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Clinical Trial Results:
A Phase II, multi-center, open label study of NIR178 in combination with PDR001 in patients with selected advanced solid tumors and non-Hodgkin lymphoma

Summary
EudraCT number	2017-000241-49
Trial protocol	DE BE CZ AT ES NL FR IT
Global end of trial date	14 Feb 2023

Results information
Results version number	v1(current)
This version publication date	21 Feb 2024
First version publication date	21 Feb 2024
Other versions

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

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Trial information

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Sponsor protocol code

CNIR178X2201

ISRCTN number

US NCT number

NCT03207867

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

Novartis campus, Basel, Switzerland, CH-4056

Public contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com

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

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

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

Analysis stage

Final

Date of interim/final analysis

14 Feb 2023

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

14 Feb 2023

Was the trial ended prematurely?

Yes

Main objective of the trial

The primary objectives of the trial were: Part 1: To evaluate the efficacy of NIR178 and PDR001 combination in patients with selected advanced solid tumors and diffuse large B cell lymphoma (DLBCL). Part 2: To assess the efficacy of continuous and several intermittent dosing schedules of NIR178 in combination with PDR001 in non-small cell lung cancer (NSCLC). Part 3: To evaluate efficacy of intermittent or continuous dosing schedule of NIR178 in one or two selected tumor types.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

28 Aug 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Argentina: 1

Country: Number of subjects enrolled

Australia: 8

Country: Number of subjects enrolled

Austria: 17

Country: Number of subjects enrolled

Belgium: 19

Country: Number of subjects enrolled

Czechia: 26

Country: Number of subjects enrolled

France: 9

Country: Number of subjects enrolled

Germany: 24

Country: Number of subjects enrolled

Italy: 26

Country: Number of subjects enrolled

Japan: 9

Country: Number of subjects enrolled

Netherlands: 14

Country: Number of subjects enrolled

Singapore: 23

Country: Number of subjects enrolled

Spain: 21

Country: Number of subjects enrolled

Switzerland: 29

Country: Number of subjects enrolled

Taiwan: 53

Country: Number of subjects enrolled

United States: 36

Worldwide total number of subjects

315

EEA total number of subjects

156

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)

199

From 65 to 84 years

115

85 years and over

Subject disposition

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Recruitment details

Participants took part in 21 investigative sites in 15 countries.

Screening details

The screening period began once patients had signed the study informed consent. Screening evaluations had to be completed within 21 days prior to the first dose of treatment except for the radiological tumor assessment which had to be performed within 28 days prior to the first dose. After screening, the treatment period started on Cycle 1 Day 1.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Part 1: RCC naïve 160 mg

Arm description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with renal cell carcinoma (RCC) who had not been previously treated with immuno-oncology therapy

Arm type

Experimental

Investigational medicinal product name

NIR178

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

NIR178 160 mg was administered twice daily (BID) continuously. NIR178 was administered orally as a capsule within 60 minutes prior to PDR001 infusion.

Investigational medicinal product name

PDR001

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

PDR001 400 mg was administered via intravenous (i.v.) infusion over 30 minutes once every 4 weeks (Q4W).

Part 1: RCC naïve 240 mg

Arm description

NIR178 240 mg twice daily continuous in combination with PDR001 in patients with renal cell carcinoma (RCC) who had not been previously treated with immuno-oncology therapy

Arm type

Experimental

Investigational medicinal product name

PDR001

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

PDR001 400 mg was administered via i.v. infusion over 30 minutes once every 4 weeks (Q4W).

Investigational medicinal product name

NIR178

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

NIR178 240 mg was administered BID continuously. NIR178 was administered orally as a capsule within 60 minutes prior to PDR001 infusion.

Part 1: RCC pre 240 mg

Arm description

NIR178 240 mg twice daily continuous in combination with PDR001 in patients with renal cell carcinoma (RCC) who had been pretreated with immuno-oncology therapy

Arm type

Experimental

Investigational medicinal product name

PDR001

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

PDR001 400 mg was administered via i.v. infusion over 30 minutes once every 4 weeks (Q4W).

Investigational medicinal product name

NIR178

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

NIR178 240 mg was administered BID continuously. NIR178 was administered orally as a capsule within 60 minutes prior to PDR001 infusion.

Part 1: Pancreatic 160 mg

Arm description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with pancreatic cancer

Arm type

Experimental

Investigational medicinal product name

NIR178

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

NIR178 160 mg was administered BID continuously. NIR178 was administered orally as a capsule within 60 minutes prior to PDR001 infusion.

Investigational medicinal product name

PDR001

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

PDR001 400 mg was administered via i.v. infusion over 30 minutes once every 4 weeks (Q4W).

Part 1: Urothelial 160 mg

Arm description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with urothelial cancer

Arm type

Experimental

Investigational medicinal product name

PDR001

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

PDR001 400 mg was administered via i.v. infusion over 30 minutes once every 4 weeks (Q4W).

Investigational medicinal product name

NIR178

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

NIR178 160 mg was administered BID continuously. NIR178 was administered orally as a capsule within 60 minutes prior to PDR001 infusion.

Part 1: H-N naïve 160 mg

Arm description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with squamous cell carcinoma of head and neck (HNSCC) who had not been previously treated with immuno-oncology therapy

Arm type

Experimental

Investigational medicinal product name

PDR001

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

PDR001 400 mg was administered via i.v. infusion over 30 minutes once every 4 weeks (Q4W).

Investigational medicinal product name

NIR178

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

NIR178 160 mg was administered BID continuously. NIR178 was administered orally as a capsule within 60 minutes prior to PDR001 infusion.

Part 1: H-N pre 160 mg

Arm description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with squamous cell carcinoma of head and neck (HNSCC) who had been pretreated with immuno-oncology therapy

Arm type

Experimental

Investigational medicinal product name

PDR001

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

PDR001 400 mg was administered via i.v. infusion over 30 minutes once every 4 weeks (Q4W).

Investigational medicinal product name

NIR178

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

NIR178 160 mg was administered BID continuously. NIR178 was administered orally as a capsule within 60 minutes prior to PDR001 infusion.

Part 1: H-N pre 240 mg

Arm description

NIR178 240 mg twice daily continuous in combination with PDR001 in patients with squamous cell carcinoma of head and neck (HNSCC) who had been pretreated with immuno-oncology therapy

Arm type

Experimental

Investigational medicinal product name

PDR001

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

PDR001 400 mg was administered via i.v. infusion over 30 minutes once every 4 weeks (Q4W).

Investigational medicinal product name

NIR178

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

NIR178 240 mg was administered BID continuously. NIR178 was administered orally as a capsule within 60 minutes prior to PDR001 infusion.

Part 1: MSS CRC wt 160 mg

Arm description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with microsatellite stable colorectal cancer (MSS CRC) with RAS wildtype

Arm type

Experimental

Investigational medicinal product name

PDR001

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

PDR001 400 mg was administered via i.v. infusion over 30 minutes once every 4 weeks (Q4W).

Investigational medicinal product name

NIR178

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

NIR178 160 mg was administered BID continuously. NIR178 was administered orally as a capsule within 60 minutes prior to PDR001 infusion.

Part 1: MSS CRC mu 160 mg

Arm description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with microsatellite stable colorectal cancer (MSS CRC) with RAS mutant

Arm type

Experimental

Investigational medicinal product name

PDR001

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

PDR001 400 mg was administered via i.v. infusion over 30 minutes once every 4 weeks (Q4W).

Investigational medicinal product name

NIR178

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

NIR178 160 mg was administered BID continuously. NIR178 was administered orally as a capsule within 60 minutes prior to PDR001 infusion.

Part 1: MSS CRC unk 160 mg

Arm description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with microsatellite stable colorectal cancer (MSS CRC) with unknown RAS status

Arm type

Experimental

Investigational medicinal product name

PDR001

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

PDR001 400 mg was administered via i.v. infusion over 30 minutes once every 4 weeks (Q4W).

Investigational medicinal product name

NIR178

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

NIR178 160 mg was administered BID continuously. NIR178 was administered orally as a capsule within 60 minutes prior to PDR001 infusion.

Part 1: TNBC 160 mg

Arm description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with triple negative breast cancer (TNBC)

Arm type

Experimental

Investigational medicinal product name

PDR001

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

PDR001 400 mg was administered via i.v. infusion over 30 minutes once every 4 weeks (Q4W).

Investigational medicinal product name

NIR178

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

NIR178 160 mg was administered BID continuously. NIR178 was administered orally as a capsule within 60 minutes prior to PDR001 infusion.

Part 1: Melanoma naïve 160 mg

Arm description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with cutaneous melanoma who had not been previously treated with immuno-oncology therapy

Arm type

Experimental

Investigational medicinal product name

PDR001

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

PDR001 400 mg was administered via i.v. infusion over 30 minutes once every 4 weeks (Q4W).

Investigational medicinal product name

NIR178

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

NIR178 160 mg was administered BID continuously. NIR178 was administered orally as a capsule within 60 minutes prior to PDR001 infusion.

Part 1: Melanoma pre 160 mg

Arm description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with cutaneous melanoma who had been pretreated with immuno-oncology therapy

Arm type

Experimental

Investigational medicinal product name

PDR001

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

PDR001 400 mg was administered via i.v. infusion over 30 minutes once every 4 weeks (Q4W).

Investigational medicinal product name

NIR178

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

NIR178 160 mg was administered BID continuously. NIR178 was administered orally as a capsule within 60 minutes prior to PDR001 infusion.

Part 1: DLBCL 160 mg

Arm description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with diffuse large B-cell lymphoma (DLBCL)

Arm type

Experimental

Investigational medicinal product name

PDR001

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

PDR001 400 mg was administered via i.v. infusion over 30 minutes once every 4 weeks (Q4W).

Investigational medicinal product name

NIR178

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

NIR178 160 mg was administered BID continuously. NIR178 was administered orally as a capsule within 60 minutes prior to PDR001 infusion.

Part 1: DLBCL 240 mg

Arm description

NIR178 240 mg twice daily continuous in combination with PDR001 in patients with diffuse large B-cell lymphoma (DLBCL)

Arm type

Experimental

Investigational medicinal product name

PDR001

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

PDR001 400 mg was administered via i.v. infusion over 30 minutes once every 4 weeks (Q4W).

Investigational medicinal product name

NIR178

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

NIR178 240 mg was administered BID continuously. NIR178 was administered orally as a capsule within 60 minutes prior to PDR001 infusion.

Part 1: mCRPC 240 mg

Arm description

NIR178 240 mg twice daily continuous in combination with PDR001 in patients with metastatic castration resistant prostate cancer (mCRPC)

Arm type

Experimental

Investigational medicinal product name

PDR001

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

PDR001 400 mg was administered via i.v. infusion over 30 minutes once every 4 weeks (Q4W).

Investigational medicinal product name

NIR178

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

NIR178 240 mg was administered BID continuously. NIR178 was administered orally as a capsule within 60 minutes prior to PDR001 infusion.

Part 2: NSCLC 160 mg cont

Arm description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with non-small cell lung cancer (NSCLC)

Arm type

Experimental

Investigational medicinal product name

PDR001

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

PDR001 400 mg was administered via i.v. infusion over 30 minutes once every 4 weeks (Q4W).

Investigational medicinal product name

NIR178

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

NIR178 160 mg was administered BID continuously. NIR178 was administered orally as a capsule within 60 minutes prior to PDR001 infusion.

Part 2: NSCLC 160 mg 2wk-on/2wk-off

Arm description

NIR178 160 mg twice daily 2 weeks on/2 weeks off in combination with PDR001 in patients with non-small cell lung cancer (NSCLC)

Arm type

Experimental

Investigational medicinal product name

PDR001

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

PDR001 400 mg was administered via i.v. infusion over 30 minutes once every 4 weeks (Q4W).

Investigational medicinal product name

NIR178

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

NIR178 160 mg was administered BID 2 weeks on/2 weeks off. NIR178 was administered orally as a capsule within 60 minutes prior to PDR001 infusion.

Part 2: NSCLC 160 mg 1wk-on/1wk-off

Arm description

NIR178 160 mg twice daily 1 week on/1 week off in combination with PDR001 in patients with non-small cell lung cancer (NSCLC)

Arm type

Experimental

Investigational medicinal product name

PDR001

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

PDR001 400 mg was administered via i.v. infusion over 30 minutes once every 4 weeks (Q4W).

Investigational medicinal product name

NIR178

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

NIR178 160 mg was administered BID 1 week on/1 week off. NIR178 was administered orally as a capsule within 60 minutes prior to PDR001 infusion.

Part 3: TNBC 160 mg cont

Arm description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with triple negative breast cancer (TNBC)

Arm type

Experimental

Investigational medicinal product name

PDR001

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

PDR001 400 mg was administered via i.v. infusion over 30 minutes once every 4 weeks (Q4W).

Investigational medicinal product name

NIR178

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

NIR178 160 mg was administered BID continuously. NIR178 was administered orally as a film-coated tablet (FCT) within 60 minutes prior to PDR001 infusion.

JSR: 80 mg cont

Arm description

NIR178 80 mg twice daily continuous in combination with PDR001 (starting Cycle 2 Day 1) in the Japan safety run-in

Arm type

Experimental

Investigational medicinal product name

NIR178

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

NIR178 80 mg was administered BID continuously. NIR178 was administered orally as a capsule within 60 minutes prior to PDR001 infusion.

Investigational medicinal product name

PDR001

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

PDR001 400 mg was administered via i.v. infusion over 30 minutes once every 4 weeks (Q4W). Treatment with PDR001 was started on Cycle 2 Day 1.

JSR: 160 mg cont

Arm description

NIR178 160 mg twice daily continuous in combination with PDR001 (starting Cycle 2 Day 1) in the Japan safety run-in

Arm type

Experimental

Investigational medicinal product name

PDR001

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

PDR001 400 mg was administered via i.v. infusion over 30 minutes once every 4 weeks (Q4W). Treatment with PDR001 was started on Cycle 2 Day 1.

Investigational medicinal product name

NIR178

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

NIR178 160 mg was administered BID continuously. NIR178 was administered orally as a capsule within 60 minutes prior to PDR001 infusion.

JSR: 240 mg cont

Arm description

NIR178 140 mg twice daily continuous in combination with PDR001 (starting Cycle 1 Day 1) in the Japan safety run-in

Arm type

Experimental

Investigational medicinal product name

PDR001

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

PDR001 400 mg was administered via i.v. infusion over 30 minutes once every 4 weeks (Q4W). Treatment with PDR001 was started on Cycle 1 Day 1.

Investigational medicinal product name

NIR178

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

NIR178 240 mg was administered BID continuously. NIR178 was administered orally as a capsule within 60 minutes prior to PDR001 infusion.

Number of subjects in period 1	Part 1: RCC naïve 160 mg	Part 1: RCC naïve 240 mg	Part 1: RCC pre 240 mg	Part 1: Pancreatic 160 mg	Part 1: Urothelial 160 mg	Part 1: H-N naïve 160 mg	Part 1: H-N pre 160 mg	Part 1: H-N pre 240 mg	Part 1: MSS CRC wt 160 mg	Part 1: MSS CRC mu 160 mg	Part 1: MSS CRC unk 160 mg	Part 1: TNBC 160 mg	Part 1: Melanoma naïve 160 mg	Part 1: Melanoma pre 160 mg	Part 1: DLBCL 160 mg	Part 1: DLBCL 240 mg	Part 1: mCRPC 240 mg	Part 2: NSCLC 160 mg cont	Part 2: NSCLC 160 mg 2wk-on/2wk-off	Part 2: NSCLC 160 mg 1wk-on/1wk-off	Part 3: TNBC 160 mg cont	JSR: 80 mg cont	JSR: 160 mg cont	JSR: 240 mg cont
Started	11	12	11	14	14	15	11	12	27	29	2	30	3	13	13	6	15	22	20	20	6	3	3	3
Completed	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Not completed	11	12	11	14	14	15	11	12	27	29	2	30	3	13	13	6	15	22	20	20	6	3	3	3
Physician decision	3	5	-	3	2	-	-	-	4	2	-	4	-	-	2	1	1	2	1	3	-	-	-	-
Adverse Event	1	-	1	-	-	2	1	1	2	2	-	-	-	-	-	-	3	1	2	1	-	-	-	-
Death	-	-	-	-	-	1	-	3	1	2	-	1	-	1	-	-	-	2	-	1	-	-	-	-
Progressive Disease	7	7	9	10	11	10	9	8	19	23	2	24	3	11	9	5	10	14	13	14	6	3	3	3
Patient/guardian Decision	-	-	1	1	1	2	1	-	1	-	-	1	-	1	2	-	1	3	4	1	-	-	-	-

Baseline characteristics

Top of page

Reporting group title

Part 1: RCC naïve 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with renal cell carcinoma (RCC) who had not been previously treated with immuno-oncology therapy

Reporting group title

Part 1: RCC naïve 240 mg

Reporting group description

NIR178 240 mg twice daily continuous in combination with PDR001 in patients with renal cell carcinoma (RCC) who had not been previously treated with immuno-oncology therapy

Reporting group title

Part 1: RCC pre 240 mg

Reporting group description

NIR178 240 mg twice daily continuous in combination with PDR001 in patients with renal cell carcinoma (RCC) who had been pretreated with immuno-oncology therapy

Reporting group title

Part 1: Pancreatic 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with pancreatic cancer

Reporting group title

Part 1: Urothelial 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with urothelial cancer

Reporting group title

Part 1: H-N naïve 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with squamous cell carcinoma of head and neck (HNSCC) who had not been previously treated with immuno-oncology therapy

Reporting group title

Part 1: H-N pre 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with squamous cell carcinoma of head and neck (HNSCC) who had been pretreated with immuno-oncology therapy

Reporting group title

Part 1: H-N pre 240 mg

Reporting group description

NIR178 240 mg twice daily continuous in combination with PDR001 in patients with squamous cell carcinoma of head and neck (HNSCC) who had been pretreated with immuno-oncology therapy

Reporting group title

Part 1: MSS CRC wt 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with microsatellite stable colorectal cancer (MSS CRC) with RAS wildtype

Reporting group title

Part 1: MSS CRC mu 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with microsatellite stable colorectal cancer (MSS CRC) with RAS mutant

Reporting group title

Part 1: MSS CRC unk 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with microsatellite stable colorectal cancer (MSS CRC) with unknown RAS status

Reporting group title

Part 1: TNBC 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with triple negative breast cancer (TNBC)

Reporting group title

Part 1: Melanoma naïve 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with cutaneous melanoma who had not been previously treated with immuno-oncology therapy

Reporting group title

Part 1: Melanoma pre 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with cutaneous melanoma who had been pretreated with immuno-oncology therapy

Reporting group title

Part 1: DLBCL 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with diffuse large B-cell lymphoma (DLBCL)

Reporting group title

Part 1: DLBCL 240 mg

Reporting group description

NIR178 240 mg twice daily continuous in combination with PDR001 in patients with diffuse large B-cell lymphoma (DLBCL)

Reporting group title

Part 1: mCRPC 240 mg

Reporting group description

NIR178 240 mg twice daily continuous in combination with PDR001 in patients with metastatic castration resistant prostate cancer (mCRPC)

Reporting group title

Part 2: NSCLC 160 mg cont

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with non-small cell lung cancer (NSCLC)

Reporting group title

Part 2: NSCLC 160 mg 2wk-on/2wk-off

Reporting group description

NIR178 160 mg twice daily 2 weeks on/2 weeks off in combination with PDR001 in patients with non-small cell lung cancer (NSCLC)

Reporting group title

Part 2: NSCLC 160 mg 1wk-on/1wk-off

Reporting group description

NIR178 160 mg twice daily 1 week on/1 week off in combination with PDR001 in patients with non-small cell lung cancer (NSCLC)

Reporting group title

Part 3: TNBC 160 mg cont

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with triple negative breast cancer (TNBC)

Reporting group title

JSR: 80 mg cont

Reporting group description

NIR178 80 mg twice daily continuous in combination with PDR001 (starting Cycle 2 Day 1) in the Japan safety run-in

Reporting group title

JSR: 160 mg cont

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 (starting Cycle 2 Day 1) in the Japan safety run-in

Reporting group title

JSR: 240 mg cont

Reporting group description

NIR178 140 mg twice daily continuous in combination with PDR001 (starting Cycle 1 Day 1) in the Japan safety run-in

Reporting group values	Part 1: RCC naïve 160 mg	Part 1: RCC naïve 240 mg	Part 1: RCC pre 240 mg	Part 1: Pancreatic 160 mg	Part 1: Urothelial 160 mg	Part 1: H-N naïve 160 mg	Part 1: H-N pre 160 mg	Part 1: H-N pre 240 mg	Part 1: MSS CRC wt 160 mg	Part 1: MSS CRC mu 160 mg	Part 1: MSS CRC unk 160 mg	Part 1: TNBC 160 mg	Part 1: Melanoma naïve 160 mg	Part 1: Melanoma pre 160 mg	Part 1: DLBCL 160 mg	Part 1: DLBCL 240 mg	Part 1: mCRPC 240 mg	Part 2: NSCLC 160 mg cont	Part 2: NSCLC 160 mg 2wk-on/2wk-off	Part 2: NSCLC 160 mg 1wk-on/1wk-off	Part 3: TNBC 160 mg cont	JSR: 80 mg cont	JSR: 160 mg cont	JSR: 240 mg cont	Total
Number of subjects	11	12	11	14	14	15	11	12	27	29	2	30	3	13	13	6	15	22	20	20	6	3	3	3	315
Age categorical
Units: Subjects
In utero	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Adults (18-64 years)	5	6	9	9	6	10	7	8	21	21	2	26	2	10	8	3	4	11	12	8	4	2	2	3	199
From 65-84 years	6	6	2	5	8	5	4	4	6	8	0	4	1	3	5	3	10	11	8	12	2	1	1	0	115
85 years and over	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	1
Age Continuous
Units: years
arithmetic mean (standard deviation)	65.5 ± 10.86	60.0 ± 11.96	60.6 ± 8.54	60.4 ± 8.98	66.9 ± 9.63	61.6 ± 7.13	59.4 ± 9.05	60.2 ± 7.07	56.5 ± 9.04	58.1 ± 11.21	46.0 ± 15.56	49.8 ± 10.81	50.3 ± 20.65	54.2 ± 14.87	55.0 ± 18.65	61.5 ± 13.10	68.3 ± 8.14	65.0 ± 9.02	61.8 ± 9.51	64.2 ± 8.94	58.5 ± 16.16	61.3 ± 10.69	57.0 ± 9.54	44.3 ± 8.33	-
Sex: Female, Male
Units: participants
Female	3	0	2	6	5	2	3	3	9	8	1	30	1	3	7	3	0	7	7	8	6	3	1	1	119
Male	8	12	9	8	9	13	8	9	18	21	1	0	2	10	6	3	15	15	13	12	0	0	2	2	196
Race/Ethnicity, Customized
Units: Subjects
White	9	3	10	13	5	14	9	12	20	23	2	21	1	13	7	0	13	10	7	7	1	0	0	0	200
Black or African American	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	3	3	3	10
Asian	2	8	0	0	8	1	0	0	6	1	0	2	2	0	4	6	2	11	13	12	0	0	0	0	78
American Indian or Alaska Native	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Other	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	1	0	0	3	0	0	0	5
Unknown	0	1	1	1	0	0	1	0	0	5	0	7	0	0	2	0	0	0	0	1	2	0	0	0	21

End points

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Reporting group title

Part 1: RCC naïve 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with renal cell carcinoma (RCC) who had not been previously treated with immuno-oncology therapy

Reporting group title

Part 1: RCC naïve 240 mg

Reporting group description

NIR178 240 mg twice daily continuous in combination with PDR001 in patients with renal cell carcinoma (RCC) who had not been previously treated with immuno-oncology therapy

Reporting group title

Part 1: RCC pre 240 mg

Reporting group description

NIR178 240 mg twice daily continuous in combination with PDR001 in patients with renal cell carcinoma (RCC) who had been pretreated with immuno-oncology therapy

Reporting group title

Part 1: Pancreatic 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with pancreatic cancer

Reporting group title

Part 1: Urothelial 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with urothelial cancer

Reporting group title

Part 1: H-N naïve 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with squamous cell carcinoma of head and neck (HNSCC) who had not been previously treated with immuno-oncology therapy

Reporting group title

Part 1: H-N pre 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with squamous cell carcinoma of head and neck (HNSCC) who had been pretreated with immuno-oncology therapy

Reporting group title

Part 1: H-N pre 240 mg

Reporting group description

NIR178 240 mg twice daily continuous in combination with PDR001 in patients with squamous cell carcinoma of head and neck (HNSCC) who had been pretreated with immuno-oncology therapy

Reporting group title

Part 1: MSS CRC wt 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with microsatellite stable colorectal cancer (MSS CRC) with RAS wildtype

Reporting group title

Part 1: MSS CRC mu 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with microsatellite stable colorectal cancer (MSS CRC) with RAS mutant

Reporting group title

Part 1: MSS CRC unk 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with microsatellite stable colorectal cancer (MSS CRC) with unknown RAS status

Reporting group title

Part 1: TNBC 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with triple negative breast cancer (TNBC)

Reporting group title

Part 1: Melanoma naïve 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with cutaneous melanoma who had not been previously treated with immuno-oncology therapy

Reporting group title

Part 1: Melanoma pre 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with cutaneous melanoma who had been pretreated with immuno-oncology therapy

Reporting group title

Part 1: DLBCL 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with diffuse large B-cell lymphoma (DLBCL)

Reporting group title

Part 1: DLBCL 240 mg

Reporting group description

NIR178 240 mg twice daily continuous in combination with PDR001 in patients with diffuse large B-cell lymphoma (DLBCL)

Reporting group title

Part 1: mCRPC 240 mg

Reporting group description

NIR178 240 mg twice daily continuous in combination with PDR001 in patients with metastatic castration resistant prostate cancer (mCRPC)

Reporting group title

Part 2: NSCLC 160 mg cont

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with non-small cell lung cancer (NSCLC)

Reporting group title

Part 2: NSCLC 160 mg 2wk-on/2wk-off

Reporting group description

NIR178 160 mg twice daily 2 weeks on/2 weeks off in combination with PDR001 in patients with non-small cell lung cancer (NSCLC)

Reporting group title

Part 2: NSCLC 160 mg 1wk-on/1wk-off

Reporting group description

NIR178 160 mg twice daily 1 week on/1 week off in combination with PDR001 in patients with non-small cell lung cancer (NSCLC)

Reporting group title

Part 3: TNBC 160 mg cont

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with triple negative breast cancer (TNBC)

Reporting group title

JSR: 80 mg cont

Reporting group description

NIR178 80 mg twice daily continuous in combination with PDR001 (starting Cycle 2 Day 1) in the Japan safety run-in

Reporting group title

JSR: 160 mg cont

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 (starting Cycle 2 Day 1) in the Japan safety run-in

Reporting group title

JSR: 240 mg cont

Reporting group description

NIR178 140 mg twice daily continuous in combination with PDR001 (starting Cycle 1 Day 1) in the Japan safety run-in

Subject analysis set title

Part 1: RCC naïve + pre 240 mg

Subject analysis set type

Full analysis

Subject analysis set description

NIR178 240 mg twice daily continuous in combination with PDR001 in patients with renal cell carcinoma (RCC), naïve and pretreated with immuno-oncology therapy

Subject analysis set title

Part 1: H-N naïve + pre 160 mg

Subject analysis set type

Full analysis

Subject analysis set description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with squamous cell carcinoma of head and neck (HNSCC), naïve and pretreated with immuno-oncology therapy

Subject analysis set title

Part 1: MSS CRC 160 mg

Subject analysis set type

Full analysis

Subject analysis set description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with microsatellite stable colorectal cancer (MSS CRC) and RAS wildtype, RAS mutant and RAS unknown status

Subject analysis set title

Part 1: Melanoma naïve + pre 160 mg

Subject analysis set type

Full analysis

Subject analysis set description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with cutaneous melanoma, naïve and pretreated with immuno-oncology therapy

Subject analysis set title

NIR178 160 mg capsule in Non-Japanese (Part 1 and 2)

Subject analysis set type

Full analysis

Subject analysis set description

Patients in Part 1 and 2 who received NIR178 160 mg as a capsule in combination with PDR001 400 mg every 4 weeks

Subject analysis set title

NIR178 240 mg capsule in Non-Japanese (Part 1)

Subject analysis set type

Full analysis

Subject analysis set description

Patients in Part 1 who received NIR178 240 mg as a capsule in combination with PDR001 400 mg every 4 weeks

Subject analysis set title

NIR178 160 mg tablet in Non-Japanese (Part 3)

Subject analysis set type

Full analysis

Subject analysis set description

Patients in Part 3 who received NIR178 160 mg as a film-coated tablet in combination with PDR001 400 mg every 4 weeks

Subject analysis set title

Non-Japanese patients

Subject analysis set type

Full analysis

Subject analysis set description

Patients in Parts 1, 2 and 3 who received NIR178 (any dose level) in combination with PDR001 400 mg every 4 weeks

Subject analysis set title

Japanese patients

Subject analysis set type

Full analysis

Subject analysis set description

Patients in the Japanese safety run-in part who received NIR178 (any dose level) in combination with PDR001 400 mg every 4 weeks

Primary: Part 1: Overall Response Rate (ORR) per RECIST v1.1 for solid tumors

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End point title

Part 1: Overall Response Rate (ORR) per RECIST v1.1 for solid tumors ^[1] ^[2]

End point description

ORR is the percentage of patients with a best overall response of complete response (CR) or partial response (PR), based on local investigator assessment per Response Evaluation Criteria for Solid Tumors (RECIST) v1.1. For RECIST v1.1, CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

End point type

Primary

End point timeframe

Up to 3.9 years

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis were planned for this endpoint
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to the 12 selected advanced solid tumors groups defined in the study protocol for efficacy assessment in Part 1

Part 1: RCC naïve 160 mg

Part 1: RCC naïve 240 mg

Part 1: RCC pre 240 mg

Part 1: Pancreatic 160 mg

Part 1: Urothelial 160 mg

Part 1: H-N naïve 160 mg

Part 1: H-N pre 160 mg

Part 1: MSS CRC wt 160 mg

Part 1: MSS CRC mu 160 mg

Part 1: TNBC 160 mg

Part 1: Melanoma pre 160 mg

Part 1: mCRPC 240 mg

Number of subjects analysed

Units: percentage of participants

number (confidence interval 90%)

27.3 (7.9 to 56.4)

25.0 (7.2 to 52.7)

0 (0.0 to 23.8)

0 (0.0 to 19.3)

7.1 (0.4 to 29.7)

13.3 (2.4 to 36.3)

0 (0.0 to 23.8)

0 (0.0 to 10.5)

3.4 (0.2 to 15.3)

10.0 (2.8 to 23.9)

0 (0.0 to 20.6)

0 (0.0 to 18.1)

No statistical analyses for this end point

Primary: Part 1: Overall Response Rate (ORR) per Cheson 2014 for DLBCL

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End point title

Part 1: Overall Response Rate (ORR) per Cheson 2014 for DLBCL ^[3] ^[4]

End point description

ORR is the percentage of patients with a best overall response of complete response (CR) or partial response (PR), based on local investigator assessment per Cheson 2014 criteria for diffuse large B-cell lymphoma (DLBCL). For Cheson 2014 criteria, CR= Target nodes/nodal masses must regress to ≤1.5 cm in longest diameter (LDi), no extralymphatic sites of disease, absent non-measured lesions, organ enlargement regress to normal, no new lesions, and bone marrow normal by morphology (if indeterminate, immunohistochemistry negative); PR= ≥50% decrease in the sum of the product of the perpendicular diameters (SPD) of up to 6 target measurable nodes, absent or regressed non-measured lesions, spleen must have regressed by >50% in length beyond normal, and no new lesions.

End point type

Primary

End point timeframe

Up to 2.5 years

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No statistical analysis were planned for this endpoint
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to the selected lymphoma group defined in the study protocol for efficacy assessment in Part 1

End point values	Part 1: DLBCL 160 mg
Number of subjects analysed	13
Units: percentage of participants
number (confidence interval 90%)	15.4 (2.8 to 41.0)

No statistical analyses for this end point

Primary: Part 3: Overall Response Rate (ORR) per RECIST v1.1 for solid tumors

Top of page

End point title

Part 3: Overall Response Rate (ORR) per RECIST v1.1 for solid tumors ^[5] ^[6]

End point description

ORR is the percentage of patients with a best overall response of complete response (CR) or partial response (PR), based on local investigator assessment per RECIST v1.1. For RECIST v1.1, CR=Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes assigned as target lesions must have a reduction in short axis to < 10 mm; PR= At least a 30% decrease in the sum of diameter of all target lesions, taking as reference the baseline sum of diameters.

End point type

Primary

End point timeframe

Up to 0.5 years

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 statistical analysis were planned for this endpoint
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to Part 3

End point values	Part 3: TNBC 160 mg cont
Number of subjects analysed	6
Units: percentage of participants
number (confidence interval 90%)	16.7 (0.9 to 58.2)

No statistical analyses for this end point

Primary: Part 2: Overall Response Rate (ORR) per RECIST v1.1 for solid tumors

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End point title

Part 2: Overall Response Rate (ORR) per RECIST v1.1 for solid tumors ^[7] ^[8]

End point description

End point type

Primary

End point timeframe

Up to 4.7 years

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 statistical analysis were planned for this endpoint
[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: This endpoint only applies to Part 2

End point values	Part 2: NSCLC 160 mg cont	Part 2: NSCLC 160 mg 2wk-on/2wk-off	Part 2: NSCLC 160 mg 1wk-on/1wk-off
Number of subjects analysed	22	20	20
Units: percentage of participants
number (confidence interval 90%)	9.1 (1.6 to 25.9)	0 (0.0 to 13.9)	10.0 (1.8 to 28.3)

No statistical analyses for this end point

Secondary: Part 1: Overall Response Rate (ORR) per iRECIST for solid tumors

Top of page

End point title

Part 1: Overall Response Rate (ORR) per iRECIST for solid tumors ^[9]

End point description

ORR is the percentage of patients with a best overall response of complete response (iCR) or partial response (iPR), based on local investigator assessment per immune-related RECIST (iRECIST).

End point type

Secondary

End point timeframe

Up to 3.9 years

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to the 12 selected advanced solid tumors groups defined in the study protocol for efficacy assessment in Part 1

Part 1: RCC naïve 160 mg

Part 1: RCC naïve 240 mg

Part 1: RCC pre 240 mg

Part 1: Pancreatic 160 mg

Part 1: Urothelial 160 mg

Part 1: H-N naïve 160 mg

Part 1: H-N pre 160 mg

Part 1: MSS CRC wt 160 mg

Part 1: MSS CRC mu 160 mg

Part 1: TNBC 160 mg

Part 1: Melanoma pre 160 mg

Part 1: mCRPC 240 mg

Number of subjects analysed

Units: percentage of participants

number (confidence interval 90%)

36.4 (13.5 to 65.0)

25.0 (7.2 to 52.7)

0 (0.0 to 23.8)

0 (0.0 to 19.3)

7.1 (0.4 to 29.7)

13.3 (2.4 to 36.3)

0 (0.0 to 23.8)

0 (0.0 to 10.5)

3.4 (0.2 to 15.3)

10.0 (2.8 to 23.9)

0 (0.0 to 20.6)

0 (0.0 to 18.1)

No statistical analyses for this end point

Secondary: Part 2: Overall Response Rate (ORR) per iRECIST for solid tumors

Top of page

End point title

Part 2: Overall Response Rate (ORR) per iRECIST for solid tumors ^[10]

End point description

ORR is the percentage of patients with a best overall response of complete response (iCR) or partial response (iPR), based on local investigator assessment per immune-related RECIST (iRECIST).

End point type

Secondary

End point timeframe

Up to 4.7 years

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to Part 2

End point values	Part 2: NSCLC 160 mg cont	Part 2: NSCLC 160 mg 2wk-on/2wk-off	Part 2: NSCLC 160 mg 1wk-on/1wk-off
Number of subjects analysed	22	20	20
Units: percentage of participants
number (confidence interval 90%)	9.1 (1.6 to 25.9)	5.0 (0.3 to 21.6)	15.0 (4.2 to 34.4)

No statistical analyses for this end point

Secondary: Part 1: Disease Control Rate (DCR) per RECIST v1.1 for solid tumors

Top of page

End point title

Part 1: Disease Control Rate (DCR) per RECIST v1.1 for solid tumors ^[11]

End point description

DCR is the percentage of patients with a best overall response of complete response (CR), partial response (PR), stable disease (SD) or Non-CR or Non-progressive disease (NCRNPD), based on local investigator assessment per Response Evaluation Criteria for Solid Tumors (RECIST) v1.1.

End point type

Secondary

End point timeframe

Up to 3.9 years

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: This endpoint only applies to the 12 selected advanced solid tumors groups defined in the study protocol for efficacy assessment in Part 1

Part 1: RCC naïve 160 mg

Part 1: RCC naïve 240 mg

Part 1: RCC pre 240 mg

Part 1: Pancreatic 160 mg

Part 1: Urothelial 160 mg

Part 1: H-N naïve 160 mg

Part 1: H-N pre 160 mg

Part 1: MSS CRC wt 160 mg

Part 1: MSS CRC mu 160 mg

Part 1: TNBC 160 mg

Part 1: Melanoma pre 160 mg

Part 1: mCRPC 240 mg

Number of subjects analysed

Units: percentage of participants

number (confidence interval 90%)

54.5 (27.1 to 80.0)

66.7 (39.1 to 87.7)

18.2 (3.3 to 47.0)

0 (0.0 to 19.3)

28.6 (10.4 to 54.0)

40.0 (19.1 to 64.0)

63.6 (35.0 to 86.5)

25.9 (12.9 to 43.2)

17.2 (7.0 to 32.9)

33.3 (19.3 to 49.9)

0 (0.0 to 20.6)

46.7 (24.4 to 70.0)

No statistical analyses for this end point

Secondary: Part 3: Overall Response Rate (ORR) per iRECIST for solid tumors

Top of page

End point title

Part 3: Overall Response Rate (ORR) per iRECIST for solid tumors ^[12]

End point description

ORR is the percentage of patients with a best overall response of complete response (iCR) or partial response (iPR), based on local investigator assessment per immune-related RECIST (iRECIST).

End point type

Secondary

End point timeframe

Up to 0.5 years

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: This endpoint only applies to Part 3

End point values	Part 3: TNBC 160 mg cont
Number of subjects analysed	6
Units: percentage of participants
number (confidence interval 90%)	16.7 (0.9 to 58.2)

No statistical analyses for this end point

Secondary: Part 1: Mean percentage change in PSA from baseline

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End point title

Part 1: Mean percentage change in PSA from baseline ^[13]

End point description

Prostate-specific antigen (PSA) levels were assessed in serum. Rising PSA is generally a manifestation of progression of prostate cancer.

End point type

Secondary

End point timeframe

Baseline, up to 0.8 years

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: This endpoint only applies to the prostate cancer group defined in the study protocol for efficacy assessment in Part 1

End point values	Part 1: mCRPC 240 mg
Number of subjects analysed	15
Units: percentage change in PSA from baseline
arithmetic mean (standard deviation)	214.46 ± 329.459

No statistical analyses for this end point

Secondary: Part 1: Disease Control Rate (DCR) per iRECIST for solid tumors

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End point title

Part 1: Disease Control Rate (DCR) per iRECIST for solid tumors ^[14]

End point description

DCR is the percentage of patients with a best overall response of complete response (iCR), partial response (iPR), stable disease (iSD) or Non-iCR or Non-unconfirmed progressive disease (NON-iCR or NON-iUPD), based on local investigator assessment per immune-related RECIST (iRECIST).

End point type

Secondary

End point timeframe

Up to 3.9 years

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to the 12 selected advanced solid tumors groups defined in the study protocol for efficacy assessment in Part 1

Part 1: RCC naïve 160 mg

Part 1: RCC naïve 240 mg

Part 1: RCC pre 240 mg

Part 1: Pancreatic 160 mg

Part 1: Urothelial 160 mg

Part 1: H-N naïve 160 mg

Part 1: H-N pre 160 mg

Part 1: MSS CRC wt 160 mg

Part 1: MSS CRC mu 160 mg

Part 1: TNBC 160 mg

Part 1: Melanoma pre 160 mg

Part 1: mCRPC 240 mg

Number of subjects analysed

Units: percentage of participants

number (confidence interval 90%)

63.6 (35.0 to 86.5)

66.7 (39.1 to 87.7)

18.2 (3.3 to 47.0)

0 (0.0 to 19.3)

35.7 (15.3 to 61.0)

40.0 (19.1 to 64.0)

54.5 (27.1 to 80.0)

25.9 (12.9 to 43.2)

13.8 (4.9 to 28.8)

36.7 (22.1 to 53.3)

0 (0.0 to 20.6)

46.7 (24.4 to 70.0)

No statistical analyses for this end point

Secondary: Part 1: Disease Control Rate (DCR) per Cheson 2014 for DLBCL

Top of page

End point title

Part 1: Disease Control Rate (DCR) per Cheson 2014 for DLBCL ^[15]

End point description

DCR is the percentage of patients with a best overall response of complete response (CR), partial response (PR) or stable disease (SD), based on local investigator assessment per Cheson 2014 criteria for diffuse large B-cell lymphoma (DLBCL).

End point type

Secondary

End point timeframe

Up to 2.5 years

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to the selected lymphoma group defined in the study protocol for efficacy assessment in Part 1

End point values	Part 1: DLBCL 160 mg
Number of subjects analysed	13
Units: percentage of participants
number (confidence interval 90%)	23.1 (6.6 to 49.5)

No statistical analyses for this end point

Secondary: Part 2: Disease Control Rate (DCR) per RECIST v1.1 for solid tumors

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End point title

Part 2: Disease Control Rate (DCR) per RECIST v1.1 for solid tumors ^[16]

End point description

End point type

Secondary

End point timeframe

Up to 4.7 years

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to Part 2

End point values	Part 2: NSCLC 160 mg cont	Part 2: NSCLC 160 mg 2wk-on/2wk-off	Part 2: NSCLC 160 mg 1wk-on/1wk-off
Number of subjects analysed	22	20	20
Units: percentage of participants
number (confidence interval 90%)	36.4 (19.6 to 56.1)	40.0 (21.7 to 60.6)	35.0 (17.7 to 55.8)

No statistical analyses for this end point

Secondary: Part 3: Disease Control Rate (DCR) per RECIST v1.1 for solid tumors

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End point title

Part 3: Disease Control Rate (DCR) per RECIST v1.1 for solid tumors ^[17]

End point description

End point type

Secondary

End point timeframe

Up to 0.5 years

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

End point values	Part 3: TNBC 160 mg cont
Number of subjects analysed	6
Units: percentage of participants
number (confidence interval 90%)	16.7 (0.9 to 58.2)

No statistical analyses for this end point

Secondary: Part 2: Disease Control Rate (DCR) per iRECIST for solid tumors

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End point title

Part 2: Disease Control Rate (DCR) per iRECIST for solid tumors ^[18]

End point description

End point type

Secondary

End point timeframe

Up to 4.7 years

Notes
[18] - 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: This endpoint only applies to Part 2

End point values	Part 2: NSCLC 160 mg cont	Part 2: NSCLC 160 mg 2wk-on/2wk-off	Part 2: NSCLC 160 mg 1wk-on/1wk-off
Number of subjects analysed	22	20	20
Units: percentage of participants
number (confidence interval 90%)	36.4 (19.6 to 56.1)	45.0 (25.9 to 65.3)	45.0 (25.9 to 65.3)

No statistical analyses for this end point

Secondary: Part 1: Duration Of Response (DOR) per RECIST v1.1 for solid tumors

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End point title

Part 1: Duration Of Response (DOR) per RECIST v1.1 for solid tumors ^[19]

End point description

DOR only applies to patients for whom best overall response is complete response (CR) or partial response (PR) based on local investigator assessment per RECIST v1.1. DOR is defined as the time from the date of first documented response (CR or PR) to the date of first documented progression or death due to underlying cancer. If a patient did not have an event, DOR was censored at the date of last adequate tumor assessment. DOR was analyzed using Kaplan-Meier estimates as defined in the statistical analysis plan. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not available’). Therefore, not available values because of insufficient number of participants with events are indicated as ‘999’.

End point type

Secondary

End point timeframe

Up to 3.9 years

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: This endpoint only applies to the 12 selected advanced solid tumors groups defined in the study protocol for efficacy assessment in Part 1

Part 1: RCC naïve 160 mg

Part 1: RCC naïve 240 mg

Part 1: RCC pre 240 mg

Part 1: Pancreatic 160 mg

Part 1: Urothelial 160 mg

Part 1: H-N naïve 160 mg

Part 1: H-N pre 160 mg

Part 1: MSS CRC wt 160 mg

Part 1: MSS CRC mu 160 mg

Part 1: TNBC 160 mg

Part 1: Melanoma pre 160 mg

Part 1: mCRPC 240 mg

Number of subjects analysed

0 ^[20]

0 ^[21]

0 ^[22]

0 ^[23]

0 ^[24]

0 ^[25]

Units: months

median (confidence interval 90%)

999 (999 to 999)

( to )

999 (999 to 999)

( to )

999 (999 to 999)

( to )

Notes
[20] - No patients with CR or PR
[21] - No patients with CR or PR
[22] - No patients with CR or PR
[23] - No patients with CR or PR
[24] - No patients with CR or PR
[25] - No patients with CR or PR

No statistical analyses for this end point

Secondary: Part 3: Disease Control Rate (DCR) per iRECIST for solid tumors

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End point title

Part 3: Disease Control Rate (DCR) per iRECIST for solid tumors ^[26]

End point description

End point type

Secondary

End point timeframe

Up to 0.5 years

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: This endpoint only applies to Part 3

End point values	Part 3: TNBC 160 mg cont
Number of subjects analysed	6
Units: percentage of participants
number (confidence interval 90%)	16.7 (0.9 to 58.2)

No statistical analyses for this end point

Secondary: Part 1: Duration Of Response (DOR) per iRECIST for solid tumors

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End point title

Part 1: Duration Of Response (DOR) per iRECIST for solid tumors ^[27]

End point description

DOR only applies to patients for whom best overall response is complete response (iCR) or partial response (iPR) based on local investigator assessment per iRECIST. DOR is defined as the time from the date of first documented response (iCR or iPR) to the date of first documented progression or death due to underlying cancer. If a patient did not have an event, DOR was censored at the date of last adequate tumor assessment. DOR was analyzed using Kaplan-Meier estimates as defined in the statistical analysis plan. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not available’). Therefore, not available values because of insufficient number of participants with events are indicated as ‘999’.

End point type

Secondary

End point timeframe

Up to 3.9 years

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: This endpoint only applies to the 12 selected advanced solid tumors groups defined in the study protocol for efficacy assessment in Part 1

Part 1: RCC naïve 160 mg

Part 1: RCC naïve 240 mg

Part 1: RCC pre 240 mg

Part 1: Pancreatic 160 mg

Part 1: Urothelial 160 mg

Part 1: H-N naïve 160 mg

Part 1: H-N pre 160 mg

Part 1: MSS CRC wt 160 mg

Part 1: MSS CRC mu 160 mg

Part 1: TNBC 160 mg

Part 1: Melanoma pre 160 mg

Part 1: mCRPC 240 mg

Number of subjects analysed

0 ^[28]

0 ^[29]

0 ^[30]

0 ^[31]

0 ^[32]

0 ^[33]

Units: months

median (confidence interval 90%)

999 (999 to 999)

( to )

999 (999 to 999)

( to )

999 (999 to 999)

( to )

Notes
[28] - No patients with CR or PR
[29] - No patients with CR or PR
[30] - No patients with CR or PR
[31] - No patients with CR or PR
[32] - No patients with CR or PR
[33] - No patients with CR or PR

No statistical analyses for this end point

Secondary: Part 3: Duration Of Response (DOR) per iRECIST for solid tumors

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End point title

Part 3: Duration Of Response (DOR) per iRECIST for solid tumors ^[34]

End point description

End point type

Secondary

End point timeframe

Up to 0.5 years

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

End point values	Part 3: TNBC 160 mg cont
Number of subjects analysed	1
Units: months
median (confidence interval 90%)	999 (999 to 999)

No statistical analyses for this end point

Secondary: Part 3: Duration Of Response (DOR) per RECIST v1.1 for solid tumors

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End point title

Part 3: Duration Of Response (DOR) per RECIST v1.1 for solid tumors ^[35]

End point description

End point type

Secondary

End point timeframe

Up to 0.5 years

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

End point values	Part 3: TNBC 160 mg cont
Number of subjects analysed	1
Units: months
median (confidence interval 90%)	999 (999 to 999)

No statistical analyses for this end point

Secondary: Part 2: Duration Of Response (DOR) per iRECIST for solid tumors

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End point title

Part 2: Duration Of Response (DOR) per iRECIST for solid tumors ^[36]

End point description

End point type

Secondary

End point timeframe

Up to 4.7 years

Notes
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to Part 2

End point values	Part 2: NSCLC 160 mg cont	Part 2: NSCLC 160 mg 2wk-on/2wk-off	Part 2: NSCLC 160 mg 1wk-on/1wk-off
Number of subjects analysed	2	1	3
Units: months
median (confidence interval 90%)	999 (999 to 999)	999 (999 to 999)	999 (999 to 999)

No statistical analyses for this end point

Secondary: Part 2: Duration Of Response (DOR) per RECIST v1.1 for solid tumors

Top of page

End point title

Part 2: Duration Of Response (DOR) per RECIST v1.1 for solid tumors ^[37]

End point description

End point type

Secondary

End point timeframe

Up to 4.7 years

Notes
[37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to Part 2

End point values	Part 2: NSCLC 160 mg cont	Part 2: NSCLC 160 mg 2wk-on/2wk-off	Part 2: NSCLC 160 mg 1wk-on/1wk-off
Number of subjects analysed	2	0 ^[38]	2
Units: months
median (confidence interval 90%)	999 (999 to 999)	( to )	999 (999 to 999)

Notes
[38] - No patients with CR or PR

No statistical analyses for this end point

Secondary: Part 1: Duration Of Response (DOR) per Cheson 2014 for DLBCL

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End point title

Part 1: Duration Of Response (DOR) per Cheson 2014 for DLBCL ^[39]

End point description

DOR only applies to patients for whom best overall response is complete response (CR) or partial response (PR) based on local investigator assessment per Cheson 2014 criteria for DLBCL. DOR is defined as the time from the date of first documented response (CR or PR) to the date of first documented progression or death due to underlying cancer. If a patient did not have an event, DOR was censored at the date of last adequate tumor assessment. DOR was analyzed using Kaplan-Meier estimates as defined in the statistical analysis plan. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not available’). Therefore, not available values because of insufficient number of participants with events are indicated as ‘999’.

End point type

Secondary

End point timeframe

Up to 2.5 years

Notes
[39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to the selected lymphoma group defined in the study protocol for efficacy assessment in Part 1

End point values	Part 1: DLBCL 160 mg
Number of subjects analysed	2
Units: months
median (confidence interval 90%)	999 (999 to 999)

No statistical analyses for this end point

Secondary: Part 1: Progression-Free Survival (PFS) per RECIST v1.1 for solid tumors

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End point title

Part 1: Progression-Free Survival (PFS) per RECIST v1.1 for solid tumors ^[40]

End point description

End point type

Secondary

End point timeframe

Up to 3.9 years

Notes
[40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to the 12 selected advanced solid tumors groups defined in the study protocol for efficacy assessment in Part 1

Part 1: RCC naïve 160 mg

Part 1: RCC naïve 240 mg

Part 1: RCC pre 240 mg

Part 1: Pancreatic 160 mg

Part 1: Urothelial 160 mg

Part 1: H-N naïve 160 mg

Part 1: H-N pre 160 mg

Part 1: MSS CRC wt 160 mg

Part 1: MSS CRC mu 160 mg

Part 1: TNBC 160 mg

Part 1: Melanoma pre 160 mg

Part 1: mCRPC 240 mg

Number of subjects analysed

Units: months

median (confidence interval 90%)

3.5 (1.9 to 15.4)

7.2 (1.8 to 8.6)

1.9 (1.7 to 2.0)

1.7 (1.6 to 1.7)

1.9 (1.7 to 3.5)

2.0 (1.6 to 3.7)

3.5 (1.7 to 3.7)

1.7 (1.6 to 1.9)

1.9 (1.7 to 2.0)

1.7 (1.6 to 1.9)

1.8 (1.6 to 1.9)

3.7 (1.7 to 5.3)

No statistical analyses for this end point

Secondary: Part 1: Progression-Free Survival (PFS) per iRECIST for solid tumors

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End point title

Part 1: Progression-Free Survival (PFS) per iRECIST for solid tumors ^[41]

End point description

PFS is defined as the time from the date of start of treatment to the date of the first documented progression or death due to any cause, whichever happened first. If a patient did not have an event, PFS was censored at the date of the last adequate tumor assessment. Tumor response was based on local investigator assessment per iRECIST. PFS was analyzed using Kaplan-Meier estimates as defined in the statistical analysis plan. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not available’). Therefore, not available values because of insufficient number of participants with events are indicated as ‘999’.

End point type

Secondary

End point timeframe

Up to 3.9 years

Notes
[41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to the 12 selected advanced solid tumors groups defined in the study protocol for efficacy assessment in Part 1

Part 1: RCC naïve 160 mg

Part 1: RCC naïve 240 mg

Part 1: RCC pre 240 mg

Part 1: Pancreatic 160 mg

Part 1: Urothelial 160 mg

Part 1: H-N naïve 160 mg

Part 1: H-N pre 160 mg

Part 1: MSS CRC wt 160 mg

Part 1: MSS CRC mu 160 mg

Part 1: TNBC 160 mg

Part 1: Melanoma pre 160 mg

Part 1: mCRPC 240 mg

Number of subjects analysed

Units: months

median (confidence interval 90%)

8.7 (2.1 to 999)

7.2 (1.8 to 999)

1.9 (1.7 to 2.0)

1.7 (1.1 to 1.7)

2.1 (1.7 to 3.5)

2.0 (1.6 to 3.7)

3.5 (1.7 to 3.7)

1.8 (1.6 to 2.0)

1.9 (1.7 to 2.0)

1.8 (1.6 to 3.5)

1.8 (1.6 to 1.9)

3.7 (1.7 to 5.3)

No statistical analyses for this end point

Secondary: Part 3: Progression-Free Survival (PFS) per iRECIST for solid tumors

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End point title

Part 3: Progression-Free Survival (PFS) per iRECIST for solid tumors ^[42]

End point description

End point type

Secondary

End point timeframe

Up to 0.5 years

Notes
[42] - 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: This endpoint only applies to Part 3

End point values	Part 3: TNBC 160 mg cont
Number of subjects analysed	6
Units: months
median (confidence interval 90%)	1.6 (0.9 to 1.8)

No statistical analyses for this end point

Secondary: Part 3: Progression-Free Survival (PFS) per RECIST v1.1 for solid tumors

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End point title

Part 3: Progression-Free Survival (PFS) per RECIST v1.1 for solid tumors ^[43]

End point description

End point type

Secondary

End point timeframe

Up to 0.5 years

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

End point values	Part 3: TNBC 160 mg cont
Number of subjects analysed	6
Units: months
median (confidence interval 90%)	1.6 (0.9 to 1.8)

No statistical analyses for this end point

Secondary: Part 2: Progression-Free Survival (PFS) per RECIST v1.1 for solid tumors

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End point title

Part 2: Progression-Free Survival (PFS) per RECIST v1.1 for solid tumors ^[44]

End point description

End point type

Secondary

End point timeframe

Up to 4.7 years

Notes
[44] - 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: This endpoint only applies to Part 2

End point values	Part 2: NSCLC 160 mg cont	Part 2: NSCLC 160 mg 2wk-on/2wk-off	Part 2: NSCLC 160 mg 1wk-on/1wk-off
Number of subjects analysed	22	20	20
Units: months
median (confidence interval 90%)	2.0 (1.8 to 3.8)	2.1 (1.7 to 3.7)	1.9 (1.7 to 3.7)

No statistical analyses for this end point

Secondary: Part 1: Progression-Free Survival (PFS) per Cheson 2014 for DLBCL

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End point title

Part 1: Progression-Free Survival (PFS) per Cheson 2014 for DLBCL ^[45]

End point description

End point type

Secondary

End point timeframe

Up to 2.5 years

Notes
[45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to the selected lymphoma group defined in the study protocol for efficacy assessment in Part 1

End point values	Part 1: DLBCL 160 mg
Number of subjects analysed	13
Units: months
median (confidence interval 90%)	1.7 (1.4 to 2.2)

No statistical analyses for this end point

Secondary: Part 2: Progression-Free Survival (PFS) per iRECIST for solid tumors

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End point title

Part 2: Progression-Free Survival (PFS) per iRECIST for solid tumors ^[46]

End point description

End point type

Secondary

End point timeframe

Up to 4.7 years

Notes
[46] - 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: This endpoint only applies to Part 2

End point values	Part 2: NSCLC 160 mg cont	Part 2: NSCLC 160 mg 2wk-on/2wk-off	Part 2: NSCLC 160 mg 1wk-on/1wk-off
Number of subjects analysed	22	20	20
Units: months
median (confidence interval 90%)	2.1 (1.8 to 3.8)	2.2 (1.8 to 3.7)	2.8 (1.7 to 9.0)

No statistical analyses for this end point

Secondary: Part 1: 2-year Overall Survival (OS)

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End point title

Part 1: 2-year Overall Survival (OS) ^[47]

End point description

OS represents the percentage of participants who are alive after the start of study treatment. OS at 2 years was estimated using the Kaplan-Meier method as defined in the statistical analysis plan (SAP). Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not available’). Therefore, not available values because of insufficient number of participants with events are indicated as ‘999’.

End point type

Secondary

End point timeframe

2 years

Notes
[47] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to the 13 selected cancer groups (advanced solid tumors and lymphoma) defined in the study protocol for efficacy assessment in Part 1

Part 1: RCC naïve 160 mg

Part 1: RCC naïve 240 mg

Part 1: RCC pre 240 mg

Part 1: Pancreatic 160 mg

Part 1: Urothelial 160 mg

Part 1: H-N naïve 160 mg

Part 1: H-N pre 160 mg

Part 1: MSS CRC wt 160 mg

Part 1: MSS CRC mu 160 mg

Part 1: TNBC 160 mg

Part 1: Melanoma pre 160 mg

Part 1: DLBCL 160 mg

Part 1: mCRPC 240 mg

Number of subjects analysed

Units: percentage of participants

number (confidence interval 90%)

63.6 (35.5 to 82.1)

42.1 (14.6 to 67.8)

27.3 (8.9 to 49.8)

999 (999 to 999)

36.1 (15.0 to 57.9)

33.3 (15.0 to 52.9)

15.3 (1.9 to 41.2)

22.1 (9.4 to 38.2)

14.3 (4.3 to 29.9)

30.8 (16.0 to 46.9)

999 (999 to 999)

23.1 (7.5 to 43.6)

31.4 (10.8 to 54.7)

No statistical analyses for this end point

Secondary: Part 1: Change from baseline in CD8 percent marker area in tumor tissue

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End point title

Part 1: Change from baseline in CD8 percent marker area in tumor tissue ^[48]

End point description

The tumor expression of CD8 was measured by immunohistochemical (IHC) methods. Newly obtained pre- and on-treatment paired tumor samples were required and collected at screening and after approximately two cycles of therapy. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.

End point type

Secondary

End point timeframe

Screening and on-treatment (Cycle 2 Day 1 or Day 15). The duration of one cycle was 28 days.

Notes
[48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to Part 1. For the safety endpoints, patients at each study part with the same type of cancer who are treated at the same dose level and dosing schedule are pooled together, independently of the immune-oncology (IO) pretreatment status and RAS mutation status

Part 1: RCC naïve 160 mg

Part 1: RCC naïve 240 mg

Part 1: RCC pre 240 mg

Part 1: Pancreatic 160 mg

Part 1: Urothelial 160 mg

Part 1: H-N naïve 160 mg

Part 1: H-N pre 160 mg

Part 1: MSS CRC wt 160 mg

Part 1: MSS CRC mu 160 mg

Part 1: TNBC 160 mg

Part 1: Melanoma pre 160 mg

Part 1: DLBCL 160 mg

Part 1: mCRPC 240 mg

Number of subjects analysed

Units: CD8 percent marker area

arithmetic mean (standard deviation)

10.93 ± 14.227

10.53 ± 12.456

0.70 ± 2.645

-0.81 ± 0.537

0.96 ± 1.345

1.63 ± 2.372

-0.42 ± 1.477

0.70 ± 1.141

-0.01 ± 1.164

4.86 ± 3.751

0.16 ± 0.540

7.84 ± 999

2.67 ± 4.156

No statistical analyses for this end point

Secondary: Part 3: 2-year Overall Survival (OS)

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End point title

Part 3: 2-year Overall Survival (OS) ^[49]

End point description

OS represents the percentage of participants who are alive after the start of study treatment. OS at 2 years was estimated using the Kaplan-Meier method as defined in the statistical analysis plan. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not available’). Therefore, not available values because of insufficient number of participants with events are indicated as ‘999’.

End point type

Secondary

End point timeframe

2 years

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

End point values	Part 3: TNBC 160 mg cont
Number of subjects analysed	6
Units: percentage of participants
number (confidence interval 90%)	999 (999 to 999)

No statistical analyses for this end point

Secondary: Part 2: 2-year Overall Survival (OS)

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End point title

Part 2: 2-year Overall Survival (OS) ^[50]

End point description

OS represents the percentage of participants who are alive after the start of study treatment. OS at 2 years was estimated using the Kaplan-Meier method as defined in the statistical analysis plan.

End point type

Secondary

End point timeframe

2 years

Notes
[50] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to Part 2

End point values	Part 2: NSCLC 160 mg cont	Part 2: NSCLC 160 mg 2wk-on/2wk-off	Part 2: NSCLC 160 mg 1wk-on/1wk-off
Number of subjects analysed	22	20	20
Units: percentage of participants
number (confidence interval 90%)	33.6 (15.5 to 52.9)	22.7 (7.5 to 42.7)	39.7 (20.3 to 58.6)

No statistical analyses for this end point

Secondary: Part 2: Change from baseline in CD8 percent marker area in tumor tissue

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End point title

Part 2: Change from baseline in CD8 percent marker area in tumor tissue ^[51]

End point description

End point type

Secondary

End point timeframe

Screening and on-treatment (Cycle 2 Day 1 or Day 15). The duration of one cycle was 28 days.

Notes
[51] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to Part 2

End point values	Part 2: NSCLC 160 mg cont	Part 2: NSCLC 160 mg 2wk-on/2wk-off	Part 2: NSCLC 160 mg 1wk-on/1wk-off
Number of subjects analysed	6	4	4
Units: CD8 percent marker area
arithmetic mean (standard deviation)	3.81 ± 4.551	-2.35 ± 5.586	1.23 ± 2.955

No statistical analyses for this end point

Secondary: Part 3: Change from baseline in CD8 percent marker area in tumor tissue

Top of page

End point title

Part 3: Change from baseline in CD8 percent marker area in tumor tissue ^[52]

End point description

End point type

Secondary

End point timeframe

Screening and on-treatment (Cycle 2 Day 1 or Day 15). The duration of one cycle was 28 days.

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

End point values	Part 3: TNBC 160 mg cont
Number of subjects analysed	1
Units: CD8 percent marker area
arithmetic mean (standard deviation)	0.26 ± 999

No statistical analyses for this end point

Secondary: Part 1, 2 and 3: Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) during the on-treatment period

Top of page

End point title

Part 1, 2 and 3: Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) during the on-treatment period ^[53]

End point description

Number of participants with AEs (any AE regardless of seriousness) and SAEs, including changes from baseline in vital signs, electrocardiograms and laboratory results qualifying and reported as AEs. The on-treatment period is defined from the day of first administration of study treatment up to 30 days after the date of its last administration.

End point type

Secondary

End point timeframe

Up to 4 years (Part 1), 4.8 years (Part 2) and 0.6 years (Part 3)

Notes
[53] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to Part 1, 2 and 3. For the safety endpoints, patients at each study part with the same type of cancer who are treated at the same dose level and dosing schedule are pooled together, independently of the immune-oncology (IO) pretreatment status and RAS mutation status

End point values	Part 1: RCC naïve 160 mg	Part 1: Pancreatic 160 mg	Part 1: Urothelial 160 mg	Part 1: H-N pre 240 mg	Part 1: TNBC 160 mg	Part 1: DLBCL 160 mg	Part 1: DLBCL 240 mg	Part 1: mCRPC 240 mg	Part 2: NSCLC 160 mg cont	Part 2: NSCLC 160 mg 2wk-on/2wk-off	Part 2: NSCLC 160 mg 1wk-on/1wk-off	Part 3: TNBC 160 mg cont	Part 1: RCC naïve + pre 240 mg	Part 1: H-N naïve + pre 160 mg	Part 1: MSS CRC 160 mg	Part 1: Melanoma naïve + pre 160 mg
Number of subjects analysed	11	14	14	12	30	13	6	15	22	20	20	6	23	26	58	16
Units: participants
AEs	10	14	14	12	29	13	5	14	22	18	18	6	22	26	57	15
Treatment-related AEs	7	9	9	9	23	11	2	12	15	14	9	4	16	16	34	6
SAEs	3	9	7	5	11	6	0	4	11	7	7	3	7	15	28	3
Treatment-related SAEs	0	2	1	2	2	2	0	2	6	3	0	0	2	3	7	0
Fatal SAEs	1	1	0	1	1	1	0	0	1	2	0	0	0	2	3	0
Treatment-related fatal SAEs	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: Part 1, 2 and 3: Number of participants with dose reductions and dose interruptions of NIR178

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End point title

Part 1, 2 and 3: Number of participants with dose reductions and dose interruptions of NIR178 ^[54]

End point description

Number of participants with at least one dose reduction of NIR178 and number of participants with at least one dose interruption of NIR178. Dose or schedule adjustments were permitted for patients who did not tolerate the protocol-specified dosing schedule.

End point type

Secondary

End point timeframe

Up to 3.9 years (Part 1), 4.7 years (Part 2) and 0.5 years (Part 3)

Notes
[54] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to Part 1, 2 and 3. For the safety endpoints, patients at each study part with the same type of cancer who are treated at the same dose level and dosing schedule are pooled together, independently of the immune-oncology (IO) pretreatment status and RAS mutation status

End point values	Part 1: RCC naïve 160 mg	Part 1: Pancreatic 160 mg	Part 1: Urothelial 160 mg	Part 1: H-N pre 240 mg	Part 1: TNBC 160 mg	Part 1: DLBCL 160 mg	Part 1: DLBCL 240 mg	Part 1: mCRPC 240 mg	Part 2: NSCLC 160 mg cont	Part 2: NSCLC 160 mg 2wk-on/2wk-off	Part 2: NSCLC 160 mg 1wk-on/1wk-off	Part 3: TNBC 160 mg cont	Part 1: RCC naïve + pre 240 mg	Part 1: H-N naïve + pre 160 mg	Part 1: MSS CRC 160 mg	Part 1: Melanoma naïve + pre 160 mg
Number of subjects analysed	11	14	14	12	30	13	6	15	22	20	20	6	23	26	58	16
Units: participants
At least one dose reduction	2	0	2	1	3	1	0	2	2	1	1	0	1	8	7	1
At least one dose interruption	6	2	8	3	9	3	1	5	8	5	4	0	9	12	20	3

No statistical analyses for this end point

Secondary: Part 1, 2 and 3: Number of participants with dose reductions and dose interruptions of PDR001

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End point title

Part 1, 2 and 3: Number of participants with dose reductions and dose interruptions of PDR001 ^[55]

End point description

Number of participants with at least one dose reduction of PDR001 and number of participants with at least one dose interruption of PDR001. Dose or schedule adjustments were permitted for patients who did not tolerate the protocol-specified dosing schedule. Dose reductions were not permitted for PDR001.

End point type

Secondary

End point timeframe

Up to 3.9 years (Part 1), 4.7 years (Part 2) and 0.5 years (Part 3)

Notes
[55] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to Part 1, 2 and 3. For the safety endpoints, patients at each study part with the same type of cancer who are treated at the same dose level and dosing schedule are pooled together, independently of the immune-oncology (IO) pretreatment status and RAS mutation status

End point values	Part 1: RCC naïve 160 mg	Part 1: Pancreatic 160 mg	Part 1: Urothelial 160 mg	Part 1: H-N pre 240 mg	Part 1: TNBC 160 mg	Part 1: DLBCL 160 mg	Part 1: DLBCL 240 mg	Part 1: mCRPC 240 mg	Part 2: NSCLC 160 mg cont	Part 2: NSCLC 160 mg 2wk-on/2wk-off	Part 2: NSCLC 160 mg 1wk-on/1wk-off	Part 3: TNBC 160 mg cont	Part 1: RCC naïve + pre 240 mg	Part 1: H-N naïve + pre 160 mg	Part 1: MSS CRC 160 mg	Part 1: Melanoma naïve + pre 160 mg
Number of subjects analysed	11	14	14	12	30	13	6	15	22	20	20	6	23	26	58	16
Units: participants
At least one dose reduction	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
At least one dose interruption	6	1	6	1	8	0	0	2	6	4	2	0	7	9	13	2

No statistical analyses for this end point

Secondary: Part 1, 2 and 3: Dose intensity of NIR178

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End point title

Part 1, 2 and 3: Dose intensity of NIR178 ^[56]

End point description

Dose intensity of NIR178 was calculated as cumulative actual dose in milligrams divided by duration of exposure in days.

End point type

Secondary

End point timeframe

Up to 3.9 years (Part 1), 4.7 years (Part 2) and 0.5 years (Part 3)

Notes
[56] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to Part 1, 2 and 3. For the safety endpoints, patients at each study part with the same type of cancer who are treated at the same dose level and dosing schedule are pooled together, independently of the immune-oncology (IO) pretreatment status and RAS mutation status

Part 1: RCC naïve 160 mg

Part 1: Pancreatic 160 mg

Part 1: Urothelial 160 mg

Part 1: H-N pre 240 mg

Part 1: TNBC 160 mg

Part 1: DLBCL 160 mg

Part 1: DLBCL 240 mg

Part 1: mCRPC 240 mg

Part 2: NSCLC 160 mg cont

Part 2: NSCLC 160 mg 2wk-on/2wk-off

Part 2: NSCLC 160 mg 1wk-on/1wk-off

Part 3: TNBC 160 mg cont

Part 1: RCC naïve + pre 240 mg

Part 1: H-N naïve + pre 160 mg

Part 1: MSS CRC 160 mg

Part 1: Melanoma naïve + pre 160 mg

Number of subjects analysed

Units: mg/day

median (full range (min-max))

316.7 (187 to 320)

320.0 (241 to 320)

295.7 (140 to 320)

480.0 (272 to 480)

320.0 (179 to 320)

320.0 (233 to 320)

480.0 (363 to 480)

480.0 (382 to 496)

320.0 (137 to 320)

160.0 (96 to 173)

160.0 (71 to 189)

320.0 (319 to 320)

477.3 (321 to 480)

309.8 (141 to 320)

320.0 (134 to 320)

320.0 (208 to 320)

No statistical analyses for this end point

Secondary: Part 1, 2 and 3: Dose intensity of PDR001

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End point title

Part 1, 2 and 3: Dose intensity of PDR001 ^[57]

End point description

Dose intensity of PDR001 was calculated as cumulative actual dose in milligrams divided by duration of exposure in days and then multiplied by 28 days.

End point type

Secondary

End point timeframe

Up to 3.9 years (Part 1), 4.7 years (Part 2) and 0.5 years (Part 3)

Notes
[57] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to Part 1, 2 and 3. For the safety endpoints, patients at each study part with the same type of cancer who are treated at the same dose level and dosing schedule are pooled together, independently of the immune-oncology (IO) pretreatment status and RAS mutation status

Part 1: RCC naïve 160 mg

Part 1: Pancreatic 160 mg

Part 1: Urothelial 160 mg

Part 1: H-N pre 240 mg

Part 1: TNBC 160 mg

Part 1: DLBCL 160 mg

Part 1: DLBCL 240 mg

Part 1: mCRPC 240 mg

Part 2: NSCLC 160 mg cont

Part 2: NSCLC 160 mg 2wk-on/2wk-off

Part 2: NSCLC 160 mg 1wk-on/1wk-off

Part 3: TNBC 160 mg cont

Part 1: RCC naïve + pre 240 mg

Part 1: H-N naïve + pre 160 mg

Part 1: MSS CRC 160 mg

Part 1: Melanoma naïve + pre 160 mg

Number of subjects analysed

Units: mg/28 days

median (full range (min-max))

394.2 (300 to 400)

400.0 (395 to 400)

393.1 (350 to 400)

400.0 (365 to 407)

400.0 (305 to 404)

400.0 (386 to 400)

400.0 (400 to 400)

400.0 (378 to 404)

400.0 (224 to 406)

400.0 (300 to 401)

400.0 (387 to 410)

400.0 (400 to 400)

396.2 (267 to 431)

398.2 (319 to 402)

400.0 (236 to 405)

400.0 (389 to 406)

No statistical analyses for this end point

Secondary: Part 1, 2 and 3: Number of participants with anti-PDR001 antibodies

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End point title

Part 1, 2 and 3: Number of participants with anti-PDR001 antibodies ^[58]

End point description

PDR001 immunogenicity was evaluated in serum samples. Patient anti-drug antibodies (ADA) status was defined as follows: • ADA-negative at baseline: ADA-negative sample at baseline • ADA-positive at baseline: ADA-positive sample at baseline • ADA-negative post-baseline: ADA-negative sample at baseline and at least 1 post-baseline sample, all of which are ADA-negative samples • Treatment-reduced ADA-positive: ADA-positive sample at baseline and at least 1 post-baseline sample, all of which are ADA-negative samples • Treatment-induced ADA-positive: ADA-negative sample at baseline and at least 1 treatment-induced ADA-positive sample • Treatment-boosted ADA-positive: ADA-positive sample at baseline and at least 1 treatment-boosted ADA-positive sample • ADA-inconclusive: patient who does not qualify for any of the above definitions or a patient for which the baseline sample is missing

End point type

Secondary

End point timeframe

Up to approximately 5 years

Notes
[58] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to Part 1, 2 and 3. For the safety endpoints, patients at each study part with the same type of cancer who are treated at the same dose level and dosing schedule are pooled together, independently of the immune-oncology (IO) pretreatment status and RAS mutation status

End point values	Part 1: RCC naïve 160 mg	Part 1: Pancreatic 160 mg	Part 1: Urothelial 160 mg	Part 1: H-N pre 240 mg	Part 1: TNBC 160 mg	Part 1: DLBCL 160 mg	Part 1: DLBCL 240 mg	Part 1: mCRPC 240 mg	Part 2: NSCLC 160 mg cont	Part 2: NSCLC 160 mg 2wk-on/2wk-off	Part 2: NSCLC 160 mg 1wk-on/1wk-off	Part 3: TNBC 160 mg cont	Part 1: RCC naïve + pre 240 mg	Part 1: H-N naïve + pre 160 mg	Part 1: MSS CRC 160 mg	Part 1: Melanoma naïve + pre 160 mg
Number of subjects analysed	11	12	13	11	27	10	6	13	21	19	17	6	23	24	52	13
Units: participants
ADA-negative at baseline	11	12	13	11	27	10	6	13	21	19	17	6	23	24	49	13
ADA-positive at baseline	0	0	0	0	0	0	0	0	0	0	0	0	0	0	3	0
ADA-negative post-baseline	10	11	12	11	25	10	6	11	21	14	14	5	23	22	48	13
Treatment-reduced ADA-positive	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0
Treatment-induced ADA-positive	1	1	1	0	2	0	0	2	0	5	3	1	0	2	1	0
Treatment-boosted ADA-positive	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
ADA-inconclusive	0	0	0	0	0	0	0	0	0	0	0	0	0	0	2	0

No statistical analyses for this end point

Secondary: Japan Safety Run-in: Number of participants with Dose-Limiting Toxicities (DLTs)

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End point title

Japan Safety Run-in: Number of participants with Dose-Limiting Toxicities (DLTs) ^[59]

End point description

A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value of Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 3 assessed as unrelated to disease, disease progression, inter-current illness or concomitant medications, which occurs within the first 28 days of treatment with NIR178 as single agent or in combination with PDR001 during the Japan safety run-in part of the study. Other clinically significant toxicities may be considered to be DLTs, even if not CTCAE grade 3 or higher.

End point type

Secondary

End point timeframe

28 days

Notes
[59] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to the Japan Safety Run-in

End point values	JSR: 80 mg cont	JSR: 160 mg cont	JSR: 240 mg cont
Number of subjects analysed	3	3	3
Units: participants	0	0	0

No statistical analyses for this end point

Secondary: All study parts: Maximum observed plasma concentration (Cmax) of NIR178

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End point title

All study parts: Maximum observed plasma concentration (Cmax) of NIR178 ^[60]

End point description

Pharmacokinetic (PK) parameters were calculated based on NIR178 plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed plasma concentration following a dose. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.

End point type

Secondary

End point timeframe

Cycle 1 Day 1 (all), Cycle 1 Day 7 (1wk-on/1wk-off), Cycle 1 Day 14 (2wk-on/2wk-off) and Cycle 1 Day 28 (continuous dosing): pre-dose, 15 and 30 minutes, 1, 1.5, 2, 3, 4 and 8 hours after morning dose and 12 hours after evening dose. 1 cycle=28 days

Notes
[60] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Patients from the same ethnicity (Non-Japanese, Japanese) treated with the same formulation (capsule, tablet) at the same NIR178 dose level are pooled together.

End point values	JSR: 80 mg cont	JSR: 160 mg cont	JSR: 240 mg cont	NIR178 160 mg capsule in Non-Japanese (Part 1 and 2)	NIR178 240 mg capsule in Non-Japanese (Part 1)	NIR178 160 mg tablet in Non-Japanese (Part 3)
Number of subjects analysed	3 ^[61]	3 ^[62]	3 ^[63]	206 ^[64]	54 ^[65]	6 ^[66]
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1 (all regimens)	81.8 ± 99.9	30.1 ± 32.9	234 ± 70.9	129 ± 335.0	160 ± 247.8	75.1 ± 382.3
Cycle 1 Day 7 (1 wk-on/1 wk-off)	999 ± 999	999 ± 999	999 ± 999	576 ± 83.1	999 ± 999	999 ± 999
Cycle 1 Day 14 (2 wk-on/2 wk-off)	999 ± 999	999 ± 999	999 ± 999	392 ± 212.7	999 ± 999	999 ± 999
Cycle 1 Day 28 (continuous)	311 ± 91.5	167 ± 40.9	3760 ± 39.6	297 ± 291.4	622 ± 154.3	723 ± 295.5

Notes
[61] - n=3 (C1D1), 0 (C1D7), 0 (C1D14), 3 (C1D28)
[62] - n=3 (C1D1), 0 (C1D7), 0 (C1D14), 3 (C1D28)
[63] - n=3 (C1D1), 0 (C1D7), 0 (C1D14), 3 (C1D28)
[64] - n=206 (C1D1), 17 (C1D7), 11 (C1D14), 100 (C1D28)
[65] - n=54 (C1D1), 0 (C1D7), 0 (C1D14), 41 (C1D28)
[66] - n=6 (C1D1), 0 (C1D7), 0 (C1D14), 4 (C1D28)

No statistical analyses for this end point

Secondary: Japan Safety Run-in: Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) during the on-treatment period

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End point title

Japan Safety Run-in: Number of participants with Adverse Events (AEs) and Serious Adverse Events (SAEs) during the on-treatment period ^[67]

End point description

End point type

Secondary

End point timeframe

Up to 0.7 years

Notes
[67] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint only applies to the Japan Safety Run-in

End point values	JSR: 80 mg cont	JSR: 160 mg cont	JSR: 240 mg cont
Number of subjects analysed	3	3	3
Units: participants
AEs	3	3	3
Treatment-related AEs	0	2	1
SAEs	2	1	1
Treatment-related SAEs	0	1	0
Fatal SAEs	0	0	0
Treatment-related fatal SAEs	0	0	0

No statistical analyses for this end point

Secondary: All study parts: Time to reach maximum plasma concentration (Tmax) of NIR178

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End point title

All study parts: Time to reach maximum plasma concentration (Tmax) of NIR178 ^[68]

End point description

Pharmacokinetic (PK) parameters were calculated based on NIR178 plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) plasma concentration following a dose. Actual recorded sampling times were considered for the calculations. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.

End point type

Secondary

End point timeframe

Notes
[68] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Patients from the same ethnicity (Non-Japanese, Japanese) treated with the same formulation (capsule, tablet) at the same NIR178 dose level are pooled together.

End point values	JSR: 80 mg cont	JSR: 160 mg cont	JSR: 240 mg cont	NIR178 160 mg capsule in Non-Japanese (Part 1 and 2)	NIR178 240 mg capsule in Non-Japanese (Part 1)	NIR178 160 mg tablet in Non-Japanese (Part 3)
Number of subjects analysed	3 ^[69]	3 ^[70]	3 ^[71]	206 ^[72]	54 ^[73]	6 ^[74]
Units: hours
median (full range (min-max))
Cycle 1 Day 1 (all regimens)	1.50 (1.47 to 1.50)	1.50 (0.583 to 3.95)	3.00 (2.03 to 3.03)	2.00 (0.250 to 8.00)	2.13 (0.50 to 8.00)	1.50 (0.450 to 4.05)
Cycle 1 Day 7 (1 wk-on/1 wk-off)	999 (999 to 999)	999 (999 to 999)	999 (999 to 999)	1.45 (0.50 to 4.00)	999 (999 to 999)	999 (999 to 999)
Cycle 1 Day 14 (2 wk-on/2 wk-off)	999 (999 to 999)	999 (999 to 999)	999 (999 to 999)	1.97 (0.550 to 7.67)	999 (999 to 999)	999 (999 to 999)
Cycle 1 Day 28 (continuous)	1.43 (0.50 to 1.48)	1.45 (0.50 to 1.50)	2.87 (1.92 to 4.00)	2.00 (0.267 to 8.00)	2.02 (0.250 to 7.60)	1.52 (0.50 to 3.00)

Notes
[69] - n=3 (C1D1), 0 (C1D7), 0 (C1D14), 3 (C1D28)
[70] - n=3 (C1D1), 0 (C1D7), 0 (C1D14), 3 (C1D28)
[71] - n=3 (C1D1), 0 (C1D7), 0 (C1D14), 3 (C1D28)
[72] - n=206 (C1D1), 17 (C1D7), 11 (C1D14), 100 (C1D28)
[73] - n=54 (C1D1), 0 (C1D7), 0 (C1D14), 41 (C1D28)
[74] - n=6 (C1D1), 0 (C1D7), 0 (C1D14), 4 (C1D28)

No statistical analyses for this end point

Secondary: All study parts: Area under the plasma concentration-time curve from time zero to 12 hours post dose (AUC0-12hr) of NIR178

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End point title

All study parts: Area under the plasma concentration-time curve from time zero to 12 hours post dose (AUC0-12hr) of NIR178 ^[75]

End point description

PK parameters were calculated based on NIR178 plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC0-12hr calculation. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.

End point type

Secondary

End point timeframe

Notes
[75] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Patients from the same ethnicity (Non-Japanese, Japanese) treated with the same formulation (capsule, tablet) at the same NIR178 dose level are pooled together.

End point values	JSR: 80 mg cont	JSR: 160 mg cont	JSR: 240 mg cont	NIR178 160 mg capsule in Non-Japanese (Part 1 and 2)	NIR178 240 mg capsule in Non-Japanese (Part 1)	NIR178 160 mg tablet in Non-Japanese (Part 3)
Number of subjects analysed	3 ^[76]	2 ^[77]	1 ^[78]	95 ^[79]	24 ^[80]	4 ^[81]
Units: hr*ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1 (all regimens)	170 ± 124.9	63.3 ± 88.0	550 ± 999	295 ± 198.3	487 ± 126.3	232 ± 437.4
Cycle 1 Day 7 (1 wk-on/1 wk-off)	999 ± 999	999 ± 999	999 ± 999	1260 ± 63.2	999 ± 999	999 ± 999
Cycle 1 Day 14 (2 wk-on/2 wk-off)	999 ± 999	999 ± 999	999 ± 999	1680 ± 94.4	999 ± 999	999 ± 999
Cycle 1 Day 28 (continuous)	697 ± 131.8	242 ± 13.5	12800 ± 999	918 ± 187.5	1620 ± 147.9	938 ± 414.2

Notes
[76] - n=3 (C1D1), 0 (C1D7), 0 (C1D14), 3 (C1D28)
[77] - n=2 (C1D1), 0 (C1D7), 0 (C1D14), 2 (C1D28)
[78] - n=1 (C1D1), 0 (C1D7), 0 (C1D14), 1 (C1D28)
[79] - n=95 (C1D1), 12 (C1D7), 7 (C1D14), 63 (C1D28)
[80] - n=24 (C1D1), 0 (C1D7), 0 (C1D14), 24 (C1D28)
[81] - n=4 (C1D1), 0 (C1D7), 0 (C1D14), 3 (C1D28)

No statistical analyses for this end point

Secondary: All study parts: Maximum observed plasma concentration (Cmax) of NJI765 (NIR178 metabolite)

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End point title

All study parts: Maximum observed plasma concentration (Cmax) of NJI765 (NIR178 metabolite) ^[82]

End point description

NJI765 is a NIR178 metabolite. PK parameters were calculated based on NJI765 plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed plasma concentration following a dose. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.

End point type

Secondary

End point timeframe

Notes
[82] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Patients from the same ethnicity (Non-Japanese, Japanese) treated with the same formulation (capsule, tablet) at the same NIR178 dose level are pooled together.

End point values	JSR: 80 mg cont	JSR: 160 mg cont	JSR: 240 mg cont	NIR178 160 mg capsule in Non-Japanese (Part 1 and 2)	NIR178 240 mg capsule in Non-Japanese (Part 1)	NIR178 160 mg tablet in Non-Japanese (Part 3)
Number of subjects analysed	2 ^[83]	3 ^[84]	3 ^[85]	201 ^[86]	54 ^[87]	6 ^[88]
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1 (all regimens)	999 ± 999	25.9 ± 77.0	28.5 ± 99.9	25.5 ± 85.2	33.7 ± 64.2	20.1 ± 99.2
Cycle 1 Day 7 (1 wk-on/1 wk-off)	999 ± 999	999 ± 999	999 ± 999	62.9 ± 39.4	999 ± 999	999 ± 999
Cycle 1 Day 14 (2 wk-on/2 wk-off)	999 ± 999	999 ± 999	999 ± 999	71.3 ± 43.3	999 ± 999	999 ± 999
Cycle 1 Day 28 (continuous)	45.6 ± 74.0	53.9 ± 64.2	111 ± 36.6	42.6 ± 77.3	77.3 ± 49.9	54.1 ± 102.4

Notes
[83] - n=0 (C1D1), 0 (C1D7), 0 (C1D14), 2 (C1D28)
[84] - n=3 (C1D1), 0 (C1D7), 0 (C1D14), 3 (C1D28)
[85] - n=3 (C1D1), 0 (C1D7), 0 (C1D14), 3 (C1D28)
[86] - n=201 (C1D1), 17 (C1D7), 8 (C1D14), 96 (C1D28)
[87] - n=54 (C1D1), 0 (C1D7), 0 (C1D14), 40 (C1D28)
[88] - n=6 (C1D1), 0 (C1D7), 0 (C1D14), 4 (C1D28)

No statistical analyses for this end point

Secondary: All study parts: Time to reach maximum plasma concentration (Tmax) of NJI765 (NIR178 metabolite)

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End point title

All study parts: Time to reach maximum plasma concentration (Tmax) of NJI765 (NIR178 metabolite) ^[89]

End point description

NJI765 is a NIR178 metabolite. Pharmacokinetic (PK) parameters were calculated based on NJI765 plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) plasma concentration following a dose. Actual recorded sampling times were considered for the calculations. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.

End point type

Secondary

End point timeframe

Notes
[89] - 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: Patients from the same ethnicity (Non-Japanese, Japanese) treated with the same formulation (capsule, tablet) at the same NIR178 dose level are pooled together.

End point values	JSR: 80 mg cont	JSR: 160 mg cont	JSR: 240 mg cont	NIR178 160 mg capsule in Non-Japanese (Part 1 and 2)	NIR178 240 mg capsule in Non-Japanese (Part 1)	NIR178 160 mg tablet in Non-Japanese (Part 3)
Number of subjects analysed	2 ^[90]	3 ^[91]	3 ^[92]	201 ^[93]	54 ^[94]	6 ^[95]
Units: hours
median (full range (min-max))
Cycle 1 Day 1 (all regimens)	999 (999 to 999)	1.95 (0.583 to 2.00)	3.00 (2.03 to 3.03)	2.00 (0.250 to 8.05)	2.08 (0.50 to 8.00)	2.10 (0.450 to 4.05)
Cycle 1 Day 7 (1 wk-on/1 wk-off)	999 (999 to 999)	999 (999 to 999)	999 (999 to 999)	1.50 (0.50 to 4.00)	999 (999 to 999)	999 (999 to 999)
Cycle 1 Day 14 (2 wk-on/2 wk-off)	999 (999 to 999)	999 (999 to 999)	999 (999 to 999)	1.98 (0.550 to 3.00)	999 (999 to 999)	999 (999 to 999)
Cycle 1 Day 28 (continuous)	2.23 (1.43 to 3.02)	1.45 (0.50 to 1.50)	2.87 (1.92 to 4.00)	2.00 (0.483 to 8.03)	2.10 (0.250 to 7.88)	0.750 (0.50 to 2.03)

Notes
[90] - n=0 (C1D1), 0 (C1D7), 0 (C1D14), 2 (C1D28)
[91] - n=3 (C1D1), 0 (C1D7), 0 (C1D14), 3 (C1D28)
[92] - n=3 (C1D1), 0 (C1D7), 0 (C1D14), 3 (C1D28)
[93] - n=201 (C1D1), 17 (C1D7), 8 (C1D14), 96 (C1D28)
[94] - n=54 (C1D1), 0 (C1D7), 0 (C1D14), 40 (C1D28)
[95] - n=6 (C1D1), 0 (C1D7), 0 (C1D14), 4 (C1D28)

No statistical analyses for this end point

Secondary: All study parts: Area under the plasma concentration-time curve from time zero to 12 hours post dose (AUC0-12hr) of NJI765 (NIR178 metabolite)

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End point title

All study parts: Area under the plasma concentration-time curve from time zero to 12 hours post dose (AUC0-12hr) of NJI765 (NIR178 metabolite) ^[96]

End point description

NJI765 is a NIR178 metabolite. PK parameters were calculated based on NJI765 plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC0-12hr calculation. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.

End point type

Secondary

End point timeframe

Notes
[96] - 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: Patients from the same ethnicity (Non-Japanese, Japanese) treated with the same formulation (capsule, tablet) at the same NIR178 dose level are pooled together.

End point values	JSR: 80 mg cont	JSR: 160 mg cont	JSR: 240 mg cont	NIR178 160 mg capsule in Non-Japanese (Part 1 and 2)	NIR178 240 mg capsule in Non-Japanese (Part 1)	NIR178 160 mg tablet in Non-Japanese (Part 3)
Number of subjects analysed	0 ^[97]	3 ^[98]	1 ^[99]	62 ^[100]	20 ^[101]	2 ^[102]
Units: hr*ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1 (all regimens)	±	117 ± 68.2	119 ± 999	98.2 ± 87.1	122 ± 75.6	77.1 ± 35.9
Cycle 1 Day 7 (1 wk-on/1 wk-off)	±	999 ± 999	999 ± 999	243 ± 57.5	999 ± 999	999 ± 999
Cycle 1 Day 14 (2 wk-on/2 wk-off)	±	999 ± 999	999 ± 999	288 ± 23.7	999 ± 999	999 ± 999
Cycle 1 Day 28 (continuous)	±	277 ± 69.0	362 ± 999	214 ± 76.6	382 ± 43.7	226 ± 147.0

Notes
[97] - No data available
[98] - n=3 (C1D1), 0 (C1D7), 0 (C1D14), 2 (C1D28)
[99] - n=1 (C1D1), 0 (C1D7), 0 (C1D14), 1 (C1D28)
[100] - n=62 (C1D1), 8 (C1D7), 5 (C1D14), 41 (C1D28)
[101] - n=20 (C1D1), 0 (C1D7), 0 (C1D14), 16 (C1D28)
[102] - n=2 (C1D1), 0 (C1D7), 0 (C1D14), 2 (C1D28)

No statistical analyses for this end point

Secondary: All study parts: Time to reach maximum serum concentration (Tmax) of PDR001

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End point title

All study parts: Time to reach maximum serum concentration (Tmax) of PDR001

End point description

PK parameters were calculated based on PDR001 serum concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) serum concentration following a dose. Actual recorded sampling times were considered for the calculations.

End point type

Secondary

End point timeframe

First dose (Cycle 1 Day 1 or Cycle 2 Day 1 for Japanese patients treated with NIR178 80 or 160 mg) and Cycle 3 Day 1: pre-infusion, 1, 168, 336, 504 and 672 hours after end of infusion. Average duration of infusion=30 minutes. 1 cycle=28 days

End point values	Non-Japanese patients	Japanese patients
Number of subjects analysed	257 ^[103]	3 ^[104]
Units: hours
median (full range (min-max))
First dose (Cycle 1 Day 1 or Cycle 2 Day 1)	1.50 (0.333 to 718)	1.50 (1.48 to 1.52)
Cycle 3 Day 1	1.50 (0.550 to 358)	1.65 (1.65 to 1.65)

Notes
[103] - n=257 (first dose), 132 (C3D1)
[104] - n=3 (first dose), 1 (C3D1)

No statistical analyses for this end point

Secondary: All study parts: Maximum observed serum concentration (Cmax) of PDR001

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End point title

All study parts: Maximum observed serum concentration (Cmax) of PDR001

End point description

PK parameters were calculated based on PDR001 serum concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed serum concentration following a dose. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.

End point type

Secondary

End point timeframe

End point values	Non-Japanese patients	Japanese patients
Number of subjects analysed	257 ^[105]	3 ^[106]
Units: µg/mL
geometric mean (geometric coefficient of variation)
First dose (Cycle 1 Day 1 or Cycle 2 Day 1)	93.2 ± 30.8	85.0 ± 12.8
Cycle 3 Day 1	126 ± 37.4	119 ± 999

Notes
[105] - n=257 (first dose), 132 (C3D1)
[106] - n=3 (first dose), 1 (C3D1)

No statistical analyses for this end point

Secondary: All study parts: Area under the serum concentration-time curve from time zero to 28 days post dose (AUC0-28day) of PDR001

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End point title

All study parts: Area under the serum concentration-time curve from time zero to 28 days post dose (AUC0-28day) of PDR001

End point description

PK parameters were calculated based on PDR001 serum concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC0-28day calculation. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.

End point type

Secondary

End point timeframe

End point values	Non-Japanese patients	Japanese patients
Number of subjects analysed	236 ^[107]	3 ^[108]
Units: day*µg/mL
geometric mean (geometric coefficient of variation)
First dose (Cycle 1 Day 1 or Cycle 2 Day 1)	1140 ± 31.2	1110 ± 13.9
Cycle 3 Day 1	2030 ± 41.3	999 ± 999

Notes
[107] - n=236 (first dose), 36 (C3D1)
[108] - n=3 (first dose), 0 (C3D1)

No statistical analyses for this end point

Post-hoc: All-Collected Deaths

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End point title

All-Collected Deaths ^[109]

End point description

On-treatment and post-treatment safety follow-up deaths were collected from first dose of study medication to 150 days after last dose of NIR178+PDR001. Survival follow-up deaths were collected from 151 days after last dose of NIR178+PDR001 until end of study. All deaths refer to the sum of on-treatment and post-treatment safety follow-up deaths plus survival follow-up deaths.

End point type

Post-hoc

End point timeframe

On-treatment and safety follow-up (FU) deaths: up to 4.3 years (Part 1), 5.1 years (Part 2), 0.9 years (Part 3) and 0.9 years (JSR). Survival FU deaths: up to 4.3 years (Part 1), 5.1 years (Part 2) and 0.9 years (Part 3) and 0.9 years (JSR)

Notes
[109] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: For the safety endpoints, patients at each study part with the same type of cancer who are treated at the same dose level and dosing schedule are pooled together, independently of the immune-oncology (IO) pretreatment status and RAS mutation status

End point values	Part 1: RCC naïve 160 mg	Part 1: Pancreatic 160 mg	Part 1: Urothelial 160 mg	Part 1: H-N pre 240 mg	Part 1: TNBC 160 mg	Part 1: DLBCL 160 mg	Part 1: DLBCL 240 mg	Part 1: mCRPC 240 mg	Part 2: NSCLC 160 mg cont	Part 2: NSCLC 160 mg 2wk-on/2wk-off	Part 2: NSCLC 160 mg 1wk-on/1wk-off	Part 3: TNBC 160 mg cont	JSR: 80 mg cont	JSR: 160 mg cont	JSR: 240 mg cont	Part 1: RCC naïve + pre 240 mg	Part 1: H-N naïve + pre 160 mg	Part 1: MSS CRC 160 mg	Part 1: Melanoma naïve + pre 160 mg
Number of subjects analysed	11 ^[110]	14 ^[111]	14 ^[112]	12 ^[113]	30 ^[114]	13 ^[115]	6 ^[116]	15 ^[117]	22 ^[118]	20 ^[119]	20 ^[120]	6 ^[121]	3 ^[122]	3 ^[123]	3 ^[124]	23 ^[125]	26 ^[126]	58 ^[127]	16 ^[128]
Units: participants
On-treatment and post-treatment safety FU deaths	4	10	6	4	9	9	2	2	6	4	6	4	2	0	1	6	8	22	7
Survival FU deaths	3	3	4	4	12	2	3	7	8	9	7	1	0	0	1	7	12	22	8
All deaths	7	13	10	8	21	11	5	9	14	13	13	5	2	0	2	13	20	44	15

Notes
[110] - n=11 (on-treatment and safety FU), 7 (survival FU), 11 (all)
[111] - n=14 (on-treatment and safety FU), 4 (survival FU), 14 (all)
[112] - n=14 (on-treatment and safety FU), 8 (survival FU), 14 (all)
[113] - n=12 (on-treatment and safety FU), 8 (survival FU), 12 (all)
[114] - n=30 (on-treatment and safety FU), 21 (survival FU), 30 (all)
[115] - n=13 (on-treatment and safety FU), 4 (survival FU), 13 (all)
[116] - n=6 (on-treatment and safety FU), 4 (survival FU), 6 (all)
[117] - n=15 (on-treatment and safety FU), 13 (survival FU), 15 (all)
[118] - n=22 (on-treatment and safety FU), 16 (survival FU), 22 (all)
[119] - n=20 (on-treatment and safety FU), 16 (survival FU), 20 (all)
[120] - n=20 (on-treatment and safety FU), 14 (survival FU), 20 (all)
[121] - n=6 (on-treatment and safety FU), 2 (survival FU), 6 (all)
[122] - n=3 (on-treatment and safety FU), 0 (survival FU), 3 (all)
[123] - n=3 (on-treatment and safety FU), 0 (survival FU), 3 (all)
[124] - n=3 (on-treatment and safety FU), 1 (survival FU), 3 (all)
[125] - n=23 (on-treatment and safety FU), 17 (survival FU), 23 (all)
[126] - n=26 (on-treatment and safety FU), 18 (survival FU), 26 (all)
[127] - n=58 (on-treatment and safety FU), 36 (survival FU), 58 (all)
[128] - n=16 (on-treatment and safety FU), 9 (survival FU), 16 (all)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

AEs were collected from first dose of study treatment to 150 days after last dose of NIR178+PDR001, up to 4.3 years (Part 1), 5.1 years (Part 2), 0.9 years (Part 3) and 0.9 years (Japan safety run-in; JSR).

Adverse event reporting additional description

Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.0

Reporting group title

Part 1: RCC naïve 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with renal cell carcinoma (RCC) who had not been previously treated with immuno-oncology therapy

Reporting group title

Part 1: RCC naïve + pre 240 mg

Reporting group description

NIR178 240 mg twice daily continuous in combination with PDR001 in patients with renal cell carcinoma (RCC), naïve and pretreated with immuno-oncology therapy

Reporting group title

Part 1: mCRPC 240 mg

Reporting group description

NIR178 240 mg twice daily continuous in combination with PDR001 in patients with metastatic castration resistant prostate cancer (mCRPC)

Reporting group title

Part 1: DLBCL 240 mg

Reporting group description

NIR178 240 mg twice daily continuous in combination with PDR001 in patients with diffuse large B-cell lymphoma (DLBCL)

Reporting group title

Part 1: DLBCL 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with diffuse large B-cell lymphoma (DLBCL)

Reporting group title

Part 1: Melanoma naïve + pre 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with cutaneous melanoma, naïve and pretreated with immuno-oncology therapy

Reporting group title

Part 1: TNBC 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with triple negative breast cancer (TNBC)

Reporting group title

Part 1: MSS CRC 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with microsatellite stable colorectal cancer (MSS CRC) and RAS wildtype, RAS mutant and RAS unknown status

Reporting group title

Part 1: Pancreatic 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with pancreatic cancer

Reporting group title

Part 1: Urothelial 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with urothelial cancer

Reporting group title

Part 1: H-N naïve + pre 160 mg

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with squamous cell carcinoma of head and neck (HNSCC), naïve and pretreated with immuno-oncology therapy

Reporting group title

Part 1: H-N pre 240 mg

Reporting group description

NIR178 240 mg twice daily continuous in combination with PDR001 in patients with squamous cell carcinoma of head and neck (HNSCC) who had been pretreated with immuno-oncology therapy

Reporting group title

Part 2: NSCLC 160 mg 2wk-on/2wk-off

Reporting group description

NIR178 160 mg twice daily 2 weeks on/2 weeks off in combination with PDR001 in patients with non-small cell lung cancer (NSCLC)

Reporting group title

Part 2: NSCLC 160 mg cont

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with non-small cell lung cancer (NSCLC)

Reporting group title

JSR: 160 mg cont

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 (starting Cycle 2 Day 1) in the Japan safety run-in

Reporting group title

JSR: 80 mg cont

Reporting group description

NIR178 80 mg twice daily continuous in combination with PDR001 (starting Cycle 2 Day 1) in the Japan safety run-in

Reporting group title

Part 3: TNBC 160 mg cont

Reporting group description

NIR178 160 mg twice daily continuous in combination with PDR001 in patients with triple negative breast cancer (TNBC)

Reporting group title

Part 2: NSCLC 160 mg 1wk-on/1wk-off

Reporting group description

NIR178 160 mg twice daily 1 week on/1 week off in combination with PDR001 in patients with non-small cell lung cancer (NSCLC)

Reporting group title

JSR: 240 mg cont

Reporting group description

NIR178 140 mg twice daily continuous in combination with PDR001 (starting Cycle 1 Day 1) in the Japan safety run-in

Part 1: RCC naïve 160 mg

Part 1: RCC naïve + pre 240 mg

Part 1: mCRPC 240 mg

Part 1: DLBCL 240 mg

Part 1: DLBCL 160 mg

Part 1: Melanoma naïve + pre 160 mg

Part 1: TNBC 160 mg

Part 1: MSS CRC 160 mg

Part 1: Pancreatic 160 mg

Part 1: Urothelial 160 mg

Part 1: H-N naïve + pre 160 mg

Part 1: H-N pre 240 mg

Part 2: NSCLC 160 mg 2wk-on/2wk-off

Part 2: NSCLC 160 mg cont

JSR: 160 mg cont

JSR: 80 mg cont

Part 3: TNBC 160 mg cont

Part 2: NSCLC 160 mg 1wk-on/1wk-off

JSR: 240 mg cont

Total subjects affected by serious adverse events

subjects affected / exposed

3 / 11 (27.27%)

7 / 23 (30.43%)

5 / 15 (33.33%)

0 / 6 (0.00%)

7 / 13 (53.85%)

4 / 16 (25.00%)

14 / 30 (46.67%)

28 / 58 (48.28%)

9 / 14 (64.29%)

7 / 14 (50.00%)

16 / 26 (61.54%)

5 / 12 (41.67%)

9 / 20 (45.00%)

11 / 22 (50.00%)

1 / 3 (33.33%)

2 / 3 (66.67%)

3 / 6 (50.00%)

7 / 20 (35.00%)

1 / 3 (33.33%)

number of deaths (all causes)

number of deaths resulting from adverse events

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

Cancer pain

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

1 / 26 (3.85%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Metastases to central nervous system

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Metastases to meninges

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

1 / 30 (3.33%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Neoplasm progression

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

1 / 15 (6.67%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pulmonary tumour thrombotic microangiopathy

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

1 / 22 (4.55%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Squamous cell carcinoma of the tongue

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

1 / 26 (3.85%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Tumour haemorrhage

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

1 / 26 (3.85%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Tumour pain

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

1 / 30 (3.33%)

1 / 58 (1.72%)

1 / 14 (7.14%)

0 / 14 (0.00%)

0 / 26 (0.00%)

1 / 12 (8.33%)

1 / 20 (5.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 2

0 / 1

0 / 0

0 / 2

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vascular disorders

Aortic aneurysm

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

1 / 6 (16.67%)

1 / 20 (5.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

General disorders and administration site conditions

Chest pain

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 20 (5.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Disease progression

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

1 / 30 (3.33%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Face oedema

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

1 / 26 (3.85%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Fatigue

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

1 / 15 (6.67%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

1 / 22 (4.55%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

General physical health deterioration

subjects affected / exposed

1 / 11 (9.09%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

2 / 13 (15.38%)

1 / 16 (6.25%)

0 / 30 (0.00%)

1 / 58 (1.72%)

2 / 14 (14.29%)

0 / 14 (0.00%)

2 / 26 (7.69%)

0 / 12 (0.00%)

1 / 20 (5.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

1 / 6 (16.67%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 3

0 / 1

0 / 0

0 / 1

0 / 2

0 / 0

0 / 3

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 1

0 / 0

0 / 2

0 / 1

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

Generalised oedema

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

1 / 14 (7.14%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Oedema peripheral

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pyrexia

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

1 / 13 (7.69%)

0 / 16 (0.00%)

1 / 30 (3.33%)

4 / 58 (6.90%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

2 / 4

0 / 0

deaths causally related to treatment / all

0 / 0

Reproductive system and breast disorders

Female genital tract fistula

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

1 / 14 (7.14%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Peyronie's disease

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

1 / 12 (8.33%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory, thoracic and mediastinal disorders

Chronic obstructive pulmonary disease

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 20 (5.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Cough

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Dyspnoea

subjects affected / exposed

1 / 11 (9.09%)

1 / 23 (4.35%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

2 / 30 (6.67%)

3 / 58 (5.17%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

2 / 22 (9.09%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 20 (5.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

0 / 3

0 / 0

1 / 3

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Haemoptysis

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hydrothorax

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

1 / 30 (3.33%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Interstitial lung disease

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

1 / 30 (3.33%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Mediastinal disorder

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

1 / 30 (3.33%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Pleural effusion

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

1 / 30 (3.33%)

0 / 58 (0.00%)

0 / 14 (0.00%)

1 / 14 (7.14%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

1 / 22 (4.55%)

0 / 3 (0.00%)

1 / 6 (16.67%)

3 / 20 (15.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 4

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumothorax

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

1 / 22 (4.55%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pulmonary embolism

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

1 / 30 (3.33%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pulmonary haemorrhage

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

1 / 26 (3.85%)

0 / 12 (0.00%)

1 / 20 (5.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Respiratory failure

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

2 / 20 (10.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

Investigations

Alanine aminotransferase increased

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

2 / 58 (3.45%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Amylase increased

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

1 / 22 (4.55%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Aspartate aminotransferase increased

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

2 / 58 (3.45%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Blood bilirubin increased

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

3 / 58 (5.17%)

1 / 14 (7.14%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 3

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blood creatine phosphokinase increased

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

1 / 15 (6.67%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

1 / 14 (7.14%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blood creatinine increased

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

1 / 26 (3.85%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Electrocardiogram QT prolonged

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

1 / 22 (4.55%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

General physical condition abnormal

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

1 / 13 (7.69%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 20 (5.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Hepatic enzyme increased

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

1 / 26 (3.85%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Lipase increased

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

1 / 22 (4.55%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Troponin I increased

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

1 / 15 (6.67%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Injury, poisoning and procedural complications

Fall

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 20 (5.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Multiple injuries

subjects affected / exposed

0 / 11 (0.00%)

1 / 23 (4.35%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Overdose

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

1 / 14 (7.14%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac disorders

Atrial tachycardia

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

1 / 20 (5.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Autoimmune myocarditis

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

1 / 15 (6.67%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cardiac failure

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

1 / 22 (4.55%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Myocardial infarction

subjects affected / exposed

1 / 11 (9.09%)

1 / 23 (4.35%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Supraventricular tachycardia

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

1 / 30 (3.33%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pericardial effusion

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

1 / 20 (5.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

1 / 3 (33.33%)

0 / 6 (0.00%)

2 / 20 (10.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Nervous system disorders

Cerebral haemorrhage

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

1 / 30 (3.33%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Cerebral infarction

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

1 / 12 (8.33%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cerebrospinal fluid leakage

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

1 / 20 (5.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cerebrovascular accident

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

1 / 22 (4.55%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Migraine

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Paraesthesia

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Seizure

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Spinal cord compression

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

1 / 16 (6.25%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

1 / 26 (3.85%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Syncope

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

1 / 16 (6.25%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Blood and lymphatic system disorders

Anaemia

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

1 / 15 (6.67%)

0 / 6 (0.00%)

1 / 13 (7.69%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Febrile neutropenia

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Neutropenia

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

1 / 13 (7.69%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Eye disorders

Blindness

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

1 / 26 (3.85%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gaze palsy

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

1 / 30 (3.33%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Gastrointestinal disorders

Abdominal pain

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

1 / 13 (7.69%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

1 / 14 (7.14%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 20 (5.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Ascites

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

2 / 58 (3.45%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 20 (5.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Constipation

subjects affected / exposed

1 / 11 (9.09%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Colonic fistula

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

1 / 14 (7.14%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Diarrhoea

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

1 / 26 (3.85%)

1 / 12 (8.33%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Duodenal ulcer

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

1 / 30 (3.33%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Dysphagia

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

1 / 13 (7.69%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Ileus

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Intestinal obstruction

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Large intestinal obstruction

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nausea

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

1 / 20 (5.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

1 / 3 (33.33%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Pancreatitis

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

1 / 20 (5.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Rectal haemorrhage

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

1 / 14 (7.14%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Small intestinal obstruction

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vomiting

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

1 / 13 (7.69%)

0 / 16 (0.00%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

1 / 22 (4.55%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

1 / 3 (33.33%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

deaths causally related to treatment / all

0 / 0

Upper gastrointestinal haemorrhage

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

1 / 14 (7.14%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hepatobiliary disorders

Autoimmune hepatitis

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

2 / 58 (3.45%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

2 / 22 (9.09%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Cholangitis

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

1 / 14 (7.14%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cholecystitis

subjects affected / exposed

0 / 11 (0.00%)

1 / 23 (4.35%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hepatic failure

subjects affected / exposed

0 / 11 (0.00%)

1 / 23 (4.35%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hepatic haemorrhage

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Hepatitis

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

1 / 15 (6.67%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hyperbilirubinaemia

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

3 / 58 (5.17%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 3

0 / 0

deaths causally related to treatment / all

0 / 0

Immune-mediated hepatitis

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

1 / 3 (33.33%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Liver disorder

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

1 / 15 (6.67%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Skin and subcutaneous tissue disorders

Erythema multiforme

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

1 / 20 (5.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Rash

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

1 / 14 (7.14%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Stevens-Johnson syndrome

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

1 / 20 (5.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Renal and urinary disorders

Acute kidney injury

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

1 / 30 (3.33%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 20 (5.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Haematuria

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

1 / 14 (7.14%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Nephrolithiasis

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 20 (5.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Renal impairment

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

1 / 13 (7.69%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Endocrine disorders

Adrenal insufficiency

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

2 / 22 (9.09%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Hyperthyroidism

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Musculoskeletal and connective tissue disorders

Arthralgia

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Autoimmune myositis

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

1 / 15 (6.67%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

2 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Back pain

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

1 / 16 (6.25%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

1 / 14 (7.14%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Bone pain

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

1 / 20 (5.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Flank pain

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pain in extremity

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

1 / 30 (3.33%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Sacral pain

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

1 / 26 (3.85%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Infections and infestations

Bronchitis

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

1 / 16 (6.25%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Cellulitis

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

1 / 22 (4.55%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Encephalitis

subjects affected / exposed

0 / 11 (0.00%)

1 / 23 (4.35%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Enterocolitis infectious

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

1 / 14 (7.14%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Herpes zoster

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Infection

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Influenza

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

1 / 26 (3.85%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Large intestine infection

subjects affected / exposed

1 / 11 (9.09%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Peritonitis

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

1 / 20 (5.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Pleural infection

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

1 / 20 (5.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Pneumonia

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

1 / 14 (7.14%)

3 / 26 (11.54%)

0 / 12 (0.00%)

1 / 20 (5.00%)

2 / 22 (9.09%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

0 / 1

0 / 3

0 / 0

0 / 1

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Pneumonia aspiration

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

1 / 26 (3.85%)

1 / 12 (8.33%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Scrotal abscess

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

1 / 15 (6.67%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Sepsis

subjects affected / exposed

0 / 11 (0.00%)

1 / 23 (4.35%)

0 / 15 (0.00%)

0 / 6 (0.00%)

1 / 13 (7.69%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

1 / 14 (7.14%)

2 / 14 (14.29%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

1 / 1

0 / 0

0 / 1

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

0 / 1

0 / 0

Urinary tract infection

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

1 / 14 (7.14%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Urogenital infection bacterial

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

1 / 15 (6.67%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Vascular device infection

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

1 / 30 (3.33%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 2

0 / 0

deaths causally related to treatment / all

0 / 0

Metabolism and nutrition disorders

Decreased appetite

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Diabetic ketoacidosis

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

1 / 58 (1.72%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hyperglycaemia

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

1 / 22 (4.55%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypervolaemia

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

1 / 20 (5.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hypokalaemia

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

1 / 22 (4.55%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

1 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

Hyponatraemia

subjects affected / exposed

0 / 11 (0.00%)

0 / 23 (0.00%)

0 / 15 (0.00%)

0 / 6 (0.00%)

0 / 13 (0.00%)

0 / 16 (0.00%)

0 / 30 (0.00%)

0 / 58 (0.00%)

0 / 14 (0.00%)

1 / 14 (7.14%)

0 / 26 (0.00%)

0 / 12 (0.00%)

0 / 20 (0.00%)

0 / 22 (0.00%)

0 / 3 (0.00%)

0 / 6 (0.00%)

0 / 20 (0.00%)

0 / 3 (0.00%)

occurrences causally related to treatment / all

0 / 0

0 / 1

0 / 0

deaths causally related to treatment / all

0 / 0

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

Non-serious adverse events	Part 1: RCC naïve 160 mg	Part 1: RCC naïve + pre 240 mg	Part 1: mCRPC 240 mg	Part 1: DLBCL 240 mg	Part 1: DLBCL 160 mg	Part 1: Melanoma naïve + pre 160 mg	Part 1: TNBC 160 mg	Part 1: MSS CRC 160 mg	Part 1: Pancreatic 160 mg	Part 1: Urothelial 160 mg	Part 1: H-N naïve + pre 160 mg	Part 1: H-N pre 240 mg	Part 2: NSCLC 160 mg 2wk-on/2wk-off	Part 2: NSCLC 160 mg cont	JSR: 160 mg cont	JSR: 80 mg cont	Part 3: TNBC 160 mg cont	Part 2: NSCLC 160 mg 1wk-on/1wk-off	JSR: 240 mg cont
Total subjects affected by non serious adverse events
subjects affected / exposed	10 / 11 (90.91%)	22 / 23 (95.65%)	14 / 15 (93.33%)	5 / 6 (83.33%)	13 / 13 (100.00%)	14 / 16 (87.50%)	29 / 30 (96.67%)	52 / 58 (89.66%)	14 / 14 (100.00%)	14 / 14 (100.00%)	25 / 26 (96.15%)	12 / 12 (100.00%)	16 / 20 (80.00%)	22 / 22 (100.00%)	2 / 3 (66.67%)	3 / 3 (100.00%)	6 / 6 (100.00%)	17 / 20 (85.00%)	3 / 3 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hypergammaglobulinaemia benign monoclonal
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0
Neoplasm progression
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Seborrhoeic keratosis
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Tumour pain
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	2 / 30 (6.67%)	3 / 58 (5.17%)	0 / 14 (0.00%)	1 / 14 (7.14%)	1 / 26 (3.85%)	1 / 12 (8.33%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	2	4	0	1	1	1	0	0	0	0	1	0	0
Vascular disorders
Angiopathy
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Flushing
subjects affected / exposed	0 / 11 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	1 / 58 (1.72%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	1	0	1	0	0	0	0	0	0	0	0	0
Haematoma
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	1	0	0	0	0	0	0	0	0	0	1	0	0
Hot flush
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	1 / 15 (6.67%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	1 / 58 (1.72%)	1 / 14 (7.14%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	1	0	0	0	0	1	1	1	0	0	1	0	0	0	1	0	0
Hypertension
subjects affected / exposed	0 / 11 (0.00%)	1 / 23 (4.35%)	2 / 15 (13.33%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	2 / 30 (6.67%)	2 / 58 (3.45%)	0 / 14 (0.00%)	2 / 14 (14.29%)	1 / 26 (3.85%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	1 / 3 (33.33%)
occurrences all number	0	1	3	0	1	0	3	4	0	2	1	0	0	0	0	0	0	1	1
Raynaud's phenomenon
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Lymphoedema
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	1	0	0
Hypotension
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	1 / 14 (7.14%)	1 / 14 (7.14%)	0 / 26 (0.00%)	1 / 12 (8.33%)	0 / 20 (0.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	1	2	0	2	0	1	0	0	0	1	0
Superficial vein thrombosis
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	2 / 14 (14.29%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	3	0	0	0	0	0	0	0	0	0	0
General disorders and administration site conditions
Administration site bruise
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Asthenia
subjects affected / exposed	2 / 11 (18.18%)	5 / 23 (21.74%)	1 / 15 (6.67%)	0 / 6 (0.00%)	2 / 13 (15.38%)	4 / 16 (25.00%)	5 / 30 (16.67%)	3 / 58 (5.17%)	1 / 14 (7.14%)	2 / 14 (14.29%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	2 / 22 (9.09%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	3	5	1	0	2	5	7	3	1	2	0	0	0	2	0	0	4	0	0
Axillary pain
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0
Catheter site oedema
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0
Chest discomfort
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	2 / 58 (3.45%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	2 / 20 (10.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	2	0	0	0	0	2	1	0	0	0	0	0
Discomfort
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Face oedema
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	3 / 26 (11.54%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	3	0	0	0	0	0	0	0	0
Chills
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 16 (6.25%)	2 / 30 (6.67%)	4 / 58 (6.90%)	0 / 14 (0.00%)	1 / 14 (7.14%)	3 / 26 (11.54%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	2	4	0	1	3	0	0	0	0	0	0	0	0
Chest pain
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	4 / 30 (13.33%)	2 / 58 (3.45%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)	0 / 22 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	1 / 6 (16.67%)	3 / 20 (15.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	2	0	5	2	0	0	0	0	1	0	1	0	1	4	0
Fatigue
subjects affected / exposed	4 / 11 (36.36%)	5 / 23 (21.74%)	4 / 15 (26.67%)	0 / 6 (0.00%)	1 / 13 (7.69%)	3 / 16 (18.75%)	10 / 30 (33.33%)	20 / 58 (34.48%)	5 / 14 (35.71%)	2 / 14 (14.29%)	11 / 26 (42.31%)	3 / 12 (25.00%)	6 / 20 (30.00%)	11 / 22 (50.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	3 / 6 (50.00%)	5 / 20 (25.00%)	1 / 3 (33.33%)
occurrences all number	4	5	4	0	1	3	11	21	5	2	13	3	6	12	0	1	3	6	1
Feeling of body temperature change
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0
Gait disturbance
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	1 / 58 (1.72%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
General physical health deterioration
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	1	0	0	0	0	0	0
Influenza like illness
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	2 / 26 (7.69%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	2	0	0	0	0	0	0	0	0
Malaise
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	3 / 58 (5.17%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	3	0	0	0	0	0	1	0	1	0	1	0
Oedema
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	2 / 30 (6.67%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	0	0	0	0	0	0	0	0	1	0
Non-cardiac chest pain
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	1 / 58 (1.72%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 26 (3.85%)	0 / 12 (0.00%)	1 / 20 (5.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	1	0	0	1	0	0	1	0	1	1	0	0	2	1	0
Oedema peripheral
subjects affected / exposed	2 / 11 (18.18%)	2 / 23 (8.70%)	1 / 15 (6.67%)	1 / 6 (16.67%)	2 / 13 (15.38%)	0 / 16 (0.00%)	2 / 30 (6.67%)	5 / 58 (8.62%)	2 / 14 (14.29%)	3 / 14 (21.43%)	2 / 26 (7.69%)	0 / 12 (0.00%)	0 / 20 (0.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	4 / 20 (20.00%)	0 / 3 (0.00%)
occurrences all number	2	2	1	1	2	0	2	6	3	3	3	0	0	2	0	0	0	4	0
Peripheral swelling
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	1 / 58 (1.72%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 20 (10.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	3	0
Pain
subjects affected / exposed	0 / 11 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	2 / 16 (12.50%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	4 / 20 (20.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	2	0	0	0	0	0	0	4	0	0	0	0	0	0
Pyrexia
subjects affected / exposed	1 / 11 (9.09%)	2 / 23 (8.70%)	2 / 15 (13.33%)	1 / 6 (16.67%)	4 / 13 (30.77%)	0 / 16 (0.00%)	9 / 30 (30.00%)	9 / 58 (15.52%)	1 / 14 (7.14%)	4 / 14 (28.57%)	4 / 26 (15.38%)	0 / 12 (0.00%)	4 / 20 (20.00%)	2 / 22 (9.09%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 20 (5.00%)	1 / 3 (33.33%)
occurrences all number	1	3	2	1	4	0	12	14	5	7	5	0	5	3	0	0	1	1	1
Swelling face
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	1 / 12 (8.33%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Balanoposthitis
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Breast oedema
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0
Peyronie's disease
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	1 / 12 (8.33%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Pelvic pain
subjects affected / exposed	1 / 11 (9.09%)	1 / 23 (4.35%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 26 (3.85%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	1	1	0	0	0	0	1	0	0	0	1	0	0	0	0	0	0	1	0
Intermenstrual bleeding
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1
Breast pain
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	2 / 30 (6.67%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	0	0	0	0	0	0	0	2	0	0
Vaginal discharge
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea exertional
subjects affected / exposed	1 / 11 (9.09%)	1 / 23 (4.35%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	2 / 30 (6.67%)	2 / 58 (3.45%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	2 / 20 (10.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	1	1	0	0	0	0	2	2	0	0	0	0	2	0	0	0	0	1	0
Dyspnoea
subjects affected / exposed	1 / 11 (9.09%)	1 / 23 (4.35%)	1 / 15 (6.67%)	0 / 6 (0.00%)	2 / 13 (15.38%)	1 / 16 (6.25%)	6 / 30 (20.00%)	8 / 58 (13.79%)	2 / 14 (14.29%)	4 / 14 (28.57%)	2 / 26 (7.69%)	1 / 12 (8.33%)	1 / 20 (5.00%)	5 / 22 (22.73%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 6 (16.67%)	5 / 20 (25.00%)	0 / 3 (0.00%)
occurrences all number	1	1	1	0	2	1	7	9	2	4	2	1	1	5	0	1	1	5	0
Dysphonia
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	1 / 12 (8.33%)	0 / 20 (0.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	0	0	1	0	1	0	0	0	0	0
Cough
subjects affected / exposed	0 / 11 (0.00%)	2 / 23 (8.70%)	2 / 15 (13.33%)	0 / 6 (0.00%)	2 / 13 (15.38%)	1 / 16 (6.25%)	10 / 30 (33.33%)	11 / 58 (18.97%)	2 / 14 (14.29%)	4 / 14 (28.57%)	4 / 26 (15.38%)	0 / 12 (0.00%)	2 / 20 (10.00%)	6 / 22 (27.27%)	1 / 3 (33.33%)	1 / 3 (33.33%)	0 / 6 (0.00%)	3 / 20 (15.00%)	0 / 3 (0.00%)
occurrences all number	0	3	2	0	2	1	12	13	2	6	5	0	2	6	1	1	0	4	0
Epistaxis
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	1 / 58 (1.72%)	0 / 14 (0.00%)	0 / 14 (0.00%)	2 / 26 (7.69%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	1	0	0	2	0	0	0	0	0	0	0	0
Pleural effusion
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 16 (6.25%)	1 / 30 (3.33%)	1 / 58 (1.72%)	0 / 14 (0.00%)	2 / 14 (14.29%)	1 / 26 (3.85%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 6 (16.67%)	2 / 20 (10.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	1	1	0	2	1	0	0	0	0	1	1	3	0
Oropharyngeal pain
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	2 / 58 (3.45%)	0 / 14 (0.00%)	0 / 14 (0.00%)	2 / 26 (7.69%)	0 / 12 (0.00%)	1 / 20 (5.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	3	0	0	2	0	1	1	0	0	0	0	0
Nasal congestion
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	2 / 58 (3.45%)	0 / 14 (0.00%)	1 / 14 (7.14%)	1 / 26 (3.85%)	0 / 12 (0.00%)	0 / 20 (0.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	1	1	0	0	1	0	0	0	0	0
Haemoptysis
subjects affected / exposed	0 / 11 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 58 (1.72%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	4 / 20 (20.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	1	0	1	0	0	0	0	4	1	0	0	0	1	0
Productive cough
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	2 / 58 (3.45%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 26 (3.85%)	0 / 12 (0.00%)	0 / 20 (0.00%)	2 / 22 (9.09%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 20 (10.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	3	0	0	1	0	0	4	0	0	0	2	0
Respiratory failure
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Rhinalgia
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Rhinorrhoea
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	1 / 6 (16.67%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	1 / 58 (1.72%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	3 / 22 (13.64%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	1	0	0	1	0	0	0	0	0	3	0	0	0	0	0
Sputum retention
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0
Tonsillar erythema
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Psychiatric disorders
Confusional state
subjects affected / exposed	0 / 11 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0
Anxiety
subjects affected / exposed	0 / 11 (0.00%)	2 / 23 (8.70%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	3 / 30 (10.00%)	1 / 58 (1.72%)	1 / 14 (7.14%)	0 / 14 (0.00%)	1 / 26 (3.85%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	1	0	3	1	1	0	1	0	0	0	0	0	1	1	0
Depression
subjects affected / exposed	0 / 11 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	4 / 58 (6.90%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	2	0	1	0	0	0	5	1	0	0	0	0	1	0	0	0	0	0
Mood altered
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	1 / 58 (1.72%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	1	0	0	0	0	0	0	0	0	0
Panic disorder
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Hallucination
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	1 / 58 (1.72%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Insomnia
subjects affected / exposed	0 / 11 (0.00%)	3 / 23 (13.04%)	2 / 15 (13.33%)	0 / 6 (0.00%)	2 / 13 (15.38%)	0 / 16 (0.00%)	1 / 30 (3.33%)	4 / 58 (6.90%)	2 / 14 (14.29%)	2 / 14 (14.29%)	1 / 26 (3.85%)	0 / 12 (0.00%)	3 / 20 (15.00%)	3 / 22 (13.64%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 20 (15.00%)	1 / 3 (33.33%)
occurrences all number	0	4	2	0	3	0	1	4	2	2	1	0	3	3	0	0	0	3	1
Restlessness
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 16 (6.25%)	1 / 30 (3.33%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	1	0	0	0	0	0	0	0	0	0	0	0	0
Sleep disorder
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	1 / 15 (6.67%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	2 / 58 (3.45%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	1	0	1	0	0	2	0	0	0	0	0	0	0	0	0	0	0
Stress
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	2 / 11 (18.18%)	2 / 23 (8.70%)	3 / 15 (20.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	1 / 16 (6.25%)	9 / 30 (30.00%)	11 / 58 (18.97%)	0 / 14 (0.00%)	2 / 14 (14.29%)	3 / 26 (11.54%)	1 / 12 (8.33%)	4 / 20 (20.00%)	2 / 22 (9.09%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	2	3	3	1	0	1	14	13	0	2	3	2	4	3	0	1	0	0	0
Amylase increased
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	4 / 15 (26.67%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	2 / 30 (6.67%)	1 / 58 (1.72%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	1 / 12 (8.33%)	1 / 20 (5.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 20 (10.00%)	0 / 3 (0.00%)
occurrences all number	1	0	6	0	0	0	2	1	0	1	0	1	1	1	0	0	0	5	0
Aspartate aminotransferase increased
subjects affected / exposed	2 / 11 (18.18%)	2 / 23 (8.70%)	3 / 15 (20.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	1 / 16 (6.25%)	9 / 30 (30.00%)	14 / 58 (24.14%)	1 / 14 (7.14%)	2 / 14 (14.29%)	3 / 26 (11.54%)	1 / 12 (8.33%)	4 / 20 (20.00%)	2 / 22 (9.09%)	0 / 3 (0.00%)	1 / 3 (33.33%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 3 (33.33%)
occurrences all number	4	3	3	0	1	1	12	19	1	2	3	2	4	2	0	1	0	0	1
Blood alkaline phosphatase increased
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	3 / 30 (10.00%)	3 / 58 (5.17%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	1 / 12 (8.33%)	3 / 20 (15.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 3 (33.33%)
occurrences all number	1	0	0	0	0	0	3	3	0	0	0	1	3	0	0	0	0	0	1
Bilirubin conjugated increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0
Blood bilirubin increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	4 / 58 (6.90%)	1 / 14 (7.14%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	4	1	1	0	0	0	0	0	0	0	0	0
Blood thyroid stimulating hormone increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	2 / 13 (15.38%)	0 / 16 (0.00%)	0 / 30 (0.00%)	1 / 58 (1.72%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	2	0	0	1	0	0	0	0	0	0	0	0	0	3	0
Blood creatine phosphokinase increased
subjects affected / exposed	0 / 11 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	4 / 58 (6.90%)	0 / 14 (0.00%)	1 / 14 (7.14%)	1 / 26 (3.85%)	1 / 12 (8.33%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	0	4	0	1	1	2	0	0	0	0	2	1	0
Blood creatinine increased
subjects affected / exposed	0 / 11 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)	1 / 6 (16.67%)	2 / 13 (15.38%)	2 / 16 (12.50%)	0 / 30 (0.00%)	2 / 58 (3.45%)	0 / 14 (0.00%)	3 / 14 (21.43%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	1	2	2	0	3	0	3	0	0	0	1	0	0	0	2	0
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	2	0	0	0	0	0	0	0	0	0	0	0	0	1	1
Blood phosphorus increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	1 / 58 (1.72%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 26 (3.85%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	1	0	0	2	0	0	0	0	0	0	0	0
C-reactive protein increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	2 / 15 (13.33%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 16 (6.25%)	1 / 30 (3.33%)	2 / 58 (3.45%)	0 / 14 (0.00%)	1 / 14 (7.14%)	1 / 26 (3.85%)	1 / 12 (8.33%)	1 / 20 (5.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	3	0	0	1	1	2	0	1	1	1	1	0	0	0	0	0	0
Eosinophil count increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)	1 / 6 (16.67%)	2 / 13 (15.38%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	1	2	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 11 (9.09%)	1 / 23 (4.35%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	3 / 30 (10.00%)	6 / 58 (10.34%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	1 / 12 (8.33%)	4 / 20 (20.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	1	0	0	0	0	3	6	0	1	0	1	4	0	0	0	0	0	0
Haemoglobin decreased
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
International normalised ratio increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 26 (0.00%)	1 / 12 (8.33%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	1	0	0	0	0	0	0	0
Human chorionic gonadotropin increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Lipase increased
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	4 / 15 (26.67%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 16 (6.25%)	1 / 30 (3.33%)	4 / 58 (6.90%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	1 / 12 (8.33%)	2 / 20 (10.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 20 (10.00%)	0 / 3 (0.00%)
occurrences all number	1	0	7	0	0	1	1	4	0	0	0	1	2	0	0	0	0	2	0
Oxygen saturation decreased
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Lymphocyte count decreased
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	1 / 58 (1.72%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	2 / 3 (66.67%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	0	0	0	0	0	1	0	2	0	0	0
Platelet count decreased
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	1 / 58 (1.72%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	1	0	0	0	0	0	0	0	0	0
SARS-CoV-2 test negative
subjects affected / exposed	0 / 11 (0.00%)	2 / 23 (8.70%)	1 / 15 (6.67%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	2	5	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Transaminases increased
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	0 / 58 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	1	0	0	0	0	0	0	0	0	0
SARS-CoV-2 test positive
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Weight decreased
subjects affected / exposed	0 / 11 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	2 / 58 (3.45%)	0 / 14 (0.00%)	0 / 14 (0.00%)	2 / 26 (7.69%)	0 / 12 (0.00%)	0 / 20 (0.00%)	2 / 22 (9.09%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	1	2	0	0	2	0	0	2	0	0	0	1	0
Injury, poisoning and procedural complications
Procedural pain
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	2 / 58 (3.45%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	1	0	0	0	0	0	0	0	0	0	0
Fall
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	1 / 58 (1.72%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Wound complication
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Wound necrosis
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	1	0
Bradycardia
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	1	0
Extrasystoles
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0
Coronary artery disease
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Cardiac failure congestive
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0
Palpitations
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	2 / 58 (3.45%)	1 / 14 (7.14%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	3	1	1	0	0	0	0	0	0	0	0	0
Pericardial effusion
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	1	0	0	0	0	1	0
Sinus bradycardia
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 26 (3.85%)	1 / 12 (8.33%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	1	1	0	0	0	0	0	0	0
Sinus tachycardia
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	2 / 13 (15.38%)	0 / 16 (0.00%)	0 / 30 (0.00%)	2 / 58 (3.45%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	2	0	0	2	0	0	0	0	0	0	0	0	0	0	0
Tachycardia
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 58 (1.72%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	1	2	0	0	0	0	0	0	0	0	0	0	0
Nervous system disorders
Anosmia
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0
Amnesia
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0
Dizziness
subjects affected / exposed	0 / 11 (0.00%)	2 / 23 (8.70%)	1 / 15 (6.67%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	4 / 30 (13.33%)	1 / 58 (1.72%)	5 / 14 (35.71%)	2 / 14 (14.29%)	1 / 26 (3.85%)	1 / 12 (8.33%)	1 / 20 (5.00%)	2 / 22 (9.09%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	5	3	0	1	0	5	1	5	2	1	1	1	2	0	0	1	1	0
Autonomic nervous system imbalance
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Aphasia
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	1 / 12 (8.33%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Dysaesthesia
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 58 (1.72%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	1	0	1	0	0	0	0	0	0	0	0	0
Dysgeusia
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	1 / 58 (1.72%)	0 / 14 (0.00%)	1 / 14 (7.14%)	1 / 26 (3.85%)	0 / 12 (0.00%)	0 / 20 (0.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	1	1	0	0	1	0	0	0	0	0
Neuropathy peripheral
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	1 / 58 (1.72%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Migraine
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Hypoaesthesia
subjects affected / exposed	1 / 11 (9.09%)	2 / 23 (8.70%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	2	0	0	0	0	1	0	0	0	0	0	0	1	0	0	0	0	0
Headache
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	1 / 16 (6.25%)	4 / 30 (13.33%)	3 / 58 (5.17%)	2 / 14 (14.29%)	1 / 14 (7.14%)	1 / 26 (3.85%)	2 / 12 (16.67%)	2 / 20 (10.00%)	4 / 22 (18.18%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	4	0	0	0	1	1	4	3	2	1	1	2	2	4	0	0	0	0	0
Paraesthesia
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	1 / 16 (6.25%)	3 / 30 (10.00%)	2 / 58 (3.45%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	1	2	4	2	0	1	0	0	1	0	0	0	0	0	0
Peripheral sensory neuropathy
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 58 (1.72%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	1	0	0	0	0	2	0	0	0	0	0
Presyncope
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0
Sciatica
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 16 (6.25%)	1 / 30 (3.33%)	1 / 58 (1.72%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	2	1	0	0	0	0	0	0	0	0	0	0	0
Seizure
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	1 / 12 (8.33%)	0 / 20 (0.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	1	0	0	0	0	0
Somnolence
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Tremor
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	0 / 58 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	1	0	0	0	0	0	0	0	0	0
Taste disorder
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Blood and lymphatic system disorders
Leukopenia
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	3	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Anaemia
subjects affected / exposed	0 / 11 (0.00%)	2 / 23 (8.70%)	2 / 15 (13.33%)	1 / 6 (16.67%)	3 / 13 (23.08%)	3 / 16 (18.75%)	4 / 30 (13.33%)	5 / 58 (8.62%)	3 / 14 (21.43%)	5 / 14 (35.71%)	5 / 26 (19.23%)	0 / 12 (0.00%)	3 / 20 (15.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 20 (15.00%)	0 / 3 (0.00%)
occurrences all number	0	2	2	1	3	4	5	7	3	5	5	0	3	1	0	0	0	3	0
Leukocytosis
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	2 / 14 (14.29%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	0	0	0	0	0	0	0	1	0
Lymphadenitis
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Neutropenia
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	1 / 6 (16.67%)	3 / 13 (23.08%)	0 / 16 (0.00%)	1 / 30 (3.33%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	7	0	2	0	0	0	0	0	1	0	0	0	0	0	0
Thrombocytopenia
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)	0 / 6 (0.00%)	2 / 13 (15.38%)	0 / 16 (0.00%)	0 / 30 (0.00%)	1 / 58 (1.72%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	2	0	0	1	1	0	0	0	0	0	0	0	0	0	0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 11 (0.00%)	1 / 23 (4.35%)	1 / 15 (6.67%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	2 / 58 (3.45%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 26 (3.85%)	1 / 12 (8.33%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	1	0	0	0	0	2	0	0	1	1	0	0	0	0	2	0	0
Eye disorders
Cataract
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	2 / 22 (9.09%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	3	0	0	0	0	0
Photopsia
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0
Vision blurred
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0
Abdominal distension
subjects affected / exposed	0 / 11 (0.00%)	3 / 23 (13.04%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	3 / 58 (5.17%)	0 / 14 (0.00%)	2 / 14 (14.29%)	0 / 26 (0.00%)	0 / 12 (0.00%)	3 / 20 (15.00%)	2 / 22 (9.09%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 20 (10.00%)	0 / 3 (0.00%)
occurrences all number	0	3	0	0	0	0	2	3	0	2	0	0	3	2	0	0	0	2	0
Abdominal pain upper
subjects affected / exposed	0 / 11 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	6 / 58 (10.34%)	2 / 14 (14.29%)	0 / 14 (0.00%)	1 / 26 (3.85%)	0 / 12 (0.00%)	1 / 20 (5.00%)	2 / 22 (9.09%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	0	0	6	2	0	1	0	1	2	0	0	0	0	0
Abdominal pain
subjects affected / exposed	1 / 11 (9.09%)	2 / 23 (8.70%)	2 / 15 (13.33%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 16 (6.25%)	2 / 30 (6.67%)	9 / 58 (15.52%)	4 / 14 (28.57%)	1 / 14 (7.14%)	3 / 26 (11.54%)	0 / 12 (0.00%)	1 / 20 (5.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	2	2	0	0	1	3	10	4	1	3	0	1	0	0	0	2	0	0
Diarrhoea
subjects affected / exposed	1 / 11 (9.09%)	8 / 23 (34.78%)	3 / 15 (20.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	3 / 30 (10.00%)	12 / 58 (20.69%)	0 / 14 (0.00%)	4 / 14 (28.57%)	4 / 26 (15.38%)	1 / 12 (8.33%)	1 / 20 (5.00%)	4 / 22 (18.18%)	0 / 3 (0.00%)	0 / 3 (0.00%)	3 / 6 (50.00%)	2 / 20 (10.00%)	0 / 3 (0.00%)
occurrences all number	1	9	3	0	1	0	3	12	0	9	8	1	1	4	0	0	3	6	0
Dental caries
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Ascites
subjects affected / exposed	0 / 11 (0.00%)	2 / 23 (8.70%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	4 / 58 (6.90%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	0	0	0	5	1	0	0	0	1	0	0	0	0	1	0
Constipation
subjects affected / exposed	1 / 11 (9.09%)	7 / 23 (30.43%)	2 / 15 (13.33%)	1 / 6 (16.67%)	3 / 13 (23.08%)	1 / 16 (6.25%)	2 / 30 (6.67%)	9 / 58 (15.52%)	1 / 14 (7.14%)	2 / 14 (14.29%)	4 / 26 (15.38%)	1 / 12 (8.33%)	3 / 20 (15.00%)	8 / 22 (36.36%)	1 / 3 (33.33%)	0 / 3 (0.00%)	2 / 6 (33.33%)	8 / 20 (40.00%)	1 / 3 (33.33%)
occurrences all number	1	7	2	1	3	1	2	9	1	3	4	1	4	11	1	0	2	9	1
Faeces soft
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	1 / 12 (8.33%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Dysphagia
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 16 (6.25%)	1 / 30 (3.33%)	0 / 58 (0.00%)	1 / 14 (7.14%)	1 / 14 (7.14%)	4 / 26 (15.38%)	0 / 12 (0.00%)	0 / 20 (0.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	1	1	0	1	1	4	0	0	1	0	0	0	0	0
Dyspepsia
subjects affected / exposed	2 / 11 (18.18%)	0 / 23 (0.00%)	1 / 15 (6.67%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	2 / 30 (6.67%)	4 / 58 (6.90%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	1 / 12 (8.33%)	2 / 20 (10.00%)	2 / 22 (9.09%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	3	0	1	0	0	0	3	4	0	0	0	1	2	2	0	0	0	0	0
Flatulence
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	1 / 15 (6.67%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	1 / 30 (3.33%)	5 / 58 (8.62%)	0 / 14 (0.00%)	1 / 14 (7.14%)	5 / 26 (19.23%)	1 / 12 (8.33%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	1	0	1	0	1	5	0	1	5	1	0	0	0	0	0	0	0
Dry mouth
subjects affected / exposed	1 / 11 (9.09%)	1 / 23 (4.35%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 16 (6.25%)	2 / 30 (6.67%)	2 / 58 (3.45%)	1 / 14 (7.14%)	1 / 14 (7.14%)	1 / 26 (3.85%)	1 / 12 (8.33%)	0 / 20 (0.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	1	0	0	0	1	2	2	1	1	1	1	0	1	0	0	0	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 11 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	1 / 16 (6.25%)	1 / 30 (3.33%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 26 (3.85%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 20 (10.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	1	1	0	0	0	1	0	0	0	0	0	0	2	0
Gastrointestinal disorder
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	2
Haematochezia
subjects affected / exposed	0 / 11 (0.00%)	2 / 23 (8.70%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	1 / 58 (1.72%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Ileus
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	1 / 58 (1.72%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	1	0	0	0	0	0	0	0	0	0
Haemorrhoids
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0
Nausea
subjects affected / exposed	1 / 11 (9.09%)	5 / 23 (21.74%)	5 / 15 (33.33%)	0 / 6 (0.00%)	2 / 13 (15.38%)	4 / 16 (25.00%)	9 / 30 (30.00%)	13 / 58 (22.41%)	4 / 14 (28.57%)	5 / 14 (35.71%)	6 / 26 (23.08%)	2 / 12 (16.67%)	3 / 20 (15.00%)	5 / 22 (22.73%)	0 / 3 (0.00%)	1 / 3 (33.33%)	4 / 6 (66.67%)	3 / 20 (15.00%)	1 / 3 (33.33%)
occurrences all number	1	6	5	0	3	4	13	16	4	7	6	3	4	6	0	1	6	3	1
Retching
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Stomatitis
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	1 / 30 (3.33%)	3 / 58 (5.17%)	1 / 14 (7.14%)	1 / 14 (7.14%)	3 / 26 (11.54%)	0 / 12 (0.00%)	0 / 20 (0.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	1	3	1	1	4	0	0	1	0	0	0	0	0
Toothache
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	1 / 6 (16.67%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	1	0	0	0	0	1	0	0	0	0	0	0	0	0	0
Vomiting
subjects affected / exposed	0 / 11 (0.00%)	2 / 23 (8.70%)	0 / 15 (0.00%)	0 / 6 (0.00%)	2 / 13 (15.38%)	0 / 16 (0.00%)	5 / 30 (16.67%)	12 / 58 (20.69%)	3 / 14 (21.43%)	3 / 14 (21.43%)	4 / 26 (15.38%)	0 / 12 (0.00%)	3 / 20 (15.00%)	5 / 22 (22.73%)	0 / 3 (0.00%)	1 / 3 (33.33%)	1 / 6 (16.67%)	4 / 20 (20.00%)	0 / 3 (0.00%)
occurrences all number	0	3	0	0	3	0	5	17	3	5	6	0	4	5	0	1	2	5	0
Hepatobiliary disorders
Cholestasis
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	1	0	0	0	0	0	0	0	0	0	0
Hepatic failure
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0
Hepatic steatosis
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Hepatitis
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0
Hypertransaminasaemia
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	0 / 58 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	2	0	0	1	0	0	0	0	0	0	0	0	0
Jaundice
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Immune-mediated hepatitis
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Alopecia
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Decubitus ulcer
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Dry skin
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	1 / 15 (6.67%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	1 / 30 (3.33%)	3 / 58 (5.17%)	0 / 14 (0.00%)	0 / 14 (0.00%)	2 / 26 (7.69%)	0 / 12 (0.00%)	0 / 20 (0.00%)	2 / 22 (9.09%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	2	0	1	0	1	0	1	3	0	0	2	0	0	2	1	0	0	0	0
Eczema
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	1	0	0	0	0	0	0	0	0	0	0
Hyperhidrosis
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	1 / 16 (6.25%)	1 / 30 (3.33%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	2 / 22 (9.09%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	1	1	0	0	0	0	0	0	2	0	0	0	0	0
Hyperkeratosis
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0
Night sweats
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	2 / 58 (3.45%)	1 / 14 (7.14%)	0 / 14 (0.00%)	1 / 26 (3.85%)	0 / 12 (0.00%)	0 / 20 (0.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	2	1	0	1	0	0	1	0	0	0	0	0
Intertrigo
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Rash maculo-papular
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	2 / 58 (3.45%)	0 / 14 (0.00%)	2 / 14 (14.29%)	1 / 26 (3.85%)	0 / 12 (0.00%)	0 / 20 (0.00%)	1 / 22 (4.55%)	1 / 3 (33.33%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 20 (10.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	2	0	3	2	0	0	1	1	0	0	2	0
Rash
subjects affected / exposed	2 / 11 (18.18%)	5 / 23 (21.74%)	4 / 15 (26.67%)	0 / 6 (0.00%)	2 / 13 (15.38%)	1 / 16 (6.25%)	1 / 30 (3.33%)	3 / 58 (5.17%)	0 / 14 (0.00%)	2 / 14 (14.29%)	3 / 26 (11.54%)	1 / 12 (8.33%)	2 / 20 (10.00%)	3 / 22 (13.64%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	3	5	4	0	3	1	1	3	0	2	4	1	3	3	0	0	0	1	0
Pruritus
subjects affected / exposed	3 / 11 (27.27%)	2 / 23 (8.70%)	1 / 15 (6.67%)	0 / 6 (0.00%)	1 / 13 (7.69%)	2 / 16 (12.50%)	3 / 30 (10.00%)	8 / 58 (13.79%)	0 / 14 (0.00%)	1 / 14 (7.14%)	2 / 26 (7.69%)	1 / 12 (8.33%)	2 / 20 (10.00%)	5 / 22 (22.73%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	3 / 20 (15.00%)	0 / 3 (0.00%)
occurrences all number	4	2	1	0	1	2	4	10	0	2	2	1	2	6	0	0	0	3	0
Pemphigoid
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0
Rash pruritic
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	2 / 20 (10.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	3	0	0	0	0	0	0
Skin lesion
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	1 / 58 (1.72%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	1	0	0
Skin exfoliation
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Seborrhoeic dermatitis
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	1 / 58 (1.72%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Scar pain
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	1 / 58 (1.72%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	1 / 12 (8.33%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	1	0	0	0	1	0	0	0	0	0	0	0
Vitiligo
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	1	0
Azotaemia
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0
Bladder pain
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Chronic kidney disease
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Dysuria
subjects affected / exposed	0 / 11 (0.00%)	1 / 23 (4.35%)	1 / 15 (6.67%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	1 / 58 (1.72%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	1	2	0	1	0	0	1	0	1	0	0	0	0	0	0	0	1	0
Haematuria
subjects affected / exposed	1 / 11 (9.09%)	2 / 23 (8.70%)	1 / 15 (6.67%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	2 / 14 (14.29%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	1	4	1	0	0	1	0	0	0	2	0	0	0	0	0	0	0	1	0
Leukocyturia
subjects affected / exposed	2 / 11 (18.18%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	2	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	1	0
Nocturia
subjects affected / exposed	0 / 11 (0.00%)	1 / 23 (4.35%)	1 / 15 (6.67%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	2 / 22 (9.09%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	1	0	0	0	0	0	0	0	0	0	0	2	0	0	0	0	0
Urinary retention
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	1	0	0	0	0	0	0	0	0	0	0	1	0
Urethral pain
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	2 / 22 (9.09%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	2	0	0	0	0	0
Hyperthyroidism
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	2 / 58 (3.45%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 26 (3.85%)	0 / 12 (0.00%)	1 / 20 (5.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 20 (10.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	1	2	0	0	1	0	1	0	0	0	0	2	0
Hypothyroidism
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	3 / 30 (10.00%)	5 / 58 (8.62%)	1 / 14 (7.14%)	1 / 14 (7.14%)	1 / 26 (3.85%)	0 / 12 (0.00%)	0 / 20 (0.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 20 (10.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	3	5	1	1	1	0	0	1	0	0	0	3	0
Lymphocytic hypophysitis
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0
Musculoskeletal and connective tissue disorders
Amyotrophy
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Arthralgia
subjects affected / exposed	3 / 11 (27.27%)	2 / 23 (8.70%)	2 / 15 (13.33%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	8 / 30 (26.67%)	9 / 58 (15.52%)	3 / 14 (21.43%)	0 / 14 (0.00%)	4 / 26 (15.38%)	0 / 12 (0.00%)	3 / 20 (15.00%)	3 / 22 (13.64%)	0 / 3 (0.00%)	0 / 3 (0.00%)	2 / 6 (33.33%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	3	2	2	0	0	0	9	12	3	0	5	0	3	3	0	0	4	1	0
Back pain
subjects affected / exposed	3 / 11 (27.27%)	5 / 23 (21.74%)	3 / 15 (20.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	1 / 16 (6.25%)	4 / 30 (13.33%)	5 / 58 (8.62%)	1 / 14 (7.14%)	3 / 14 (21.43%)	2 / 26 (7.69%)	0 / 12 (0.00%)	3 / 20 (15.00%)	3 / 22 (13.64%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	3	5	3	1	0	1	4	6	1	3	2	0	4	4	0	0	0	3	0
Bone pain
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	2 / 58 (3.45%)	1 / 14 (7.14%)	0 / 14 (0.00%)	1 / 26 (3.85%)	0 / 12 (0.00%)	1 / 20 (5.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	2	1	0	1	0	1	0	0	0	0	1	0
Flank pain
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	1 / 58 (1.72%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	1	0	0	0	0	1	1	0	0	0	1	0
Fracture pain
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	1 / 12 (8.33%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Mobility decreased
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Joint stiffness
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	1	0	0	0	0	0	0
Groin pain
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	1 / 58 (1.72%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	1	0	0	0	1	0	1	0	0	0	0	0	0	0	0	0
Muscle atrophy
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0
Musculoskeletal pain
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0
Musculoskeletal chest pain
subjects affected / exposed	0 / 11 (0.00%)	1 / 23 (4.35%)	1 / 15 (6.67%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 16 (6.25%)	3 / 30 (10.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 26 (3.85%)	0 / 12 (0.00%)	1 / 20 (5.00%)	2 / 22 (9.09%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	2 / 20 (10.00%)	0 / 3 (0.00%)
occurrences all number	0	1	1	0	0	1	3	0	0	0	1	0	1	2	0	0	0	3	0
Muscular weakness
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 16 (6.25%)	1 / 30 (3.33%)	5 / 58 (8.62%)	1 / 14 (7.14%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	1	1	5	1	1	0	0	0	0	0	0	0	1	0
Muscle spasms
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 58 (1.72%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	2 / 22 (9.09%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	1	0	2	2	0	0	0	0	0	4	0	0	0	0	0
Myalgia
subjects affected / exposed	1 / 11 (9.09%)	1 / 23 (4.35%)	3 / 15 (20.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	4 / 30 (13.33%)	4 / 58 (6.90%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 26 (3.85%)	2 / 12 (16.67%)	1 / 20 (5.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)	1 / 3 (33.33%)
occurrences all number	1	1	3	0	0	0	4	5	0	0	2	2	1	1	0	0	1	0	1
Neck pain
subjects affected / exposed	0 / 11 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	2 / 30 (6.67%)	1 / 58 (1.72%)	0 / 14 (0.00%)	0 / 14 (0.00%)	3 / 26 (11.54%)	1 / 12 (8.33%)	1 / 20 (5.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	0	0	2	1	0	0	3	1	1	0	0	0	0	0	0
Osteoarthritis
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Pain in extremity
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)	0 / 6 (0.00%)	2 / 13 (15.38%)	3 / 16 (18.75%)	0 / 30 (0.00%)	1 / 58 (1.72%)	1 / 14 (7.14%)	2 / 14 (14.29%)	0 / 26 (0.00%)	0 / 12 (0.00%)	1 / 20 (5.00%)	2 / 22 (9.09%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 20 (10.00%)	0 / 3 (0.00%)
occurrences all number	0	0	2	0	2	3	0	1	1	2	0	0	1	3	0	0	1	3	0
Pain in jaw
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	1 / 58 (1.72%)	0 / 14 (0.00%)	0 / 14 (0.00%)	2 / 26 (7.69%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	1	0	0	2	0	0	0	0	0	0	0	0
Trismus
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	2 / 26 (7.69%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	2	0	0	0	0	0	0	0	0
Infections and infestations
Abdominal abscess
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0
Diarrhoea infectious
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Device related infection
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
COVID-19
subjects affected / exposed	0 / 11 (0.00%)	2 / 23 (8.70%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	2	0	0	0	0	0	0	0	0	0	0	0	1	0	0	1	0	0
Body tinea
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Escherichia sepsis
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Infection
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	1 / 26 (3.85%)	0 / 12 (0.00%)	1 / 20 (5.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	2	1	0	1	0	0	0	0	0	0
Herpes zoster
subjects affected / exposed	0 / 11 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	1 / 16 (6.25%)	0 / 30 (0.00%)	1 / 58 (1.72%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	1	1	0	1	0	0	0	0	0	1	0	0	0	1	0
Gastroenteritis
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	2 / 30 (6.67%)	1 / 58 (1.72%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	2	1	0	0	0	0	0	0	0	0	0	0	0
Eye infection
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Influenza
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	2 / 30 (6.67%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	2	0	0	0	0	0	0	0	0	0	0	1	0
Nasopharyngitis
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 16 (6.25%)	1 / 30 (3.33%)	1 / 58 (1.72%)	1 / 14 (7.14%)	1 / 14 (7.14%)	1 / 26 (3.85%)	0 / 12 (0.00%)	0 / 20 (0.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	1	1	1	1	1	1	0	0	1	0	0	0	0	0
Oesophageal candidiasis
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Oral candidiasis
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	1 / 30 (3.33%)	0 / 58 (0.00%)	1 / 14 (7.14%)	1 / 14 (7.14%)	1 / 26 (3.85%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	1	0	1	1	1	0	0	0	0	0	1	1	0
Pharyngitis
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Pneumonia
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 58 (1.72%)	1 / 14 (7.14%)	0 / 14 (0.00%)	2 / 26 (7.69%)	0 / 12 (0.00%)	0 / 20 (0.00%)	3 / 22 (13.64%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	4 / 20 (20.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	1	1	0	2	0	0	4	0	0	0	4	0
Tracheitis
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0
Tonsillitis
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	1 / 6 (16.67%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Tinea versicolour
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Rash pustular
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	2 / 22 (9.09%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	0	0	2	0	0	0	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	2 / 13 (15.38%)	0 / 16 (0.00%)	3 / 30 (10.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	2 / 14 (14.29%)	1 / 26 (3.85%)	0 / 12 (0.00%)	0 / 20 (0.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	2	0	4	0	0	2	1	0	0	1	0	0	0	1	0
Urinary tract infection enterococcal
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0
Urinary tract infection
subjects affected / exposed	2 / 11 (18.18%)	1 / 23 (4.35%)	2 / 15 (13.33%)	1 / 6 (16.67%)	1 / 13 (7.69%)	0 / 16 (0.00%)	2 / 30 (6.67%)	5 / 58 (8.62%)	2 / 14 (14.29%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	2	1	2	2	1	0	4	7	2	1	0	0	0	0	0	0	0	2	0
Urogenital infection bacterial
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Vaginal infection
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Viral infection
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	1 / 58 (1.72%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	2	0	0	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0
Metabolism and nutrition disorders
Cachexia
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Decreased appetite
subjects affected / exposed	1 / 11 (9.09%)	3 / 23 (13.04%)	2 / 15 (13.33%)	0 / 6 (0.00%)	3 / 13 (23.08%)	2 / 16 (12.50%)	4 / 30 (13.33%)	17 / 58 (29.31%)	7 / 14 (50.00%)	5 / 14 (35.71%)	6 / 26 (23.08%)	0 / 12 (0.00%)	5 / 20 (25.00%)	6 / 22 (27.27%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	3 / 20 (15.00%)	2 / 3 (66.67%)
occurrences all number	1	3	2	0	3	2	4	21	7	5	8	0	5	8	0	0	1	3	2
Dehydration
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	3 / 58 (5.17%)	1 / 14 (7.14%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	3	1	0	0	0	0	0	0	0	0	0	0
Glucose tolerance impaired
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Hypercalcaemia
subjects affected / exposed	1 / 11 (9.09%)	3 / 23 (13.04%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 16 (6.25%)	1 / 30 (3.33%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 26 (3.85%)	0 / 12 (0.00%)	0 / 20 (0.00%)	3 / 22 (13.64%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	4	0	0	0	1	1	0	0	0	1	0	0	3	0	0	0	0	0
Hyperuricaemia
subjects affected / exposed	1 / 11 (9.09%)	2 / 23 (8.70%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	2	0	0	2	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Hyperlipasaemia
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	2	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Hyperkalaemia
subjects affected / exposed	0 / 11 (0.00%)	2 / 23 (8.70%)	1 / 15 (6.67%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	3 / 14 (21.43%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	2	1	0	1	0	0	0	0	4	0	0	0	1	0	0	0	2	0
Hyperglycaemia
subjects affected / exposed	1 / 11 (9.09%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	1 / 58 (1.72%)	2 / 14 (14.29%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	1	0	0	0	0	0	2	1	2	1	0	0	0	0	0	0	0	0	0
Hypoalbuminaemia
subjects affected / exposed	1 / 11 (9.09%)	1 / 23 (4.35%)	0 / 15 (0.00%)	0 / 6 (0.00%)	2 / 13 (15.38%)	1 / 16 (6.25%)	2 / 30 (6.67%)	1 / 58 (1.72%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 26 (3.85%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	2 / 20 (10.00%)	0 / 3 (0.00%)
occurrences all number	1	1	0	0	2	1	2	1	0	0	1	0	0	0	0	0	1	2	0
Hypocalcaemia
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)	0 / 6 (0.00%)	0 / 13 (0.00%)	1 / 16 (6.25%)	0 / 30 (0.00%)	0 / 58 (0.00%)	1 / 14 (7.14%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	1	0	0	1	1	0	0	0	1	0	0	0	0	0
Hypokalaemia
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)	0 / 6 (0.00%)	3 / 13 (23.08%)	0 / 16 (0.00%)	3 / 30 (10.00%)	4 / 58 (6.90%)	3 / 14 (21.43%)	2 / 14 (14.29%)	1 / 26 (3.85%)	0 / 12 (0.00%)	3 / 20 (15.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	1 / 6 (16.67%)	1 / 20 (5.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	5	0	4	6	6	3	1	0	6	1	0	0	1	1	0
Hypomagnesaemia
subjects affected / exposed	0 / 11 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	3 / 30 (10.00%)	1 / 58 (1.72%)	2 / 14 (14.29%)	0 / 14 (0.00%)	1 / 26 (3.85%)	0 / 12 (0.00%)	1 / 20 (5.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	0	0	0	0	3	1	2	0	2	0	1	1	0	0	0	0	0
Hyponatraemia
subjects affected / exposed	0 / 11 (0.00%)	1 / 23 (4.35%)	0 / 15 (0.00%)	0 / 6 (0.00%)	2 / 13 (15.38%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	1 / 14 (7.14%)	2 / 14 (14.29%)	1 / 26 (3.85%)	0 / 12 (0.00%)	1 / 20 (5.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	1 / 3 (33.33%)
occurrences all number	0	1	0	0	2	0	0	0	1	2	2	0	1	1	0	0	0	0	1
Hypophosphataemia
subjects affected / exposed	0 / 11 (0.00%)	1 / 23 (4.35%)	1 / 15 (6.67%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	1 / 30 (3.33%)	3 / 58 (5.17%)	0 / 14 (0.00%)	0 / 14 (0.00%)	2 / 26 (7.69%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	1	1	0	1	0	1	3	0	0	2	0	0	0	0	0	0	0	0
Iron deficiency
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	1 / 12 (8.33%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0	0	0
Malnutrition
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	1 / 58 (1.72%)	0 / 14 (0.00%)	0 / 14 (0.00%)	1 / 26 (3.85%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	1	0	0	1	0	0	0	0	0	0	0	0
Obesity
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	1 / 13 (7.69%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	1	0	0	0	0	0	0	0	0	0	0	0	0	0	0
Vitamin D deficiency
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	1 / 30 (3.33%)	0 / 58 (0.00%)	0 / 14 (0.00%)	1 / 14 (7.14%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	0	0	1	0	0	1	0	0	0	2	0	0	0	0	0
Vitamin B12 deficiency
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	1 / 15 (6.67%)	0 / 6 (0.00%)	0 / 13 (0.00%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	1 / 22 (4.55%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	1	0	0	0	0	0	0	0	0	0	0	1	0	0	0	0	0
Tumour lysis syndrome
subjects affected / exposed	0 / 11 (0.00%)	0 / 23 (0.00%)	0 / 15 (0.00%)	0 / 6 (0.00%)	2 / 13 (15.38%)	0 / 16 (0.00%)	0 / 30 (0.00%)	0 / 58 (0.00%)	0 / 14 (0.00%)	0 / 14 (0.00%)	0 / 26 (0.00%)	0 / 12 (0.00%)	0 / 20 (0.00%)	0 / 22 (0.00%)	0 / 3 (0.00%)	0 / 3 (0.00%)	0 / 6 (0.00%)	0 / 20 (0.00%)	0 / 3 (0.00%)
occurrences all number	0	0	0	0	2	0	0	0	0	0	0	0	0	0	0	0	0	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

26 May 2017

● Updated inclusion criteria to require specific prior standard therapies for tumor types in Part 1. ● Added exclusion criteria for patients with a history of non-infectious pneumonitis or interstitial lung disease (ILD). ● Added inclusion criteria to ensure that the enrollment of patients with DLBCL was limited to patients with no available therapies of proven clinical benefit. ● Provided case definitions for treatment-emergent immune-mediated ADRs in the protocol and guidance on assessment and management of immune-related AEs. ● Included specific criteria for continuing study treatment beyond RECIST-defined radiological progression. ● Updated risk-benefit section to indicate potential for overlapping toxicities of combination immunotherapies. ● Clarified that the primary efficacy analysis was based on RECIST v1.1 for solid tumors and Cheson et al 2014 for lymphoma and that irRC criteria were used only for decisions around treatment discontinuation due to disease progression.

29 Aug 2017

● Included Japanese patients via separate safety run-in part to evaluate safety and PK properties of NIR178 as a single agent prior to their participation in different parts of the study. ● Added Overall Response assessment by iRECIST as a secondary endpoint. ● irRC criteria was replaced by iRECIST criteria for guiding decisions regarding treatment duration and/or discontinuation due to disease progression. ● First dose reduction step from 160 mg (dose level -1) was changed from 80 mg to 120 mg BID after addition of a new NIR178 capsule strength (40 mg). ● On-treatment biopsy and blood sample collection timepoint was moved from C3D15 ± 15 days and C2D1, respectively, to C2D1 +15 days to account for patients who could not obtain biopsies in Cycle 3 due to early disease progression or early response.

02 Jul 2018

● Incorporated language requiring study treatment discontinuation in the event of Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) in response to the occurrence of a case of Stevens Johnson Syndrome in the study. ● Criteria for dose reduction/interruption and re-initiation of treatment for ADRs were updated to include latest toxicity management guidelines per American Society of Clinical Oncology (ASCO), National comprehensive Cancer Network (NCCN) and European Society for Medical Oncology (ESMO). Moreover, the AST and ALT exclusion criteria was revised to align with the updated toxicity management guidelines.

29 Oct 2018

● Updated the protocol eligibility criteria and related statistical analysis sections for selected Part 1 indications based on preliminary evidence of anti-tumor activity and changes to the standard of care: ● MSS CRC: In order to evaluate efficacy and safety in patients with different RAS genotypes, enrollment continued in two sub-groups (RAS wild-type & RAS mutant) based on locally available laboratory data. RAS status was collected, including for patients that were already enrolled. ● Head & Neck: Enrollment was restricted to squamous cell carcinoma of the head and neck (HNSCC) to create a more homogenous patient population. In addition, a new treatment group (IO-pretreated HNSCC) was added. ● Melanoma: Only cutaneous melanoma patients were to be enrolled. In addition, a new treatment group (IO-pretreated melanoma) was added, and the inclusion criteria was amended to require that BRAF V600 mutant patients be treated with prior BRAF V600 inhibitor therapy. ● Scan assessments post discontinuation of study treatment no longer collected once the patient started a new antineoplastic therapy. ● Added an optional biopsy for patients that continued study treatment beyond disease progression due to overall clinical benefit. ● Removed blood sample collection for the assessment of serum cytokines used for retrospective analysis of a cytokine release syndrome AE.

28 Nov 2019

● Increased the dose of NIR178 to 240 mg BID from 160 mg BID for all newly enrolled patients based on emerging data. ● Added two new treatment groups (mCRPC and IO-pretreated RCC) in Part 1. ● Design of Part 3 was modified to allow for further evaluation of one or two tumor groups (from Parts 1 and 2). ● Removed on-treatment plasma cfDNA biomarker sample collection and added an end of treatment cfDNA sample.

22 Oct 2020

● Opened Part 3 of the study to explore PDR001 + NIR178 in TNBC patients whose disease did not express PD-L1 IC=0 (<1%). ● Introduced a new film-coated tablet (FCT) formulation of NIR178 into Part 3 of the study. ● Reduced the ECG collection plan to safety monitoring levels. ● Amended the safety run-in to assess NIR178 240 mg BID in combination with PDR001 400 mg Q4W starting at Cycle 1 in Japanese patients. ● Revised the definition of end of study to include the option for patients deriving clinical benefit to transfer to another study or to an alternative treatment option. ● Added drug-induced liver injury (DILI), autoimmune hepatitis, and pneumonitis follow-up guidance based on a Health Authority request.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
20 Apr 2018	The FDA placed study CNIR178X2201 on partial clinical hold (no new enrolment) on 20-Apr-2018 due to safety concerns related to immune related skin toxicities. Novartis voluntarily extended the temporary recruitment hold to non-US countries for CNIR178X2201. Ongoing patients could continue to receive the study drug per protocol, as long as they re-consented to participate. The FDA lifted the hold on 22-Jun-2018 after updates were made to the protocol amendment, ICF, and IB.	22 Jun 2018
02 Nov 2021	Novartis communicated to investigators the decision to halt further recruitment in the CNIR178X2201 study for business reasons based on the review of available study data.	-

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

Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com for complete trial results.

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Clinical trials

Clinical Trial Results: A Phase II, multi-center, open label study of NIR178 in combination with PDR001 in patients with selected advanced solid tumors and non-Hodgkin lymphoma

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Part 1: Overall Response Rate (ORR) per RECIST v1.1 for solid tumors

Primary: Part 1: Overall Response Rate (ORR) per RECIST v1.1 for solid tumors

Primary: Part 1: Overall Response Rate (ORR) per Cheson 2014 for DLBCL

Primary: Part 1: Overall Response Rate (ORR) per Cheson 2014 for DLBCL

Primary: Part 3: Overall Response Rate (ORR) per RECIST v1.1 for solid tumors

Primary: Part 3: Overall Response Rate (ORR) per RECIST v1.1 for solid tumors

Primary: Part 2: Overall Response Rate (ORR) per RECIST v1.1 for solid tumors

Primary: Part 2: Overall Response Rate (ORR) per RECIST v1.1 for solid tumors

Secondary: Part 1: Overall Response Rate (ORR) per iRECIST for solid tumors

Secondary: Part 1: Overall Response Rate (ORR) per iRECIST for solid tumors

Secondary: Part 2: Overall Response Rate (ORR) per iRECIST for solid tumors

Secondary: Part 2: Overall Response Rate (ORR) per iRECIST for solid tumors

Secondary: Part 1: Disease Control Rate (DCR) per RECIST v1.1 for solid tumors

Secondary: Part 1: Disease Control Rate (DCR) per RECIST v1.1 for solid tumors

Secondary: Part 3: Overall Response Rate (ORR) per iRECIST for solid tumors

Secondary: Part 3: Overall Response Rate (ORR) per iRECIST for solid tumors

Secondary: Part 1: Mean percentage change in PSA from baseline

Secondary: Part 1: Mean percentage change in PSA from baseline

Secondary: Part 1: Disease Control Rate (DCR) per iRECIST for solid tumors

Secondary: Part 1: Disease Control Rate (DCR) per iRECIST for solid tumors

Secondary: Part 1: Disease Control Rate (DCR) per Cheson 2014 for DLBCL

Secondary: Part 1: Disease Control Rate (DCR) per Cheson 2014 for DLBCL

Secondary: Part 2: Disease Control Rate (DCR) per RECIST v1.1 for solid tumors

Secondary: Part 2: Disease Control Rate (DCR) per RECIST v1.1 for solid tumors

Secondary: Part 3: Disease Control Rate (DCR) per RECIST v1.1 for solid tumors

Secondary: Part 3: Disease Control Rate (DCR) per RECIST v1.1 for solid tumors

Secondary: Part 2: Disease Control Rate (DCR) per iRECIST for solid tumors

Secondary: Part 2: Disease Control Rate (DCR) per iRECIST for solid tumors

Secondary: Part 1: Duration Of Response (DOR) per RECIST v1.1 for solid tumors

Secondary: Part 1: Duration Of Response (DOR) per RECIST v1.1 for solid tumors

Secondary: Part 3: Disease Control Rate (DCR) per iRECIST for solid tumors

Secondary: Part 3: Disease Control Rate (DCR) per iRECIST for solid tumors

Secondary: Part 1: Duration Of Response (DOR) per iRECIST for solid tumors

Secondary: Part 1: Duration Of Response (DOR) per iRECIST for solid tumors

Secondary: Part 3: Duration Of Response (DOR) per iRECIST for solid tumors

Secondary: Part 3: Duration Of Response (DOR) per iRECIST for solid tumors

Secondary: Part 3: Duration Of Response (DOR) per RECIST v1.1 for solid tumors

Secondary: Part 3: Duration Of Response (DOR) per RECIST v1.1 for solid tumors

Secondary: Part 2: Duration Of Response (DOR) per iRECIST for solid tumors

Secondary: Part 2: Duration Of Response (DOR) per iRECIST for solid tumors

Secondary: Part 2: Duration Of Response (DOR) per RECIST v1.1 for solid tumors

Secondary: Part 2: Duration Of Response (DOR) per RECIST v1.1 for solid tumors

Secondary: Part 1: Duration Of Response (DOR) per Cheson 2014 for DLBCL

Secondary: Part 1: Duration Of Response (DOR) per Cheson 2014 for DLBCL

Secondary: Part 1: Progression-Free Survival (PFS) per RECIST v1.1 for solid tumors

Secondary: Part 1: Progression-Free Survival (PFS) per RECIST v1.1 for solid tumors

Secondary: Part 1: Progression-Free Survival (PFS) per iRECIST for solid tumors

Secondary: Part 1: Progression-Free Survival (PFS) per iRECIST for solid tumors

Secondary: Part 3: Progression-Free Survival (PFS) per iRECIST for solid tumors

Secondary: Part 3: Progression-Free Survival (PFS) per iRECIST for solid tumors

Secondary: Part 3: Progression-Free Survival (PFS) per RECIST v1.1 for solid tumors

Secondary: Part 3: Progression-Free Survival (PFS) per RECIST v1.1 for solid tumors

Secondary: Part 2: Progression-Free Survival (PFS) per RECIST v1.1 for solid tumors

Secondary: Part 2: Progression-Free Survival (PFS) per RECIST v1.1 for solid tumors

Secondary: Part 1: Progression-Free Survival (PFS) per Cheson 2014 for DLBCL

Secondary: Part 1: Progression-Free Survival (PFS) per Cheson 2014 for DLBCL

Secondary: Part 2: Progression-Free Survival (PFS) per iRECIST for solid tumors

Secondary: Part 2: Progression-Free Survival (PFS) per iRECIST for solid tumors

Secondary: Part 1: 2-year Overall Survival (OS)

Secondary: Part 1: 2-year Overall Survival (OS)

Secondary: Part 1: Change from baseline in CD8 percent marker area in tumor tissue

Secondary: Part 1: Change from baseline in CD8 percent marker area in tumor tissue

Secondary: Part 3: 2-year Overall Survival (OS)

Secondary: Part 3: 2-year Overall Survival (OS)

Secondary: Part 2: 2-year Overall Survival (OS)

Secondary: Part 2: 2-year Overall Survival (OS)

Secondary: Part 2: Change from baseline in CD8 percent marker area in tumor tissue

Secondary: Part 2: Change from baseline in CD8 percent marker area in tumor tissue

Secondary: Part 3: Change from baseline in CD8 percent marker area in tumor tissue

Secondary: Part 3: Change from baseline in CD8 percent marker area in tumor tissue

Clinical Trial Results:
A Phase II, multi-center, open label study of NIR178 in combination with PDR001 in patients with selected advanced solid tumors and non-Hodgkin lymphoma