0
Drug-induced liver injury
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Cholangitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 57 (5.26%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 3 (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 / 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
Hepatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 82 (2.44%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	3 / 3	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
Hyperbilirubinaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	2 / 121 (1.65%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Hypertransaminasaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	1 / 82 (1.22%)	1 / 121 (0.83%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	1 / 1	1 / 1	1 / 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
Immune-mediated hepatitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	2 / 121 (1.65%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2	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
Jaundice
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Malignant biliary obstruction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Liver disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Jaundice cholestatic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	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
Skin and subcutaneous tissue disorders
Drug eruption
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Erythrodermic psoriasis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Rash maculo-papular
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Rash papular
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Renal and urinary disorders
Urinary tract obstruction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Hydronephrosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Acute kidney injury
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 57 (3.51%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	3 / 121 (2.48%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 3	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
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	2 / 121 (1.65%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	2 / 2	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
Hypothyroidism
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Back pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	1 / 121 (0.83%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	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
Pain in extremity
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 3 (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 / 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
Infections and infestations
Bacteraemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1	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
COVID-19
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	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
Infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Listeriosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Cellulitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Clostridium difficile colitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Enterocolitis infectious
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2	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
Pneumonia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	2 / 121 (1.65%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	2 / 2	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
Pneumonia pneumococcal
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Proteus infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Sepsis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	1 / 82 (1.22%)	1 / 121 (0.83%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 3	0 / 4	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
Septic shock
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	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 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Soft tissue infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Stoma site abscess
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Upper respiratory tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Streptococcal infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Stoma site infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Urosepsis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (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
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
Urinary tract infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 57 (3.51%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 82 (2.44%)	2 / 121 (1.65%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 2	0 / 2	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
Vascular device infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	2 / 121 (1.65%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	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
Decreased appetite
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Diabetic ketoacidosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	2 / 121 (1.65%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2	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
Hyperkalaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	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
Hypokalaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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
Hyponatraemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	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
Type 1 diabetes mellitus
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (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
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

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

Non-serious adverse events	Part 1 Cohort 1 (Trame 1.5 mg Cont)	Part 1 Cohort 1B (Trame 2 mg Int)	Part 2 Regorafenib 80/160	Part 1A Cohort 3 (Trame 1.5 mg Int)	Part 1A Cohort 3B (Trame 2 mg Int)	Part 1B Nivo 6 + Ipi 1 + Trame 1.5	Part 2 Nivo 6 + Ipi 1 + Trame 1.5	Part 1A Cohort 2 (Trame 1.5 mg Cont)	Part 1 Cohort 1D (Trame 2 mg Cont)	Part 1A Cohort 2A (Trame 1 mg Cont)
Total subjects affected by non serious adverse events
subjects affected / exposed	3 / 3 (100.00%)	3 / 3 (100.00%)	55 / 57 (96.49%)	3 / 3 (100.00%)	7 / 7 (100.00%)	82 / 82 (100.00%)	121 / 121 (100.00%)	7 / 7 (100.00%)	6 / 6 (100.00%)	3 / 3 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 57 (7.02%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	3 / 121 (2.48%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	4	0	0	1	7	0	0	0
Vascular disorders
Flushing
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	1	0
Hot flush
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	1	0	0	0
Hypertension
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	7 / 57 (12.28%)	0 / 3 (0.00%)	1 / 7 (14.29%)	13 / 82 (15.85%)	10 / 121 (8.26%)	0 / 7 (0.00%)	2 / 6 (33.33%)	1 / 3 (33.33%)
occurrences all number	0	1	8	0	1	14	13	0	2	4
Hypotension
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 57 (1.75%)	1 / 3 (33.33%)	0 / 7 (0.00%)	1 / 82 (1.22%)	3 / 121 (2.48%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	2	0	1	1	0	1	4	1	0	0
Vena cava thrombosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	0 / 121 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	2	0	0
General disorders and administration site conditions
Gait disturbance
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	1	0	0	0	0	0	0
Chills
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	1 / 57 (1.75%)	1 / 3 (33.33%)	1 / 7 (14.29%)	4 / 82 (4.88%)	9 / 121 (7.44%)	2 / 7 (28.57%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	3	0	2	2	1	4	11	3	0	0
Early satiety
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	1	0	0
Fatigue
subjects affected / exposed	3 / 3 (100.00%)	1 / 3 (33.33%)	22 / 57 (38.60%)	1 / 3 (33.33%)	6 / 7 (85.71%)	33 / 82 (40.24%)	51 / 121 (42.15%)	7 / 7 (100.00%)	4 / 6 (66.67%)	3 / 3 (100.00%)
occurrences all number	5	1	25	1	6	36	62	9	7	6
Asthenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	16 / 57 (28.07%)	0 / 3 (0.00%)	0 / 7 (0.00%)	14 / 82 (17.07%)	31 / 121 (25.62%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	19	0	0	19	36	0	0	0
Malaise
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	2 / 7 (28.57%)	2 / 6 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	1	2	2	0
Influenza like illness
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	3 / 82 (3.66%)	2 / 121 (1.65%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	3	2	0	0	0
Mucosal inflammation
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	9 / 57 (15.79%)	0 / 3 (0.00%)	1 / 7 (14.29%)	7 / 82 (8.54%)	7 / 121 (5.79%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	2	0	10	0	1	7	10	1	0	0
Xerosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 57 (7.02%)	0 / 3 (0.00%)	0 / 7 (0.00%)	3 / 82 (3.66%)	9 / 121 (7.44%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	4	0	0	3	9	0	0	0
Thirst
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Pyrexia
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	13 / 57 (22.81%)	1 / 3 (33.33%)	3 / 7 (42.86%)	17 / 82 (20.73%)	28 / 121 (23.14%)	3 / 7 (42.86%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	1	14	4	3	24	37	9	0	0
Pain
subjects affected / exposed	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	3 / 121 (2.48%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	1	0	0	0	3	0	0	0
Oedema peripheral
subjects affected / exposed	2 / 3 (66.67%)	1 / 3 (33.33%)	3 / 57 (5.26%)	1 / 3 (33.33%)	1 / 7 (14.29%)	7 / 82 (8.54%)	31 / 121 (25.62%)	0 / 7 (0.00%)	3 / 6 (50.00%)	1 / 3 (33.33%)
occurrences all number	2	1	4	1	1	8	33	0	3	2
Reproductive system and breast disorders
Pelvic pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	1	0	1	0	1	1
Vaginal haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 57 (3.51%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	2	0	0	0	4	1	0	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	5 / 57 (8.77%)	1 / 3 (33.33%)	1 / 7 (14.29%)	5 / 82 (6.10%)	23 / 121 (19.01%)	0 / 7 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)
occurrences all number	1	0	5	1	1	5	23	0	4	0
Dysphonia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	10 / 57 (17.54%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	10	0	0	0	0	0	0	0
Cough
subjects affected / exposed	1 / 3 (33.33%)	1 / 3 (33.33%)	6 / 57 (10.53%)	0 / 3 (0.00%)	1 / 7 (14.29%)	5 / 82 (6.10%)	14 / 121 (11.57%)	3 / 7 (42.86%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	1	7	0	2	8	14	3	0	0
Dyspnoea exertional
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 82 (2.44%)	0 / 121 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	2	0	2	0	0
Epistaxis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 82 (2.44%)	8 / 121 (6.61%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	2	8	1	0	0
Hiccups
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	1	0
Pleural effusion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 57 (5.26%)	0 / 3 (0.00%)	1 / 7 (14.29%)	2 / 82 (2.44%)	3 / 121 (2.48%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	3	0	1	2	3	0	0	0
Pneumonitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	1 / 82 (1.22%)	0 / 121 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	1	0	2	0	0
Pneumothorax
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Productive cough
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	1	1	0	0
Pulmonary embolism
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 82 (2.44%)	2 / 121 (1.65%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	2	2	0	1	0
Throat irritation
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 57 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	2 / 82 (2.44%)	1 / 121 (0.83%)	0 / 7 (0.00%)	2 / 6 (33.33%)	1 / 3 (33.33%)
occurrences all number	1	0	0	1	0	2	1	0	2	1
Confusional state
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	4 / 121 (3.31%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	4	1	1	0
Insomnia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	5 / 57 (8.77%)	0 / 3 (0.00%)	0 / 7 (0.00%)	3 / 82 (3.66%)	11 / 121 (9.09%)	1 / 7 (14.29%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	1	0	5	0	0	3	12	1	0	1
Investigations
Blood albumin decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	6 / 57 (10.53%)	0 / 3 (0.00%)	0 / 7 (0.00%)	5 / 82 (6.10%)	13 / 121 (10.74%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	8	0	0	6	23	0	0	0
Aspartate aminotransferase increased
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	17 / 57 (29.82%)	0 / 3 (0.00%)	1 / 7 (14.29%)	20 / 82 (24.39%)	37 / 121 (30.58%)	1 / 7 (14.29%)	1 / 6 (16.67%)	1 / 3 (33.33%)
occurrences all number	2	0	25	0	1	25	49	1	1	2
Alanine aminotransferase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	13 / 57 (22.81%)	0 / 3 (0.00%)	0 / 7 (0.00%)	14 / 82 (17.07%)	28 / 121 (23.14%)	0 / 7 (0.00%)	1 / 6 (16.67%)	1 / 3 (33.33%)
occurrences all number	0	0	19	0	0	16	37	0	1	2
Activated partial thromboplastin time prolonged
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	2 / 82 (2.44%)	0 / 121 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	2	0	1	0	0
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	4 / 82 (4.88%)	2 / 121 (1.65%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1	0	0	4	2	0	0	1
Blood creatinine increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	5 / 82 (6.10%)	8 / 121 (6.61%)	2 / 7 (28.57%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	4	0	0	5	15	2	0	3
Blood calcium decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 57 (5.26%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	3	0	0	1	1	0	0	0
Blood bilirubin increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	19 / 57 (33.33%)	1 / 3 (33.33%)	0 / 7 (0.00%)	4 / 82 (4.88%)	16 / 121 (13.22%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	26	1	0	4	20	0	0	0
Blood magnesium decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 57 (5.26%)	0 / 3 (0.00%)	1 / 7 (14.29%)	3 / 82 (3.66%)	6 / 121 (4.96%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	6	0	1	3	11	0	0	0
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	3 / 57 (5.26%)	0 / 3 (0.00%)	0 / 7 (0.00%)	5 / 82 (6.10%)	10 / 121 (8.26%)	1 / 7 (14.29%)	1 / 6 (16.67%)	1 / 3 (33.33%)
occurrences all number	1	0	3	0	0	5	10	2	1	1
Blood phosphorus decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	1	0	0	0	0	0	0	1
Blood potassium decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	6 / 57 (10.53%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 82 (2.44%)	4 / 121 (3.31%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	11	0	0	2	5	0	0	0
Blood sodium decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 57 (7.02%)	0 / 3 (0.00%)	0 / 7 (0.00%)	3 / 82 (3.66%)	10 / 121 (8.26%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	6	0	0	3	17	0	0	0
Blood thyroid stimulating hormone increased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	7 / 57 (12.28%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	8 / 121 (6.61%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	8	0	0	1	13	1	0	0
Ejection fraction decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	8 / 82 (9.76%)	4 / 121 (3.31%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	9	10	0	0	0
Lipase increased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	2 / 121 (1.65%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	2	0	1	0
White blood cell count decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 57 (7.02%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	2 / 121 (1.65%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	6	0	0	1	3	0	0	0
Lymphocyte count decreased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	2	1	0	0
Platelet count decreased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	2 / 121 (1.65%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	1	0	0	1	4	0	0	0
Weight decreased
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	10 / 57 (17.54%)	1 / 3 (33.33%)	1 / 7 (14.29%)	6 / 82 (7.32%)	17 / 121 (14.05%)	2 / 7 (28.57%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	12	2	1	6	20	2	0	0
Injury, poisoning and procedural complications
Burns first degree
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
Infusion related reaction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	1 / 82 (1.22%)	4 / 121 (3.31%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	1	4	1	1	0
Thermal burn
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	2 / 7 (28.57%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	0
Cardiac disorders
Cardiac disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
Tachycardia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	1 / 3 (33.33%)	0 / 7 (0.00%)	2 / 82 (2.44%)	3 / 121 (2.48%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	1	0	2	4	1	0	0
Sinus tachycardia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	1 / 7 (14.29%)	2 / 82 (2.44%)	2 / 121 (1.65%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	1	0	1	0	1	3	2	0	1	0
Sinus bradycardia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	1	0	0
Palpitations
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 82 (2.44%)	0 / 121 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	2	0	1	0	0
Nervous system disorders
Disturbance in attention
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Cerebral ischaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Dizziness
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	2 / 57 (3.51%)	0 / 3 (0.00%)	2 / 7 (28.57%)	8 / 82 (9.76%)	6 / 121 (4.96%)	1 / 7 (14.29%)	2 / 6 (33.33%)	0 / 3 (0.00%)
occurrences all number	2	0	2	0	3	8	7	1	2	0
Hypoaesthesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	0	0
Headache
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	7 / 57 (12.28%)	0 / 3 (0.00%)	1 / 7 (14.29%)	13 / 82 (15.85%)	8 / 121 (6.61%)	0 / 7 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)
occurrences all number	1	0	9	0	1	14	10	0	2	0
Dyskinesia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
Dysgeusia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 82 (0.00%)	10 / 121 (8.26%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	2	0	0	11	0	0	0
Taste disorder
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Presyncope
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	2 / 82 (2.44%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	2	1	0	0	0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	1 / 3 (33.33%)	0 / 7 (0.00%)	2 / 82 (2.44%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	1	0	2	1	0	0	0
Peripheral motor neuropathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
Blood and lymphatic system disorders
Increased tendency to bruise
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Thrombocytopenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	6 / 57 (10.53%)	0 / 3 (0.00%)	0 / 7 (0.00%)	7 / 82 (8.54%)	4 / 121 (3.31%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	12	0	0	7	7	1	0	0
Neutropenia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 57 (5.26%)	0 / 3 (0.00%)	1 / 7 (14.29%)	1 / 82 (1.22%)	2 / 121 (1.65%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	4	0	1	1	2	1	0	0
Anaemia
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	12 / 57 (21.05%)	2 / 3 (66.67%)	4 / 7 (57.14%)	18 / 82 (21.95%)	36 / 121 (29.75%)	4 / 7 (57.14%)	3 / 6 (50.00%)	1 / 3 (33.33%)
occurrences all number	2	0	15	3	4	22	46	4	3	5
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	1 / 82 (1.22%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0	0	0
Eye disorders
Dry eye
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	5 / 82 (6.10%)	2 / 121 (1.65%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	5	2	0	0	0
Diplopia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0
Iridocyclitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
Vision blurred
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 57 (0.00%)	1 / 3 (33.33%)	1 / 7 (14.29%)	1 / 82 (1.22%)	3 / 121 (2.48%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	1	0	0	1	1	1	3	0	0	1
Uveitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
Swelling of eyelid
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	1	0	0
Subretinal fluid
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	1 / 7 (14.29%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	1	0
Retinopathy
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	0 / 121 (0.00%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	1	0
Ocular hyperaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Visual impairment
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	1 / 121 (0.83%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	1	0
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	3 / 3 (100.00%)	2 / 3 (66.67%)	22 / 57 (38.60%)	2 / 3 (66.67%)	4 / 7 (57.14%)	45 / 82 (54.88%)	52 / 121 (42.98%)	6 / 7 (85.71%)	4 / 6 (66.67%)	2 / 3 (66.67%)
occurrences all number	3	4	35	6	5	65	83	8	6	4
Constipation
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	13 / 57 (22.81%)	1 / 3 (33.33%)	2 / 7 (28.57%)	10 / 82 (12.20%)	17 / 121 (14.05%)	0 / 7 (0.00%)	3 / 6 (50.00%)	1 / 3 (33.33%)
occurrences all number	1	0	15	1	2	10	19	0	5	2
Ascites
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 57 (3.51%)	0 / 3 (0.00%)	1 / 7 (14.29%)	4 / 82 (4.88%)	7 / 121 (5.79%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	2	0	1	4	7	0	0	1
Abdominal pain upper
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 57 (7.02%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	5 / 121 (4.13%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	5	0	0	2	5	1	0	0
Abdominal pain
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	9 / 57 (15.79%)	1 / 3 (33.33%)	1 / 7 (14.29%)	18 / 82 (21.95%)	17 / 121 (14.05%)	1 / 7 (14.29%)	1 / 6 (16.67%)	2 / 3 (66.67%)
occurrences all number	1	0	10	2	1	19	19	1	1	3
Abdominal distension
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 57 (0.00%)	1 / 3 (33.33%)	1 / 7 (14.29%)	2 / 82 (2.44%)	4 / 121 (3.31%)	0 / 7 (0.00%)	1 / 6 (16.67%)	2 / 3 (66.67%)
occurrences all number	1	0	0	2	1	2	4	0	1	2
Diarrhoea haemorrhagic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Dry mouth
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	5 / 57 (8.77%)	2 / 3 (66.67%)	0 / 7 (0.00%)	6 / 82 (7.32%)	7 / 121 (5.79%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	5	2	0	6	7	1	0	0
Dyspepsia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	3 / 57 (5.26%)	1 / 3 (33.33%)	0 / 7 (0.00%)	2 / 82 (2.44%)	7 / 121 (5.79%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	1	0	3	1	0	2	8	0	1	0
Proctalgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 57 (5.26%)	1 / 3 (33.33%)	0 / 7 (0.00%)	2 / 82 (2.44%)	2 / 121 (1.65%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	3	1	0	2	2	0	0	0
Nausea
subjects affected / exposed	3 / 3 (100.00%)	0 / 3 (0.00%)	9 / 57 (15.79%)	2 / 3 (66.67%)	5 / 7 (71.43%)	26 / 82 (31.71%)	55 / 121 (45.45%)	5 / 7 (71.43%)	2 / 6 (33.33%)	1 / 3 (33.33%)
occurrences all number	3	0	10	6	6	34	71	8	3	1
Large intestinal obstruction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	1 / 82 (1.22%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	1	0	0	0	0
Haematochezia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	4 / 121 (3.31%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	5	1	0	0
Gingival bleeding
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	1 / 121 (0.83%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	1	0
Flatulence
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	3 / 121 (2.48%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	1	4	0	1	0
Small intestinal obstruction
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
Rectal haemorrhage
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	2 / 121 (1.65%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	2	1	0	0
Stomatitis
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	8 / 57 (14.04%)	0 / 3 (0.00%)	0 / 7 (0.00%)	7 / 82 (8.54%)	10 / 121 (8.26%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	10	0	0	7	12	2	0	0
Vomiting
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	5 / 57 (8.77%)	2 / 3 (66.67%)	2 / 7 (28.57%)	17 / 82 (20.73%)	36 / 121 (29.75%)	2 / 7 (28.57%)	2 / 6 (33.33%)	2 / 3 (66.67%)
occurrences all number	2	0	8	8	6	23	55	3	3	2
Hepatobiliary disorders
Hyperbilirubinaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	1	0	1	0	0	0
Hypertransaminasaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 57 (5.26%)	0 / 3 (0.00%)	3 / 7 (42.86%)	5 / 82 (6.10%)	5 / 121 (4.13%)	2 / 7 (28.57%)	1 / 6 (16.67%)	1 / 3 (33.33%)
occurrences all number	0	0	3	0	3	5	6	2	1	1
Skin and subcutaneous tissue disorders
Blister
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Dermatitis acneiform
subjects affected / exposed	2 / 3 (66.67%)	3 / 3 (100.00%)	2 / 57 (3.51%)	3 / 3 (100.00%)	6 / 7 (85.71%)	20 / 82 (24.39%)	39 / 121 (32.23%)	4 / 7 (57.14%)	5 / 6 (83.33%)	3 / 3 (100.00%)
occurrences all number	2	4	2	3	8	24	44	5	5	3
Drug eruption
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 82 (2.44%)	0 / 121 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	2	0	1	0	0
Dry skin
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 57 (3.51%)	1 / 3 (33.33%)	1 / 7 (14.29%)	1 / 82 (1.22%)	9 / 121 (7.44%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	1	0	2	1	1	1	9	0	2	0
Erythema
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	2 / 82 (2.44%)	3 / 121 (2.48%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	2	3	1	0	0
Hyperhidrosis
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	3 / 82 (3.66%)	2 / 121 (1.65%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	3	2	0	0	0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	25 / 57 (43.86%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	29	0	0	1	1	0	0	0
Photosensitivity reaction
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0
Pruritus
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 57 (8.77%)	1 / 3 (33.33%)	3 / 7 (42.86%)	27 / 82 (32.93%)	31 / 121 (25.62%)	2 / 7 (28.57%)	1 / 6 (16.67%)	2 / 3 (66.67%)
occurrences all number	0	0	5	1	3	31	38	3	1	3
Pruritus allergic
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Rash pruritic
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	2 / 121 (1.65%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	1	2	1	0	0
Rash erythematous
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	5 / 82 (6.10%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	6	1	0	0	0
Rash maculo-papular
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	6 / 57 (10.53%)	1 / 3 (33.33%)	2 / 7 (28.57%)	16 / 82 (19.51%)	13 / 121 (10.74%)	1 / 7 (14.29%)	0 / 6 (0.00%)	2 / 3 (66.67%)
occurrences all number	0	0	6	1	2	17	18	1	0	3
Rash papular
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	4 / 82 (4.88%)	2 / 121 (1.65%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	5	3	1	0	0
Rash
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	6 / 57 (10.53%)	0 / 3 (0.00%)	3 / 7 (42.86%)	39 / 82 (47.56%)	51 / 121 (42.15%)	4 / 7 (57.14%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	6	0	4	43	58	6	2	0
Skin fissures
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	1	0	0
Skin lesion
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	1 / 7 (14.29%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	1	1	0	1
Renal and urinary disorders
Proteinuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 57 (8.77%)	0 / 3 (0.00%)	0 / 7 (0.00%)	4 / 82 (4.88%)	4 / 121 (3.31%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	7	0	0	4	5	1	0	0
Hydronephrosis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	2 / 82 (2.44%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	2	1	0	0	0
Haematuria
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	6 / 121 (4.96%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	2	0	1	0	0	0	7	0	0	0
Dysuria
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 57 (5.26%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	2 / 121 (1.65%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	4	0	0	0	2	0	0	0
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 57 (1.75%)	1 / 3 (33.33%)	1 / 7 (14.29%)	4 / 82 (4.88%)	2 / 121 (1.65%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	1	0	1	1	1	4	2	0	2	0
Hypothyroidism
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 57 (3.51%)	1 / 3 (33.33%)	1 / 7 (14.29%)	7 / 82 (8.54%)	4 / 121 (3.31%)	2 / 7 (28.57%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	1	0	2	1	1	7	4	2	1	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	8 / 57 (14.04%)	0 / 3 (0.00%)	0 / 7 (0.00%)	6 / 82 (7.32%)	9 / 121 (7.44%)	1 / 7 (14.29%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	9	0	0	7	9	1	0	1
Arthritis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0
Back pain
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	4 / 57 (7.02%)	0 / 3 (0.00%)	1 / 7 (14.29%)	9 / 82 (10.98%)	11 / 121 (9.09%)	1 / 7 (14.29%)	2 / 6 (33.33%)	0 / 3 (0.00%)
occurrences all number	1	0	4	0	2	9	12	1	2	0
Coccydynia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
Pain in extremity
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	5 / 57 (8.77%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 82 (0.00%)	6 / 121 (4.96%)	0 / 7 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	0	7	0	1	0	6	0	2	0
Myalgia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	6 / 121 (4.96%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	1	6	1	0	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	1	1	0	0
Muscle spasms
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	3 / 82 (3.66%)	5 / 121 (4.13%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	1	0	0	3	7	0	0	0
Joint range of motion decreased
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Infections and infestations
Gingivitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
COVID-19
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	6 / 57 (10.53%)	0 / 3 (0.00%)	0 / 7 (0.00%)	8 / 82 (9.76%)	6 / 121 (4.96%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	6	0	0	8	6	0	0	0
Candida infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	2 / 7 (28.57%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	2	0	0
Cellulitis
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	0 / 82 (0.00%)	2 / 121 (1.65%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	2	0	0	0
Mucosal infection
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0
Urinary tract infection
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 57 (3.51%)	1 / 3 (33.33%)	0 / 7 (0.00%)	4 / 82 (4.88%)	7 / 121 (5.79%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	3	0	2	1	0	6	12	3	0	0
Paronychia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	3 / 82 (3.66%)	3 / 121 (2.48%)	0 / 7 (0.00%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	3	4	0	1	0
Pneumonia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	3 / 82 (3.66%)	1 / 121 (0.83%)	0 / 7 (0.00%)	2 / 6 (33.33%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	3	1	0	2	0
Rash pustular
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	0 / 82 (0.00%)	1 / 121 (0.83%)	0 / 7 (0.00%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	1	0	0	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	15 / 57 (26.32%)	1 / 3 (33.33%)	1 / 7 (14.29%)	13 / 82 (15.85%)	32 / 121 (26.45%)	2 / 7 (28.57%)	4 / 6 (66.67%)	2 / 3 (66.67%)
occurrences all number	1	0	17	1	1	13	37	2	4	2
Dehydration
subjects affected / exposed	2 / 3 (66.67%)	0 / 3 (0.00%)	0 / 57 (0.00%)	1 / 3 (33.33%)	0 / 7 (0.00%)	2 / 82 (2.44%)	4 / 121 (3.31%)	2 / 7 (28.57%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	2	0	0	2	0	2	5	3	0	0
Hyperglycaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	10 / 57 (17.54%)	0 / 3 (0.00%)	1 / 7 (14.29%)	5 / 82 (6.10%)	11 / 121 (9.09%)	1 / 7 (14.29%)	1 / 6 (16.67%)	1 / 3 (33.33%)
occurrences all number	0	0	13	0	1	6	13	1	1	5
Hypokalaemia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	3 / 57 (5.26%)	0 / 3 (0.00%)	0 / 7 (0.00%)	2 / 82 (2.44%)	6 / 121 (4.96%)	3 / 7 (42.86%)	1 / 6 (16.67%)	0 / 3 (0.00%)
occurrences all number	1	0	4	0	0	3	6	9	1	0
Hypocalcaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 57 (1.75%)	0 / 3 (0.00%)	0 / 7 (0.00%)	1 / 82 (1.22%)	1 / 121 (0.83%)	2 / 7 (28.57%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	2	0	0	1	2	2	0	0
Hypoalbuminaemia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 57 (3.51%)	1 / 3 (33.33%)	1 / 7 (14.29%)	5 / 82 (6.10%)	9 / 121 (7.44%)	2 / 7 (28.57%)	3 / 6 (50.00%)	0 / 3 (0.00%)
occurrences all number	2	0	3	1	1	6	10	2	4	0
Hyperphosphataemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	1
Hypomagnesaemia
subjects affected / exposed	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	1 / 7 (14.29%)	3 / 82 (3.66%)	3 / 121 (2.48%)	1 / 7 (14.29%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	1	0	0	0	1	3	4	4	0	1
Hypovolaemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 57 (0.00%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	1 / 7 (14.29%)	0 / 6 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0
Hypophosphataemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 57 (5.26%)	0 / 3 (0.00%)	0 / 7 (0.00%)	0 / 82 (0.00%)	0 / 121 (0.00%)	2 / 7 (28.57%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	4	0	0	0	0	2	0	1
Hyponatraemia
subjects affected / exposed	0 / 3 (0.00%)	0 / 3 (0.00%)	4 / 57 (7.02%)	1 / 3 (33.33%)	0 / 7 (0.00%)	5 / 82 (6.10%)	12 / 121 (9.92%)	0 / 7 (0.00%)	0 / 6 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	4	1	0	5	12	0	0	1

More information

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Were there any global substantial amendments to the protocol? Yes

06 Oct 2020

CA2099N9 has been revised to enroll participants to the selected triplet regimen in the second line (2L) and third line (3L) setting. The sample size of the study expansion has been increased to a total of 200 patients to allow for further assessment of clinical safety, efficacy, and biomarker development in microsatellite stable metastatic colorectal cancer (MSS mCRC).

17 Dec 2021

The main reasons for Protocol Amendment 03 are to expand the eligibility criteria of Part 2 to include participants who have received at least 2 (no more than 4) prior lines of therapy, and to move the secondary objective of efficacy assessments in the consensus molecular subtype (CMS) to the exploratory objectives; therefore, overall response rate in CMS was removed from the sample size calculations. Additional updates include removal of the 40 mg (10 mg/mL) potency of nivolumab solution for use moving forward, clarification of tissue collection requirements, clarification of nivolumab intravenous administration procedure, and clarification of treatment discontinuation requirements. Administrative Letters 04 and 05 are also incorporated.

03 May 2023

Based on the emerging data, Bristol-Myers Squibb Company (BMS) has made a strategic decision to expedite the CA2099N9 study closure. This decision is not related to any safety concerns. The protocol has been revised to reduce the assessments and data collection to minimize the burden on study participants and site staff. In addition, some of the exploratory objectives are removed, the key objectives are achievable with reduced data collection and shorter follow-up.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results: A Study Of Nivolumab In Combination With Trametinib With Or Without Ipilimumab In Participants With Previously Treated Metastatic Colorectal Cancers

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Dose Limiting Toxicities in Part 1 and Part 1A

Primary: Dose Limiting Toxicities in Part 1 and Part 1A

Primary: Safety Related Events in Part 1 and Part 1 A

Primary: Safety Related Events in Part 1 and Part 1 A

Primary: Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests

Primary: Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Thyroid Tests

Primary: Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests

Primary: Clinical Laboratory Abnormalities in Part 1 and Part 1A: Specific Liver Tests

Primary: Objective Response Rate in Part 1B and Part 2

Primary: Objective Response Rate in Part 1B and Part 2

Secondary: Objective Response Rate in Part 1 and Part 1A

Secondary: Objective Response Rate in Part 1 and Part 1A

Secondary: Disease Control Rate in Part 1 and Part 1A

Secondary: Disease Control Rate in Part 1 and Part 1A

Secondary: Duration of Response in Part 1 and Part 1A

Secondary: Duration of Response in Part 1 and Part 1A

Secondary: Time to Response in Part 1 and Part 1A

Secondary: Time to Response in Part 1 and Part 1A

Secondary: Progression Free Survival in Part 1 and Part 1A

Secondary: Progression Free Survival in Part 1 and Part 1A

Secondary: Overall Survival in Part 1 and Part 1A

Secondary: Overall Survival in Part 1 and Part 1A

Secondary: Safety Related Events in Part 1B and Part 2

Secondary: Safety Related Events in Part 1B and Part 2

Secondary: Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests

Secondary: Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Thyroid Tests

Secondary: Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Liver Tests

Secondary: Clinical Laboratory Abnormalities in Part 1B and Part 2: Specific Liver Tests

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Study Of Nivolumab In Combination With Trametinib With Or Without Ipilimumab In Participants With Previously Treated Metastatic Colorectal Cancers