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Clinical Trial Results:
A Phase 1/2 Study of the Combination of Lirilumab (Anti-KIR) Plus Nivolumab (Anti-PD-1) or Lirilumab Plus Nivolumab and Ipilimumab in Advanced Refractory Solid Tumors

Summary
EudraCT number	2016-001359-36
Trial protocol	IT FR ES
Global end of trial date	13 Dec 2019

Results information
Results version number	v1(current)
This version publication date	24 Dec 2022
First version publication date	24 Dec 2022
Other versions

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

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Trial information

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Sponsor protocol code

CA223-001

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Bristol-Myers Squibb

Sponsor organisation address

Chaussée de la Hulpe 185, Brussels, Belgium, 1170

Public contact

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

Scientific contact

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

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

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

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

Analysis stage

Final

Date of interim/final analysis

26 Aug 2020

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

13 Dec 2019

Was the trial ended prematurely?

Main objective of the trial

Part 1: To assess the safety and tolerability of lirilumab given in combination with nivolumab and to identify DLTs and the MTD of the combination in subjects with advanced (metastatic and/or unresectable) solid tumors. Part 2: To assess the safety and preliminary anti-tumor activity of the combination of lirilumab and nivolumab in subjects with advanced solid tumors. Part 3: To estimate the ORR of lirilumab given in combination with nivolumab in subjects with recurrent or metastatic SCCHN that has relapsed or progressed within 6 months of the last dose of a platinum-containing therapy and whose tumors express PD-L1. Part 5: To assess the safety and preliminary anti-tumor activity of the combination of lirilumab with nivolumab and ipilimumab in subjects with platinum-refractory recurrent or metastatic SCCHN.

Protection of trial subjects

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

Background therapy

Evidence for comparator

Actual start date of recruitment

12 Oct 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

France: 105

Country: Number of subjects enrolled

Italy: 38

Country: Number of subjects enrolled

Spain: 3

Country: Number of subjects enrolled

Switzerland: 1

Country: Number of subjects enrolled

United States: 190

Worldwide total number of subjects

337

EEA total number of subjects

146

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)

215

From 65 to 84 years

121

85 years and over

Subject disposition

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Recruitment details

Screening details

Part 4 and Part 6 of the study were removed from the protocol study design prior to enrolling any subjects.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Carer

Are arms mutually exclusive

Yes

Part 1/2 Liri 0.1 + Nivo 3

Arm description

Participants receive Lirilumab 0.1 mg/kg every 4 weeks (Q4W) and Nivolumab 3 mg/kg every 2 weeks (Q2W) for twelve 8-week treatment cycles.

Arm type

Experimental

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

(BMS-936558

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

3 mg/kg administered as a 60-minute infusion

Investigational medicinal product name

Lirilumab

Investigational medicinal product code

Other name

BMS-986015

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

0.1 mg/kg administered as a 60-minute infusion, 30 minutes after completion of the nivolumab infusion.

Part 1/2: Liri 0.3 + Nivo 3

Arm description

Participants receive Lirilumab 0.3 mg/kg every 4 weeks (Q4W) and Nivolumab 3 mg/kg every 2 weeks (Q2W) for twelve 8-week treatment cycles.

Arm type

Experimental

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

(BMS-936558

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

3 mg/kg administered as a 60-minute infusion

Investigational medicinal product name

Lirilumab

Investigational medicinal product code

Other name

BMS-986015

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

0.3 mg/kg administered as a 60-minute infusion, 30 minutes after completion of the nivolumab infusion.

Part 1/2: Liri 1 + Nivo 3

Arm description

Participants receive Lirilumab 1 mg/kg every 4 weeks (Q4W) and Nivolumab 3 mg/kg every 2 weeks (Q2W) for twelve 8-week treatment cycles.

Arm type

Experimental

Investigational medicinal product name

Lirilumab

Investigational medicinal product code

Other name

BMS-986015

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

1 mg/kg administered as a 60-minute infusion, 30 minutes after completion of the nivolumab infusion.

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

(BMS-936558

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

3 mg/kg administered as a 60-minute infusion

Part 1/2: Liri 3 + Nivo 3

Arm description

Participants receive Lirilumab 3 mg/kg every 4 weeks (Q4W) and Nivolumab 3 mg/kg every 2 weeks (Q2W) for twelve 8-week treatment cycles.

Arm type

Experimental

Investigational medicinal product name

Lirilumab

Investigational medicinal product code

Other name

BMS-986015

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

3 mg/kg administered as a 60-minute infusion, 30 minutes after completion of the nivolumab infusion.

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

(BMS-936558

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

3 mg/kg administered as a 60-minute infusion

Part 3: PBO + Nivo 240

Arm description

Participants receive Placebo every 4 weeks (Q4W) and a flat dose of nivolumab monotherapy (240mg) every 2 weeks (Q2W) for 8-week cycles until progressive disease.

Arm type

Experimental

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

BMS-936558

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

240 mg administered as a 30-minute infusion

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Normal Saline (ie, 0.9% Sodium Chloride Injection) administered as a 60-minute infusion, 30 minutes after completion of the nivolumab infusion.

Part 3: Liri 240 + Nivo 240

Arm description

Participants receive Lirilumab 240 mg every 4 weeks (Q4W) and a flat dose of nivolumab 240 mg every 2 weeks (Q2W) for 8-week cycles until progressive disease.

Arm type

Experimental

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

BMS-936558

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

240 mg administered as a 30-minute infusion

Investigational medicinal product name

lirilumab

Investigational medicinal product code

Other name

BMS-986015

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

240 mg administered as a 60-minute infusion, 30 minutes after completion of the nivolumab infusion.

Part 5: Liri 3 + Nivo 3 + Ipi 1

Arm description

Participants receive Lirilumab 3 mg/kg IV every 4 weeks (Q4W), Nivolumab 3 mg/kg IV every 2 weeks (Q2W), and Ipilimumab 1 mg/kg IV every 6 weeks (Q6W) for 12-week cycles until progressive disease

Arm type

Experimental

Investigational medicinal product name

lirilumab

Investigational medicinal product code

Other name

BMS-986015

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

3 mg/kg administered as a 60-minute infusion, 30 minutes after completion of the nivolumab infusion.

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

BMS-734016

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

1 mg/kg administered as a 30-minute infusion, 30 minutes after completion of the nivolumab infusion.

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

(BMS-936558

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

3 mg/kg administered as a 30-minute infusion.

Number of subjects in period 1	Part 1/2 Liri 0.1 + Nivo 3	Part 1/2: Liri 0.3 + Nivo 3	Part 1/2: Liri 1 + Nivo 3	Part 1/2: Liri 3 + Nivo 3	Part 3: PBO + Nivo 240	Part 3: Liri 240 + Nivo 240	Part 5: Liri 3 + Nivo 3 + Ipi 1
Started	4	16	15	287	2	3	10
Completed	0	6	5	23	0	0	0
Not completed	4	10	10	264	2	3	10
Adverse event, serious fatal	-	-	-	1	-	-	-
Disease progression	3	5	5	204	1	3	5
Participant withdrew consent	-	1	-	8	-	-	-
Poor/non-comliance	-	1	-	1	-	-	-
Study drug toxicity	1	1	1	15	-	-	5
Maximum clinical benefit	-	1	1	3	-	-	-
Adverse Event unrelated to drug	-	-	3	21	-	-	-
Other reason	-	-	-	3	1	-	-
No longer meets study criteria	-	-	-	1	-	-	-
Participant request to stop therapy	-	1	-	6	-	-	-
Lost to follow-up	-	-	-	1	-	-	-

Baseline characteristics

Top of page

Reporting group title

Part 1/2 Liri 0.1 + Nivo 3

Reporting group description

Participants receive Lirilumab 0.1 mg/kg every 4 weeks (Q4W) and Nivolumab 3 mg/kg every 2 weeks (Q2W) for twelve 8-week treatment cycles.

Reporting group title

Part 1/2: Liri 0.3 + Nivo 3

Reporting group description

Participants receive Lirilumab 0.3 mg/kg every 4 weeks (Q4W) and Nivolumab 3 mg/kg every 2 weeks (Q2W) for twelve 8-week treatment cycles.

Reporting group title

Part 1/2: Liri 1 + Nivo 3

Reporting group description

Participants receive Lirilumab 1 mg/kg every 4 weeks (Q4W) and Nivolumab 3 mg/kg every 2 weeks (Q2W) for twelve 8-week treatment cycles.

Reporting group title

Part 1/2: Liri 3 + Nivo 3

Reporting group description

Participants receive Lirilumab 3 mg/kg every 4 weeks (Q4W) and Nivolumab 3 mg/kg every 2 weeks (Q2W) for twelve 8-week treatment cycles.

Reporting group title

Part 3: PBO + Nivo 240

Reporting group description

Participants receive Placebo every 4 weeks (Q4W) and a flat dose of nivolumab monotherapy (240mg) every 2 weeks (Q2W) for 8-week cycles until progressive disease.

Reporting group title

Part 3: Liri 240 + Nivo 240

Reporting group description

Participants receive Lirilumab 240 mg every 4 weeks (Q4W) and a flat dose of nivolumab 240 mg every 2 weeks (Q2W) for 8-week cycles until progressive disease.

Reporting group title

Part 5: Liri 3 + Nivo 3 + Ipi 1

Reporting group description

Participants receive Lirilumab 3 mg/kg IV every 4 weeks (Q4W), Nivolumab 3 mg/kg IV every 2 weeks (Q2W), and Ipilimumab 1 mg/kg IV every 6 weeks (Q6W) for 12-week cycles until progressive disease

Reporting group values	Part 1/2 Liri 0.1 + Nivo 3	Part 1/2: Liri 0.3 + Nivo 3	Part 1/2: Liri 1 + Nivo 3	Part 1/2: Liri 3 + Nivo 3	Part 3: PBO + Nivo 240	Part 3: Liri 240 + Nivo 240	Part 5: Liri 3 + Nivo 3 + Ipi 1	Total
Number of subjects	4	16	15	287	2	3	10	337
Age Categorical
Age categorical
Units: Participants
< 65 years old	4	10	9	184	1	2	5	215
>= 65 years old	0	6	6	103	1	1	5	122
Age Continuous
Units: Years
arithmetic mean (standard deviation)	53.3 ( 12.09 )	58.1 ( 13.11 )	58.7 ( 16.85 )	59.7 ( 11.37 )	65.5 ( 10.61 )	55.3 ( 21.08 )	67.1 ( 10.40 )	-
Sex: Female, Male
Units: Participants
Female	2	5	7	80	1	1	1	97
Male	2	11	8	207	1	2	9	240
Race/Ethnicity, Customized
Race
Units: Subjects
White	4	16	15	237	2	3	10	287
Black/African American	0	0	0	10	0	0	0	10
American Indian / Alaska Native	0	0	0	1	0	0	0	1
Asian	0	0	0	10	0	0	0	10
Other	0	0	0	29	0	0	0	29
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	0	0	0	6	0	0	0	6
Not Hispanic or Latino	4	15	15	175	1	1	8	219
Unknown or Not Reported	0	1	0	106	1	2	2	112

End points

Top of page

Reporting group title

Part 1/2 Liri 0.1 + Nivo 3

Reporting group description

Participants receive Lirilumab 0.1 mg/kg every 4 weeks (Q4W) and Nivolumab 3 mg/kg every 2 weeks (Q2W) for twelve 8-week treatment cycles.

Reporting group title

Part 1/2: Liri 0.3 + Nivo 3

Reporting group description

Participants receive Lirilumab 0.3 mg/kg every 4 weeks (Q4W) and Nivolumab 3 mg/kg every 2 weeks (Q2W) for twelve 8-week treatment cycles.

Reporting group title

Part 1/2: Liri 1 + Nivo 3

Reporting group description

Participants receive Lirilumab 1 mg/kg every 4 weeks (Q4W) and Nivolumab 3 mg/kg every 2 weeks (Q2W) for twelve 8-week treatment cycles.

Reporting group title

Part 1/2: Liri 3 + Nivo 3

Reporting group description

Participants receive Lirilumab 3 mg/kg every 4 weeks (Q4W) and Nivolumab 3 mg/kg every 2 weeks (Q2W) for twelve 8-week treatment cycles.

Reporting group title

Part 3: PBO + Nivo 240

Reporting group description

Participants receive Placebo every 4 weeks (Q4W) and a flat dose of nivolumab monotherapy (240mg) every 2 weeks (Q2W) for 8-week cycles until progressive disease.

Reporting group title

Part 3: Liri 240 + Nivo 240

Reporting group description

Participants receive Lirilumab 240 mg every 4 weeks (Q4W) and a flat dose of nivolumab 240 mg every 2 weeks (Q2W) for 8-week cycles until progressive disease.

Reporting group title

Part 5: Liri 3 + Nivo 3 + Ipi 1

Reporting group description

Participants receive Lirilumab 3 mg/kg IV every 4 weeks (Q4W), Nivolumab 3 mg/kg IV every 2 weeks (Q2W), and Ipilimumab 1 mg/kg IV every 6 weeks (Q6W) for 12-week cycles until progressive disease

Primary: Number of Participants with Adverse Events (AEs) - Parts 1, 2 and 5

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End point title

Number of Participants with Adverse Events (AEs) - Parts 1, 2 and 5 ^[1] ^[2]

End point description

An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation subject administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment.

End point type

Primary

End point timeframe

From first dose to 150 days post last dose (up to an average of 51 weeks and a maximum of 2.5 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: Only summary statistics 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: Endpoint is specific only to certain arms of the study

End point values	Part 1/2 Liri 0.1 + Nivo 3	Part 1/2: Liri 0.3 + Nivo 3	Part 1/2: Liri 1 + Nivo 3	Part 1/2: Liri 3 + Nivo 3	Part 5: Liri 3 + Nivo 3 + Ipi 1
Number of subjects analysed	4	16	15	287	10
Units: Participants	4	16	15	284	10

No statistical analyses for this end point

Primary: Number of Participants with Serious Adverse Events (SAEs) - Parts 1, 2 and 5

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End point title

Number of Participants with Serious Adverse Events (SAEs) - Parts 1, 2 and 5 ^[3] ^[4]

End point description

A Serious Adverse Event (SAE) is any untoward medical occurrence that at any dose: results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an important medical event.

End point type

Primary

End point timeframe

From first dose to 150 days post last dose (up to an average of 51 weeks and a maximum of 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: Only summary statistics 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: Endpoint is specific only to certain arms of the study

End point values	Part 1/2 Liri 0.1 + Nivo 3	Part 1/2: Liri 0.3 + Nivo 3	Part 1/2: Liri 1 + Nivo 3	Part 1/2: Liri 3 + Nivo 3	Part 5: Liri 3 + Nivo 3 + Ipi 1
Number of subjects analysed	4	16	15	287	10
Units: Participants	1	8	9	205	7

No statistical analyses for this end point

Primary: Number of Participants with Adverse Events (AEs) Leading to Discontinuation - Parts 1, 2 and 5

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End point title

Number of Participants with Adverse Events (AEs) Leading to Discontinuation - Parts 1, 2 and 5 ^[5] ^[6]

End point description

Number of participants that experienced an AE leading to discontinuation during the course of the study. An AE is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a clinical investigation subject administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment.

End point type

Primary

End point timeframe

From first dose to 150 days post last dose (up to an average of 51 weeks and a maximum of 2.5 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: Only summary statistics 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: Endpoint is specific only to certain arms of the study

End point values	Part 1/2 Liri 0.1 + Nivo 3	Part 1/2: Liri 0.3 + Nivo 3	Part 1/2: Liri 1 + Nivo 3	Part 1/2: Liri 3 + Nivo 3	Part 5: Liri 3 + Nivo 3 + Ipi 1
Number of subjects analysed	4	16	15	287	10
Units: Participants	1	1	4	49	5

No statistical analyses for this end point

Primary: The Number of Participant Deaths in the Study - Parts 1, 2 and 5

Top of page

End point title

The Number of Participant Deaths in the Study - Parts 1, 2 and 5 ^[7] ^[8]

End point description

The number of participants who died during the course of the study.

End point type

Primary

End point timeframe

From first dose to 150 days post last dose (up to an average of 51 weeks and a maximum of 2.5 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: Only summary statistics 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: Endpoint is specific only to certain arms of the study

End point values	Part 1/2 Liri 0.1 + Nivo 3	Part 1/2: Liri 0.3 + Nivo 3	Part 1/2: Liri 1 + Nivo 3	Part 1/2: Liri 3 + Nivo 3	Part 5: Liri 3 + Nivo 3 + Ipi 1
Number of subjects analysed	4	16	15	287	10
Units: Participants	2	7	5	219	5

No statistical analyses for this end point

Primary: Number of Participants with Clinical Laboratory Test Abnormalities - Parts 1, 2 and 5

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End point title

Number of Participants with Clinical Laboratory Test Abnormalities - Parts 1, 2 and 5 ^[9] ^[10]

End point description

Number of participants that experienced a clinical laboratory test abnormality during the course of the study, including hematology and serum chemistry, and thyroid panel abnormalities. Abnormalities considered are those Grade 3-4 events with a >= 1 grade increase from baseline. Laboratory tests are graded using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 where Grade 3 is severe, and Grade 4 is life threatening. 99999= N/A (0 participants with available laboratory test measurements) NOTE: The number of participants analyzed for each laboratory parameter may vary depending on the number of participants with available laboratory test measurements. Baseline is defined as the last non-missing measurement prior to the first dosing date and time.

End point type

Primary

End point timeframe

From first dose to 150 days post last dose (up to an average of 51 weeks and a maximum of 2.5 years)

Notes
[9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: Only summary statistics planned for this endpoint
[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: Endpoint is specific only to certain arms of the study

End point values	Part 1/2 Liri 0.1 + Nivo 3	Part 1/2: Liri 0.3 + Nivo 3	Part 1/2: Liri 1 + Nivo 3	Part 1/2: Liri 3 + Nivo 3	Part 5: Liri 3 + Nivo 3 + Ipi 1
Number of subjects analysed	4	16	15	287	10
Units: Participants
Absolute Neutrophil Count - Grade 3	0	0	0	2	0
Absolute Neutrophil Count - Grade 4	0	1	0	0	0
Alanine Amino Transferase (ALT) - Grade 3	0	0	1	0	0
Alanine Amino Transferase (ALT) - Grade 4	0	0	0	0	0
Albumin - Grade 3	0	0	0	1	0
Albumin - Grade 4	0	0	0	0	0
Alkaline Phosphatase (ALP) - Grade 3	0	1	0	6	0
Alkaline Phosphatase (ALP) - Grade 4	0	0	0	0	0
Amylase, Total - Grade 3	0	0	0	8	0
Amylase, Total - Grade 4	0	0	0	1	0
APTT - Grade 3	99999	0	0	0	0
APTT - Grade 4	99999	0	0	0	0
Aspartate Aminotransferase (AST) - Grade 3	0	1	0	4	0
Aspartate Aminotransferase (AST) - Grade 4	0	0	1	0	0
Bilirubin, Total - Grade 3	0	0	0	1	0
Bilirubin, Total - Grade 4	0	0	0	0	0
Calcium, Corrected - Grade 3	99999	99999	99999	0	0
Calcium, Corrected - Grade 4	99999	99999	99999	0	0
Calcium, Ionized - Grade 3	99999	0	99999	0	0
Calcium, Ionized - Grade 4	99999	0	99999	0	0
Calcium, Total - Grade 3	0	0	0	6	0
Calcium, Total - Grade 4	0	0	0	4	0
Creatine Kinase (CK) - Grade 3	99999	99999	99999	0	0
Creatine Kinase (CK) - Grade 4	99999	99999	99999	0	0
Creatinine - Grade 3	0	0	0	0	1
Creatinine - Grade 4	0	0	0	0	0
Fibrinogen - Grade 3	99999	99999	99999	0	0
Fibrinogen - Grade 4	99999	99999	99999	0	0
G-Glutamyl Transferase (GGT) - Grade 3	99999	99999	99999	0	99999
G-Glutamyl Transferase (GGT) - Grade 4	99999	99999	99999	0	99999
Glucose, Fasting Serum - Grade 3	99999	0	99999	1	0
Glucose, Fasting Serum - Grade 4	99999	0	99999	0	0
Glucose, Serum - Grade 3	99999	99999	0	0	99999
Glucose, Serum - Grade 4	99999	99999	0	0	99999
Hemoglobin - Grade 3	0	1	1	24	1
Hemoglobin - Grade 4	0	0	0	0	0
Leukocytes - Grade 3	0	1	0	3	0
Leukocytes - Grade 4	0	0	0	3	0
Lipase, Total (Colorimetric Assay) - Grade 3	0	2	2	18	0
Lipase, Total (Colorimetric Assay) - Grade 4	0	0	0	7	0
Lipase, Total (Turbidimetric Assay) - Grade 3	99999	99999	99999	0	99999
Lipase, Total (Turbidimetric Assay) - Grade 4	99999	99999	99999	0	99999
Lymphocytes (Absolute) - Grade 3	0	3	4	64	4
Lymphocytes (Absolute) - Grade 4	0	0	0	9	0
Magnesium, Serum - Grade 3	0	0	0	1	0
Magnesium, Serum - Grade 4	0	0	0	1	0
Neutrophils (Absolute) - Grade 3	0	0	0	2	0
Neutrophils (Absolute) - Grade 4	99999	1	0	0	0
pH, Arterial Blood - Grade 3	99999	99999	99999	0	99999
pH, Arterial Blood - Grade 4	0	99999	99999	0	99999
Phosphorus, Inorganic - Grade 3	0	0	3	10	1
Phosphorus, Inorganic - Grade 4	0	0	0	0	0
Platelet Count - Grade 3	0	0	0	0	0
Platelet Count - Grade 4	0	0	0	1	0
Potassium, Serum - Grade 3	0	0	0	6	0
Potassium, Serum - Grade 4	0	0	0	3	1
Sodium Serum - Grade 3	0	1	1	26	1
Sodium Serum - Grade 4	0	0	0	0	0

No statistical analyses for this end point

Primary: Objective Response Rate (ORR)

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End point title

Objective Response Rate (ORR) ^[11]

End point description

Objective Response Rate (ORR) is defined as the percent of participants whose best overall response (BOR) is either a complete response (CR) or partial response (PR). BOR for a participant was derived using investigator-provided tumor measurements per RECIST v1.1. CR is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

End point type

Primary

End point timeframe

From first dose up to approximately 2.5 years

Notes
[11] - 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: Only summary statistics planned for this endpoint

End point values	Part 1/2 Liri 0.1 + Nivo 3	Part 1/2: Liri 0.3 + Nivo 3	Part 1/2: Liri 1 + Nivo 3	Part 1/2: Liri 3 + Nivo 3	Part 3: PBO + Nivo 240	Part 3: Liri 240 + Nivo 240	Part 5: Liri 3 + Nivo 3 + Ipi 1
Number of subjects analysed	4	16	15	287	2	3	10
Units: Percentage of participants
number (confidence interval 95%)	25.0 (0.6 to 80.6)	37.5 (15.2 to 64.6)	40.0 (16.3 to 67.7)	14.6 (10.8 to 19.3)	50.0 (1.3 to 98.7)	0 (0.0 to 70.8)	0 (0.0 to 30.8)

No statistical analyses for this end point

Secondary: Disease Control Rate (DCR) - Part 3

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End point title

Disease Control Rate (DCR) - Part 3 ^[12]

End point description

Disease Control Rate (DCR) is defined as the percentage of participants with a best overall response (BOR) of complete response (CR), partial response (PR), or stable disease (SD). CR is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. SD is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest sum diameters while on study. All participants will be monitored by radiographic assessment every 8 weeks from first dose to Week 48, and every 12 weeks thereafter until PD or treatment discontinuation.

End point type

Secondary

End point timeframe

From first dose up to approximately 2.5 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: Endpoint is specific only to certain arms of the study

End point values	Part 3: PBO + Nivo 240	Part 3: Liri 240 + Nivo 240
Number of subjects analysed	2	3
Units: Percentage of participants
number (confidence interval 95%)	50.0 (1.3 to 98.7)	33.3 (0.8 to 90.6)

No statistical analyses for this end point

Secondary: Median Duration of Response (mDOR) - Parts 3 and 5

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End point title

Median Duration of Response (mDOR) - Parts 3 and 5 ^[13]

End point description

DOR is defined as the time from the date of first response (CR or PR) to the date of first objectively documented tumor progression as determined using RECIST v1.1 or death due to any cause, whichever occurs first. Participant who remain alive and have not progressed were censored on the date of their last evaluable tumor assessment. Participants who started subsequent anticancer therapy without a prior reported progression were censored at the last evaluable tumor assessment prior to initiation of the subsequent anticancer therapy. CR is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. 99999 = N/A (Insufficient number of participants with events)

End point type

Secondary

End point timeframe

From first dose to the date of the first documented tumor progression as determined or death due to any cause, whichever occurs first. (Up to approximately 2.5 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: Endpoint is specific only to certain arms of the study

End point values	Part 3: PBO + Nivo 240	Part 3: Liri 240 + Nivo 240	Part 5: Liri 3 + Nivo 3 + Ipi 1
Number of subjects analysed	1	0 ^[14]	0 ^[15]
Units: weeks
median (full range (min-max))	99999 (40.0 to 99999)	( to )	( to )

Notes
[14] - 0 participants with a confirmed BOR of CR or PR.
[15] - 0 participants with a confirmed BOR of CR or PR.

No statistical analyses for this end point

Secondary: Median Time to Response (mTTR) - Part 3

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End point title

Median Time to Response (mTTR) - Part 3 ^[16]

End point description

TTR is defined as the time from the first dosing date to the date of the first documented objective response (CR or PR). CR is defined as the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR is defined as at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.

End point type

Secondary

End point timeframe

From date of first dose of study medication to the date of the first documented objective response (up to approximately 2.5 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: Endpoint is specific only to certain arms of the study

End point values	Part 3: PBO + Nivo 240	Part 3: Liri 240 + Nivo 240
Number of subjects analysed	1	0 ^[17]
Units: Weeks
median (full range (min-max))	8.10 (8.1 to 8.1)	( to )

Notes
[17] - 0 participants with CR or PR

No statistical analyses for this end point

Secondary: The Number of Participants with >=50% or >=80% Tumor Reduction - Parts 3 and 5

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End point title

The Number of Participants with >=50% or >=80% Tumor Reduction - Parts 3 and 5 ^[18]

End point description

Depth of response is defined as the target tumor burden percent change from baseline at nadir for each participant as measured by the number of participants with >= 50% and >= 80% tumor reduction. Tumor assessments are performed every 8 weeks from first dose date for 48 weeks, and then every 12 weeks thereafter until progressive disease (PD) or treatment discontinuation, whichever occurs earlier.

End point type

Secondary

End point timeframe

From first dose until progressive disease (PD) or treatment discontinuation, whichever occurs earlier. (Up to approximately 2.5 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: Endpoint is specific only to certain arms of the study

End point values	Part 3: PBO + Nivo 240	Part 3: Liri 240 + Nivo 240	Part 5: Liri 3 + Nivo 3 + Ipi 1
Number of subjects analysed	2	3	10
Units: Participants
WITH >=50% TUMOR REDUCTION	1	2	0
WITH >=80% TUMOR REDUCTION	0	1	0

No statistical analyses for this end point

Secondary: Overall Survival (OS) - Part 3

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End point title

Overall Survival (OS) - Part 3 ^[19]

End point description

Overall Survival (OS) is defined as the time from date of first dose of study medication to the date of death for any cause. A subject who has not died will be censored at last known date alive. OS for a subject who initiated new cancer treatment, will also be censored at the date of the new treatment initiation. Estimated by Kaplan-Meier Method. 0.99999 = N/A (=Time point at which % of survivors drops below 50% has not been reached due to insufficient number of events and/or follow up)

End point type

Secondary

End point timeframe

From date of first dose of study medication to the date of death for any cause. (Up to approximately 2.5 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: Endpoint is specific only to certain arms of the study

End point values	Part 3: PBO + Nivo 240	Part 3: Liri 240 + Nivo 240
Number of subjects analysed	2	3
Units: Years
median (full range (min-max))	0.99999 (0.2 to 1.2)	0.3 (0.1 to 0.8)

No statistical analyses for this end point

Secondary: Progression Free Survival (PFS) - Part 3

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End point title

Progression Free Survival (PFS) - Part 3 ^[20]

End point description

PFS is the time from the first dose to the date of first objectively documented disease progression or death due to any cause. Participants who died without a reported prior progression was considered to have progressed on the date of their death. Participants with no progression were censored on the last evaluable tumor assessment date. Participants who started subsequent therapy with no prior progression were censored at the last evaluable tumor assessment prior to initiation of the subsequent therapy. Participants with no post-baseline tumor assessment were censored on the date of first dose. Progression is defined as at least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an absolute increase of at least 5 mm (The appearance of new lesions is also considered progression and clinical deterioration in the absence of radiographic evidence is not). 9.99999 = N/A (Insufficient number of participants with events)

End point type

Secondary

End point timeframe

From first dose to the date of first objectively documented disease progression or death due to any cause, whichever occurs first. (Up to approximately 2.5 years)

Notes
[20] - 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: Endpoint is specific only to certain arms of the study

End point values	Part 3: PBO + Nivo 240	Part 3: Liri 240 + Nivo 240
Number of subjects analysed	2	3
Units: Months
median (full range (min-max))	9.99999 (1.1 to 11.0)	1.6 (1.1 to 7.4)

No statistical analyses for this end point

Secondary: Progression Free Survival Rate (PFSR) at 6 months - Part 3

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End point title

Progression Free Survival Rate (PFSR) at 6 months - Part 3 ^[21]

End point description

Percentage of treated participants remaining progression free and surviving at 6 months. For those participants who remain alive and have not progressed, PFS will be censored on the date of the last tumor assessment. Progression is defined as At least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). Clinical deterioration in the absence of radiographic evidence is not considered progression.

End point type

Secondary

End point timeframe

At 6 months after first dose

Notes
[21] - 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: Endpoint is specific only to certain arms of the study

End point values	Part 3: PBO + Nivo 240	Part 3: Liri 240 + Nivo 240
Number of subjects analysed	2	3
Units: Percentage of participants
number (confidence interval 95%)	50.0 (0.6 to 91.0)	33.3 (0.9 to 77.4)

No statistical analyses for this end point

Secondary: Number of Participants with Adverse Events (AEs) - Part 3

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End point title

Number of Participants with Adverse Events (AEs) - Part 3 ^[22]

End point description

End point type

Secondary

End point timeframe

From first dose to 150 days post last dose (up to an average of 51 weeks and a maximum of 2.5 years)

Notes
[22] - 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: Endpoint is specific only to certain arms of the study

End point values	Part 3: PBO + Nivo 240	Part 3: Liri 240 + Nivo 240
Number of subjects analysed	2	3
Units: Participants	2	3

No statistical analyses for this end point

Secondary: Number of Participants with Serious Adverse Events (SAEs) - Part 3

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End point title

Number of Participants with Serious Adverse Events (SAEs) - Part 3 ^[23]

End point description

End point type

Secondary

End point timeframe

From first dose to 150 days post last dose (up to an average of 51 weeks and a maximum of 2.5 years)

Notes
[23] - 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: Endpoint is specific only to certain arms of the study

End point values	Part 3: PBO + Nivo 240	Part 3: Liri 240 + Nivo 240
Number of subjects analysed	2	3
Units: Participants	2	3

No statistical analyses for this end point

Secondary: Number of Participants with Adverse Events (AEs) Leading to Discontinuation - Part 3

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End point title

Number of Participants with Adverse Events (AEs) Leading to Discontinuation - Part 3 ^[24]

End point description

End point type

Secondary

End point timeframe

From first dose to 150 days post last dose (up to an average of 51 weeks and a maximum of 2.5 years)

Notes
[24] - 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: Endpoint is specific only to certain arms of the study

End point values	Part 3: PBO + Nivo 240	Part 3: Liri 240 + Nivo 240
Number of subjects analysed	2	3
Units: Participants	0	0

No statistical analyses for this end point

Secondary: The Number of Participant Deaths in the Study - Part 3

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End point title

The Number of Participant Deaths in the Study - Part 3 ^[25]

End point description

The number of participants who died during the course of the study.

End point type

Secondary

End point timeframe

From first dose to 150 days post last dose (up to an average of 51 weeks and a maximum of 2.5 years)

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

End point values	Part 3: PBO + Nivo 240	Part 3: Liri 240 + Nivo 240
Number of subjects analysed	2	3
Units: Participants	1	3

No statistical analyses for this end point

Secondary: Number of Participants with Clinical Laboratory Test Abnormalities - Part 3

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End point title

Number of Participants with Clinical Laboratory Test Abnormalities - Part 3 ^[26]

End point description

End point type

Secondary

End point timeframe

From first dose to 150 days post last dose (up to an average of 51 weeks and a maximum of 2.5 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: Endpoint is specific only to certain arms of the study

End point values	Part 3: PBO + Nivo 240	Part 3: Liri 240 + Nivo 240
Number of subjects analysed	2	3
Units: Participants
Absolute Neutrophil Count - Grade 3	0	0
Absolute Neutrophil Count - Grade 4	0	0
Alanine Amino Transferase (ALT) - Grade 3	0	0
Alanine Amino Transferase (ALT) - Grade 4	0	0
Albumin - Grade 3	0	0
Albumin - Grade 4	0	0
Alkaline Phosphatase (ALP) - Grade 3	0	0
Alkaline Phosphatase (ALP) - Grade 4	0	0
Amylase, Total - Grade 3	1	0
Amylase, Total - Grade 4	0	0
APTT - Grade 3	99999	99999
APTT - Grade 4	99999	99999
Aspartate Aminotransferase (AST) - Grade 3	0	0
Aspartate Aminotransferase (AST) - Grade 4	0	0
Bilirubin, Total - Grade 3	0	0
Bilirubin, Total - Grade 4	0	0
Calcium, Corrected - Grade 3	99999	0
Calcium, Corrected - Grade 4	99999	0
Calcium, Ionized - Grade 3	0	99999
Calcium, Ionized - Grade 4	0	99999
Calcium, Total - Grade 3	0	0
Calcium, Total - Grade 4	0	0
Creatine Kinase (CK) - Grade 3	99999	99999
Creatine Kinase (CK) - Grade 4	99999	99999
Creatinine - Grade 3	0	0
Creatinine - Grade 4	0	0
Fibrinogen - Grade 3	99999	99999
Fibrinogen - Grade 4	99999	99999
G-Glutamyl Transferase (GGT) - Grade 3	0	0
G-Glutamyl Transferase (GGT) - Grade 4	99999	99999
Glucose, Fasting Serum - Grade 3	99999	99999
Glucose, Fasting Serum - Grade 4	0	0
Glucose, Serum - Grade 3	0	0
Glucose, Serum - Grade 4	0	0
Hemoglobin - Grade 3	0	0
Hemoglobin - Grade 4	0	0
Leukocytes - Grade 3	0	0
Leukocytes - Grade 4	0	0
Lipase, Total (Colorimetric Assay) - Grade 3	0	0
Lipase, Total (Colorimetric Assay) - Grade 4	1	0
Lipase, Total (Turbidimetric Assay) - Grade 3	99999	99999
Lipase, Total (Turbidimetric Assay) - Grade 4	99999	99999
Lymphocytes (Absolute) - Grade 3	0	2
Lymphocytes (Absolute) - Grade 4	1	0
Magnesium, Serum - Grade 3	0	0
Magnesium, Serum - Grade 4	0	0
Neutrophils (Absolute) - Grade 3	0	0
Neutrophils (Absolute) - Grade 4	0	0
pH, Arterial Blood - Grade 3	99999	99999
pH, Arterial Blood - Grade 4	99999	99999
Phosphorus, Inorganic - Grade 3	0	0
Phosphorus, Inorganic - Grade 4	0	0
Platelet Count - Grade 3	0	0
Platelet Count - Grade 4	0	0
Potassium, Serum - Grade 3	0	0
Potassium, Serum - Grade 4	0	0
Sodium Serum - Grade 3	0	0
Sodium Serum - Grade 4	0	0

No statistical analyses for this end point

Secondary: Number of Participants with Anti-Drug Antibodies (ADA) - Parts 1, 2 and 5

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End point title

Number of Participants with Anti-Drug Antibodies (ADA) - Parts 1, 2 and 5 ^[27]

End point description

Number of participants observed as ADA positive at baseline, ADA positive (post-baseline), and ADA negative (post-baseline). Baseline is defined as the last sample before initiation of treatment. Baseline ADA Positive Participant: A participant with baseline ADA positive sample. ADA Positive Participant: Participant with >=1 ADA +ve sample relative to baseline (baseline ADA -ve, or ADA titer >= 9-fold for Lirilumab and >= 4-fold for Nivolumab relative to baseline +ve titer) at any time after first dose during the defined observation time period. ADA Negative Participant: A participant with no ADA positive sample after the initiation of treatment. 99999= N/A (0 participants who received at least 1 dose of drug and have at least 1 ADA sample available) NOTE: The number of participants analyzed for each ADA parameter may vary depending on the number of participants with available ADA samples.

End point type

Secondary

End point timeframe

From first dose to 100 days after last dose (up to approximately 126 weeks)

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: Endpoint is specific only to certain arms of the study

End point values	Part 1/2 Liri 0.1 + Nivo 3	Part 1/2: Liri 0.3 + Nivo 3	Part 1/2: Liri 1 + Nivo 3	Part 1/2: Liri 3 + Nivo 3	Part 5: Liri 3 + Nivo 3 + Ipi 1
Number of subjects analysed	4	15	13	255	4 ^[28]
Units: Participants
Baseline ADA Positive - Liri	0	2	0	21	1
ADA Positive - Liri	1	1	0	20	0
ADA Negative - Liri	3	10	10	234	4
Baseline ADA Positive - Nivo	0	1	3	14	1
ADA Positive - Nivo	0	1	0	43	0
ADA Negative - Nivo	4	14	13	212	3
Baseline ADA Positive - Ipi	99999	99999	99999	99999	1
ADA Positive - Ipi	99999	99999	99999	99999	0
ADA Negative - Ipi	99999	99999	99999	99999	3

Notes
[28] - 0 participants who received at least 1 dose of drug and have at least 1 ADA sample available

No statistical analyses for this end point

Secondary: The Number of Participants with PD-L1 Status at Pretreatment - Parts 1, 2 and 5

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End point title

The Number of Participants with PD-L1 Status at Pretreatment - Parts 1, 2 and 5 ^[29]

End point description

The number of participants with 1% or 5% PD-L1 expression in the tumor cell membrane. Participants are considered positive if they show >=1% or >= 5% PD-L1 expression in the tumor cell membrane and negative if they show < 1% or < 5%. PD-L1 expression is defined as the percent of tumor cells demonstrating plasma membrane PDL1 staining of any intensity. PD-L1 will be evaluated by immunohistochemistry (IHC). PD-L1 status at pretreatment is considered positive if any pretreatment sample is positive. PDL1= programmed cell death ligand 1

End point type

Secondary

End point timeframe

Pre-dose Day 1 (Cycles 1 ,3 ,5, 7, 9), Pre-dose Day 29 (Cycle 1, 2)

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

End point values	Part 1/2 Liri 0.1 + Nivo 3	Part 1/2: Liri 0.3 + Nivo 3	Part 1/2: Liri 1 + Nivo 3	Part 1/2: Liri 3 + Nivo 3	Part 5: Liri 3 + Nivo 3 + Ipi 1
Number of subjects analysed	3	11	13	231	1
Units: Number of participants
PD-L1 1 percent - positive	2	5	9	127	1
PD-L1 1 percent - negative	1	6	4	104	0
PD-L1 5 percent - positive	2	4	4	77	0
PD-L1 5 percent - negative	1	7	9	154	1

No statistical analyses for this end point

Secondary: Maximum Observed Plasma Concentration (Cmax) - Parts 1, 2 and 5

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End point title

Maximum Observed Plasma Concentration (Cmax) - Parts 1, 2 and 5 ^[30]

End point description

Pharmacokinetics of lirilumab were derived from serum concentration versus time data. Geometric CV data is not available, therefore the Arithmetic %CV is represented in the table below. 99999= N/A (insufficient number of participants with available serum concentration data to calculate %CV) NOTE: The number of participants analyzed for each cycle may vary depending on the number of participants with available serum concentration data.

End point type

Secondary

End point timeframe

Pre-dose, end of infusion, 24, 168, and 336 hours post dose on day 1 cycle 1 and pre-dose on day 29 cycle 1. Pre-dose, end of infusion, 24 and 168 hours post dose on cycle 2 day 29.

Notes
[30] - 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: Endpoint is specific only to certain arms of the study

End point values	Part 1/2 Liri 0.1 + Nivo 3	Part 1/2: Liri 0.3 + Nivo 3	Part 1/2: Liri 1 + Nivo 3	Part 1/2: Liri 3 + Nivo 3	Part 5: Liri 3 + Nivo 3 + Ipi 1
Number of subjects analysed	4	13	11	249	2
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1	2223.10 ( 27 )	6509.35 ( 27 )	22250.96 ( 29 )	52034.18 ( 33 )	65333.91 ( 3 )
Cycle 2	2277.39 ( 6 )	7286.95 ( 24 )	25623.89 ( 20 )	69224.70 ( 26 )	81600.00 ( 99999 )

No statistical analyses for this end point

Secondary: Area Under the Plasma Concentration-Time Curve from Time Zero to the Time of the Last Quantifiable Concentration [AUC(0-T)] - Parts 1, 2 and 5

Top of page

End point title

Area Under the Plasma Concentration-Time Curve from Time Zero to the Time of the Last Quantifiable Concentration [AUC(0-T)] - Parts 1, 2 and 5 ^[31]

End point description

End point type

Secondary

End point timeframe

Pre-dose, end of infusion, 24, 168, and 336 hours post dose on day 1 cycle 1 and pre-dose on day 29 cycle 1. Pre-dose, end of infusion, 24 and 168 hours post dose on cycle 2 day 29.

Notes
[31] - 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: Endpoint is specific only to certain arms of the study

End point values	Part 1/2 Liri 0.1 + Nivo 3	Part 1/2: Liri 0.3 + Nivo 3	Part 1/2: Liri 1 + Nivo 3	Part 1/2: Liri 3 + Nivo 3	Part 5: Liri 3 + Nivo 3 + Ipi 1
Number of subjects analysed	4	13	11	249	2
Units: hour*ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1	360903.09 ( 23 )	734836.53 ( 45 )	4462883.03 ( 35 )	9647500.52 ( 37 )	8819119.61 ( 29 )
Cycle 2	569516.79 ( 26 )	1367259.80 ( 67 )	6547184.03 ( 37 )	11731186.91 ( 51 )	9958714.89 ( 99999 )

No statistical analyses for this end point

Secondary: Area Under the Plasma Concentration-Time Curve in 1 Dosing Interval [AUC(TAU)] - Parts 1, 2 and 5

Top of page

End point title

Area Under the Plasma Concentration-Time Curve in 1 Dosing Interval [AUC(TAU)] - Parts 1, 2 and 5 ^[32]

End point description

End point type

Secondary

End point timeframe

Pre-dose, end of infusion, 24, 168, and 336 hours post dose on day 1 cycle 1 and pre-dose on day 29 cycle 1. Pre-dose, end of infusion, 24 and 168 hours post dose on cycle 2 day 29.

Notes
[32] - 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: Endpoint is specific only to certain arms of the study

End point values	Part 1/2 Liri 0.1 + Nivo 3	Part 1/2: Liri 0.3 + Nivo 3	Part 1/2: Liri 1 + Nivo 3	Part 1/2: Liri 3 + Nivo 3	Part 5: Liri 3 + Nivo 3 + Ipi 1
Number of subjects analysed	4	12	11	209	1
Units: hour*ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1	366418.73 ( 21 )	1155363.50 ( 33 )	4462883.03 ( 35 )	11418017.10 ( 28 )	10843715.48 ( 99999 )
Cycle 2	569516.79 ( 26 )	1726615.52 ( 44 )	6712959.58 ( 31 )	18504162.18 ( 28 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Time of Maximum Observed Concentration (Tmax) - Parts 1, 2 and 5

Top of page

End point title

Time of Maximum Observed Concentration (Tmax) - Parts 1, 2 and 5 ^[33]

End point description

Pharmacokinetics of lirilumab were derived from serum concentration versus time data. NOTE: The number of participants analyzed for each cycle may vary depending on the number of participants with available serum concentration data.

End point type

Secondary

End point timeframe

Pre-dose, end of infusion, 24, 168, and 336 hours post dose on day 1 cycle 1 and pre-dose on day 29 cycle 1. Pre-dose, end of infusion, 24 and 168 hours post dose on cycle 2 day 29.

Notes
[33] - 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: Endpoint is specific only to certain arms of the study

End point values	Part 1/2 Liri 0.1 + Nivo 3	Part 1/2: Liri 0.3 + Nivo 3	Part 1/2: Liri 1 + Nivo 3	Part 1/2: Liri 3 + Nivo 3	Part 5: Liri 3 + Nivo 3 + Ipi 1
Number of subjects analysed	4	13	11	249	2
Units: hour
median (full range (min-max))
Cycle 1	1.13 (1.0 to 1.3)	1.05 (0.8 to 21.7)	1.07 (1.0 to 1.6)	1.22 (0.1 to 161.3)	1.03 (1.0 to 1.1)
Cycle 2	1.08 (1.0 to 1.5)	1.02 (1.0 to 1.6)	1.13 (0.9 to 25.5)	1.18 (0.8 to 168.1)	1.33 (1.33 to 1.33)

No statistical analyses for this end point

Secondary: Half-life (T-HALF) - Parts 1, 2 and 5

Top of page

End point title

Half-life (T-HALF) - Parts 1, 2 and 5 ^[34]

End point description

Pharmacokinetics of lirilumab were derived from serum concentration versus time data.

End point type

Secondary

End point timeframe

Pre-dose, end of infusion, 24 and 168 hours post dose on cycle 2 day 29.

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: Endpoint is specific only to certain arms of the study

End point values	Part 1/2 Liri 0.1 + Nivo 3	Part 1/2: Liri 0.3 + Nivo 3	Part 1/2: Liri 1 + Nivo 3	Part 1/2: Liri 3 + Nivo 3	Part 5: Liri 3 + Nivo 3 + Ipi 1
Number of subjects analysed	3	7	7	94	0 ^[35]
Units: hour
arithmetic mean (standard deviation)	383.96 ( 235.421 )	273.89 ( 234.588 )	515.07 ( 361.525 )	281.31 ( 237.236 )	( )

Notes
[35] - 0 treated participants with available serum concentration data.

No statistical analyses for this end point

Secondary: Clearance per Time (CLT) - Parts 1, 2 and 5

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End point title

Clearance per Time (CLT) - Parts 1, 2 and 5 ^[36]

End point description

Pharmacokinetics of lirilumab were derived from serum concentration versus time data. Geometric CV data is not available, therefore the Arithmetic %CV is represented in the table below.

End point type

Secondary

End point timeframe

Pre-dose, end of infusion, 24 and 168 hours post dose on cycle 2 day 29.

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: Endpoint is specific only to certain arms of the study

End point values	Part 1/2 Liri 0.1 + Nivo 3	Part 1/2: Liri 0.3 + Nivo 3	Part 1/2: Liri 1 + Nivo 3	Part 1/2: Liri 3 + Nivo 3	Part 5: Liri 3 + Nivo 3 + Ipi 1
Number of subjects analysed	3	6	10	75	0 ^[37]
Units: liter per hour
geometric mean (geometric coefficient of variation)	0.01 ( 22 )	0.01 ( 38 )	0.01 ( 35 )	0.01 ( 30 )	( )

Notes
[37] - 0 treated participants with available serum concentration data.

No statistical analyses for this end point

Secondary: Trough Observed Concentration (Cmin, also known as CTAU) - Parts 1, 2 and 5

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End point title

Trough Observed Concentration (Cmin, also known as CTAU) - Parts 1, 2 and 5 ^[38]

End point description

Pharmacokinetics of lirilumab were derived from serum concentration versus time data. Geometric CV data is not available, therefore the Arithmetic %CV is represented in the table below. 99999= N/A (insufficient number of participants with available serum concentration data to calculate) NOTE: The number of participants analyzed for each cycle may vary depending on the number of participants with available serum concentration data.

End point type

Secondary

End point timeframe

Pre-dose, end of infusion, 24, 168, and 336 hours post dose on day 1 cycle 1 and pre-dose on day 29 cycle 1. Pre-dose, end of infusion, 24 and 168 hours post dose on cycle 2 day 29.

Notes
[38] - 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: Endpoint is specific only to certain arms of the study

End point values	Part 1/2 Liri 0.1 + Nivo 3	Part 1/2: Liri 0.3 + Nivo 3	Part 1/2: Liri 1 + Nivo 3	Part 1/2: Liri 3 + Nivo 3	Part 5: Liri 3 + Nivo 3 + Ipi 1
Number of subjects analysed	4	12	11	209	1
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1	87.62 ( 77 )	521.28 ( 60 )	2572.90 ( 47 )	6195.04 ( 45 )	5190.00 ( 99999 )
Cycle 2	358.55 ( 68 )	1180.39 ( 65 )	4827.27 ( 32 )	11392.89 ( 45 )	99999 ( 99999 )

No statistical analyses for this end point

Secondary: Area Under the Pasma Concentration-Time Curve from Time Zero Extrapolated to Infinite Time ([AUC(INF)] - Parts 1, 2 and 5

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End point title

Area Under the Pasma Concentration-Time Curve from Time Zero Extrapolated to Infinite Time ([AUC(INF)] - Parts 1, 2 and 5 ^[39]

End point description

Pharmacokinetics of lirilumab were derived from serum concentration versus time data.

End point type

Secondary

End point timeframe

Pre-dose, end of infusion, 24, 168, and 336 hours post dose on day 1 cycle 1 and pre-dose on day 29 cycle 1. Pre-dose, end of infusion, 24 and 168 hours post dose on cycle 2 day 29.

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: Endpoint is specific only to certain arms of the study

End point values	Part 1/2 Liri 0.1 + Nivo 3	Part 1/2: Liri 0.3 + Nivo 3	Part 1/2: Liri 1 + Nivo 3	Part 1/2: Liri 3 + Nivo 3	Part 5: Liri 3 + Nivo 3 + Ipi 1
Number of subjects analysed	0 ^[40]	0 ^[41]	0 ^[42]	0 ^[43]	0 ^[44]
Units: hour*ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1	( )	( )	( )	( )	( )
Cycle 2	( )	( )	( )	( )	( )

Notes
[40] - 0 treated participants with available serum concentration data.
[41] - 0 treated participants with available serum concentration data.
[42] - 0 treated participants with available serum concentration data.
[43] - 0 treated participants with available serum concentration data.
[44] - 0 treated participants with available serum concentration data.

No statistical analyses for this end point

Secondary: Apparent Volume of Distribution During Terminal Phase (Vz) - Parts 1, 2 and 5

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End point title

Apparent Volume of Distribution During Terminal Phase (Vz) - Parts 1, 2 and 5 ^[45]

End point description

Pharmacokinetics of lirilumab were derived from serum concentration versus time data. Based on the PK sample collections, PK parameters depended on terminal phase time points including AUC(INF) and Vz are not reportable

End point type

Secondary

End point timeframe

Pre-dose, end of infusion, 24, 168, and 336 hours post dose on day 1 cycle 1 and pre-dose on day 29 cycle 1. Pre-dose, end of infusion, 24 and 168 hours post dose on cycle 2 day 29.

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: Endpoint is specific only to certain arms of the study

End point values	Part 1/2 Liri 0.1 + Nivo 3	Part 1/2: Liri 0.3 + Nivo 3	Part 1/2: Liri 1 + Nivo 3	Part 1/2: Liri 3 + Nivo 3	Part 5: Liri 3 + Nivo 3 + Ipi 1
Number of subjects analysed	0 ^[46]	0 ^[47]	0 ^[48]	0 ^[49]	0 ^[50]
Units: liter
geometric mean (geometric coefficient of variation)
Cycle 1	( )	( )	( )	( )	( )
Cycle 2	( )	( )	( )	( )	( )

Notes
[46] - 0 treated participants with available serum concentration data.
[47] - 0 treated participants with available serum concentration data.
[48] - 0 treated participants with available serum concentration data.
[49] - 0 treated participants with available serum concentration data.
[50] - 0 treated participants with available serum concentration data.

No statistical analyses for this end point

Secondary: End of Infusion Concentration (Ceoi) - Parts 1, 2 and 5 (Liri)

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End point title

End of Infusion Concentration (Ceoi) - Parts 1, 2 and 5 (Liri) ^[51]

End point description

End point type

Secondary

End point timeframe

Pre-dose and end of infusion on cycle 1 day 1 and cycle 2 day 29.

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: Endpoint is specific only to certain arms of the study

End point values	Part 1/2 Liri 0.1 + Nivo 3	Part 1/2: Liri 0.3 + Nivo 3	Part 1/2: Liri 1 + Nivo 3	Part 1/2: Liri 3 + Nivo 3	Part 5: Liri 3 + Nivo 3 + Ipi 1
Number of subjects analysed	4	13	11	249	2
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1	2223.10 ( 27 )	6434.65 ( 28 )	22250.96 ( 29 )	45163.87 ( 38 )	65333.91 ( 3 )
Cycle 2 Day 29	2277.39 ( 6 )	7286.95 ( 24 )	25185.06 ( 20 )	65874.20 ( 30 )	81600.00 ( 99999 )

No statistical analyses for this end point

Secondary: Ctrough - Parts 1, 2 and 5 (Liri)

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End point title

Ctrough - Parts 1, 2 and 5 (Liri) ^[52]

End point description

End point type

Secondary

End point timeframe

Pre-dose on cycle 1 day 29 and Pre-dose and end of infusion on cycle 2 day 29.

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: Endpoint is specific only to certain arms of the study

End point values	Part 1/2 Liri 0.1 + Nivo 3	Part 1/2: Liri 0.3 + Nivo 3	Part 1/2: Liri 1 + Nivo 3	Part 1/2: Liri 3 + Nivo 3	Part 5: Liri 3 + Nivo 3 + Ipi 1
Number of subjects analysed	3	12	11	200	1
Units: ng/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 29	192.29 ( 42 )	521.28 ( 60 )	2572.90 ( 47 )	6195.08 ( 45 )	5190.00 ( 99999 )
Cycle 2 Day 29	327.50 ( 85 )	1069.84 ( 63 )	4592.95 ( 32 )	10865.91 ( 45 )	19100.00 ( 99999 )

No statistical analyses for this end point

Secondary: End of Infusion Concentration (Ceoi) - Parts 1, 2 and 5 (Nivo)

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End point title

End of Infusion Concentration (Ceoi) - Parts 1, 2 and 5 (Nivo) ^[53]

End point description

Pharmacokinetics of nivolumab were derived from serum concentration versus time data. Geometric CV data is not available, therefore the Arithmetic %CV is represented in the table below. 99999= N/A (insufficient number of participants with available serum concentration data to calculate %CV) NOTE: The number of participants analyzed for each cycle may vary depending on the number of participants with available serum concentration data.

End point type

Secondary

End point timeframe

Pre-dose and end of infusion on cycle 1 day 1 and cycle 2 day 29.

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: Endpoint is specific only to certain arms of the study

End point values	Part 1/2 Liri 0.1 + Nivo 3	Part 1/2: Liri 0.3 + Nivo 3	Part 1/2: Liri 1 + Nivo 3	Part 1/2: Liri 3 + Nivo 3	Part 5: Liri 3 + Nivo 3 + Ipi 1
Number of subjects analysed	4	15	11	253	6
Units: μg/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 1	63.16 ( 31 )	66.33 ( 16 )	66.16 ( 24 )	52.48 ( 25 )	44.75 ( 15 )
Cycle 2 Day 29	104.47 ( 16 )	114.89 ( 28 )	116.08 ( 17 )	99.75 ( 25 )	115.37 ( 7 )

No statistical analyses for this end point

Secondary: Ctrough - Parts 1, 2 and 5 (Nivo)

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End point title

Ctrough - Parts 1, 2 and 5 (Nivo) ^[54]

End point description

Pharmacokinetics of nivolumab were derived from serum concentration versus time data. Geometric CV data is not available, therefore the Arithmetic %CV is represented in the table below. NOTE: The number of participants analyzed for each cycle may vary depending on the number of participants with available serum concentration data.

End point type

Secondary

End point timeframe

336 hours post dose on cycle 1 day 1 (cycle 1 day 15) and pre-dose and end of infusion on cycle 2 day 29.

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: Endpoint is specific only to certain arms of the study

End point values	Part 1/2 Liri 0.1 + Nivo 3	Part 1/2: Liri 0.3 + Nivo 3	Part 1/2: Liri 1 + Nivo 3	Part 1/2: Liri 3 + Nivo 3	Part 5: Liri 3 + Nivo 3 + Ipi 1
Number of subjects analysed	4	14	15	244	4
Units: μg/mL
geometric mean (geometric coefficient of variation)
Cycle 1 Day 15	19.15 ( 16 )	20.14 ( 24 )	21.36 ( 24 )	15.81 ( 32 )	17.30 ( 19 )
Cycle 2 Day 29	55.67 ( 42 )	62.18 ( 38 )	71.31 ( 21 )	50.07 ( 32 )	62.62 ( 17 )

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

All-Cause Mortality was assessed from first dose to study completion (up to 2.5 years). SAEs and NAEs were assessed from first dose to 150 days post last dose (up to an average of 51 weeks and a maximum of 2.5 years).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.0

Reporting group title

Part 1/2 Liri 0.1 + Nivo 3

Reporting group description

Participants receive Lirilumab 0.1 mg/kg every 4 weeks (Q4W) and Nivolumab 3 mg/kg every 2 weeks (Q2W) for twelve 8-week treatment cycles.

Reporting group title

Part 1/2: Liri 0.3 + Nivo 3

Reporting group description

Participants receive Lirilumab 0.3 mg/kg every 4 weeks (Q4W) and Nivolumab 3 mg/kg every 2 weeks (Q2W) for twelve 8-week treatment cycles.

Reporting group title

Part 1/2: Liri 1 + Nivo 3

Reporting group description

Participants receive Lirilumab 1 mg/kg every 4 weeks (Q4W) and Nivolumab 3 mg/kg every 2 weeks (Q2W) for twelve 8-week treatment cycles.

Reporting group title

Part 1/2: Liri 3 + Nivo 3

Reporting group description

Participants receive Lirilumab 3 mg/kg every 4 weeks (Q4W) and Nivolumab 3 mg/kg every 2 weeks (Q2W) for twelve 8-week treatment cycles.

Reporting group title

Part 3: PBO + Nivo 240

Reporting group description

Participants receive Placebo every 4 weeks (Q4W) and a flat dose of nivolumab monotherapy (240mg) every 2 weeks (Q2W) for 8-week cycles until progressive disease.

Reporting group title

Part 3: Liri 240 + Nivo 240

Reporting group description

Participants receive Lirilumab 240 mg every 4 weeks (Q4W) and a flat dose of nivolumab 240 mg every 2 weeks (Q2W) for 8-week cycles until progressive disease.

Reporting group title

Part 5: Liri 3 + Nivo 3 + Ipi 1

Reporting group description

Participants receive Lirilumab 3 mg/kg IV every 4 weeks (Q4W), Nivolumab 3 mg/kg IV every 2 weeks (Q2W), and Ipilimumab 1 mg/kg IV every 6 weeks (Q6W) for 12-week cycles until progressive disease

Serious adverse events	Part 1/2 Liri 0.1 + Nivo 3	Part 1/2: Liri 0.3 + Nivo 3	Part 1/2: Liri 1 + Nivo 3	Part 1/2: Liri 3 + Nivo 3	Part 3: PBO + Nivo 240	Part 3: Liri 240 + Nivo 240	Part 5: Liri 3 + Nivo 3 + Ipi 1
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 4 (25.00%)	8 / 16 (50.00%)	9 / 15 (60.00%)	205 / 287 (71.43%)	2 / 2 (100.00%)	3 / 3 (100.00%)	7 / 10 (70.00%)
number of deaths (all causes)	2	7	5	219	1	3	5
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer metastatic
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cancer pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infected neoplasm
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malignant melanoma in situ
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malignant neoplasm progression
subjects affected / exposed	0 / 4 (0.00%)	2 / 16 (12.50%)	1 / 15 (6.67%)	109 / 287 (37.98%)	1 / 2 (50.00%)	2 / 3 (66.67%)	2 / 10 (20.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	1 / 1	111 / 111	1 / 1	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malignant pleural effusion
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to bone
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to spine
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tumour haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	4 / 287 (1.39%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	4 / 4	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tumour pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Aneurysm
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arterial rupture
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Embolism
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	3 / 287 (1.05%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	4 / 4	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Shock
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Shock haemorrhagic
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Adverse drug reaction
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Asthenia
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Complication associated with device
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Face oedema
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	5 / 287 (1.74%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	6 / 6	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fatigue
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	9 / 287 (3.14%)	0 / 2 (0.00%)	1 / 3 (33.33%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	10 / 10	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperthermia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Localised oedema
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malaise
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	3 / 287 (1.05%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	3 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	14 / 287 (4.88%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	16 / 17	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Secretion discharge
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sudden death
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Swelling
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ulcer
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Non-Cardiac chest pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Uterine polyp
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute pulmonary oedema
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute respiratory failure
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aspiration
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 4 (0.00%)	2 / 16 (12.50%)	0 / 15 (0.00%)	24 / 287 (8.36%)	1 / 2 (50.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	24 / 25	2 / 2	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea exertional
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	6 / 287 (2.09%)	0 / 2 (0.00%)	0 / 3 (0.00%)	2 / 10 (20.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	6 / 6	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypercapnia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypoxia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	4 / 287 (1.39%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	6 / 6	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Laryngeal dyspnoea
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung disorder
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	6 / 287 (2.09%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	6 / 6	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oropharyngeal pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngeal oedema
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	4 / 287 (1.39%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	6 / 6	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	6 / 287 (2.09%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	8 / 8	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	5 / 287 (1.74%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	1 / 5	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	3 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary hypertension
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	5 / 287 (1.74%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	5 / 6	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	5 / 287 (1.74%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	5 / 5	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper airway obstruction
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune-Mediated pneumonitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Completed suicide
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mental status changes
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Product issues
Device occlusion
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device Dislocation
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
General physical condition abnormal
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	3 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lipase increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Clavicle fracture
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device placement issue
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Head injury
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	13 / 287 (4.53%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 13	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteoradionecrosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Overdose
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Radiation skin injury
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Stoma site haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tracheal obstruction
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular procedure complication
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Arrhythmia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Brain oedema
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Carotid artery aneurysm
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Central nervous system haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coma
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Embolic stroke
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	3 / 287 (1.05%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	4 / 4	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neuropathy peripheral
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Presyncope
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	1 / 2 (50.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tremor
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	13 / 287 (4.53%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	13 / 13	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bone marrow failure
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lymph node haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lymphadenopathy
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Splenic haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal hernia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	3 / 287 (1.05%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	4 / 4	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Autoimmune pancreatitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	6 / 287 (2.09%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	5 / 7	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	5 / 287 (1.74%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	2 / 5	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	7 / 287 (2.44%)	0 / 2 (0.00%)	1 / 3 (33.33%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	8 / 8	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mouth haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	3 / 287 (1.05%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	4 / 4	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Salivary gland fistula
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	4 / 287 (1.39%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	4 / 4	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subileus
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tongue haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	4 / 287 (1.39%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	5 / 6	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intra-Abdominal haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Hepatic cirrhosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic failure
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic haematoma
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Dermatitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rash maculo-papular
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tubulointerstitial nephritis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Flank pain
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	3 / 287 (1.05%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	3 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pathological fracture
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abdominal wall abscess
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Actinomycosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bacterial infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	0 / 287 (0.00%)	1 / 2 (50.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	3 / 287 (1.05%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	3 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis orbital
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia bacteraemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infective thrombosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection bacterial
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung abscess
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Otitis externa
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumocystis jirovecii pneumonia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 4 (25.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	13 / 287 (4.53%)	0 / 2 (0.00%)	1 / 3 (33.33%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	13 / 13	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia influenzal
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psoas abscess
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	13 / 287 (4.53%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	15 / 15	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal bacteraemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tracheitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	3 / 287 (1.05%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	3 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	3 / 287 (1.05%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	3 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	5 / 287 (1.74%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	5 / 5	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic ketoacidosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Failure to thrive
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Feeding disorder
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	8 / 287 (2.79%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	10 / 10	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	4 / 287 (1.39%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	6 / 6	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypomagnesaemia
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Malnutrition
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metabolic acidosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Part 1/2 Liri 0.1 + Nivo 3	Part 1/2: Liri 0.3 + Nivo 3	Part 1/2: Liri 1 + Nivo 3	Part 1/2: Liri 3 + Nivo 3	Part 3: PBO + Nivo 240	Part 3: Liri 240 + Nivo 240	Part 5: Liri 3 + Nivo 3 + Ipi 1
Total subjects affected by non serious adverse events
subjects affected / exposed	4 / 4 (100.00%)	16 / 16 (100.00%)	15 / 15 (100.00%)	271 / 287 (94.43%)	2 / 2 (100.00%)	3 / 3 (100.00%)	10 / 10 (100.00%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acrochordon
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Basal cell carcinoma
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	2	0	0	0	0
Haemangioma
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Melanocytic naevus
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Seborrhoeic keratosis
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	1 / 15 (6.67%)	3 / 287 (1.05%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	3	0	0	0
Tumour haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	6 / 287 (2.09%)	0 / 2 (0.00%)	1 / 3 (33.33%)	0 / 10 (0.00%)
occurrences all number	0	0	0	6	0	1	0
Tumour pain
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	16 / 287 (5.57%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1	0	16	0	0	1
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	1	0	0	1
Embolism
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Flushing
subjects affected / exposed	1 / 4 (25.00%)	3 / 16 (18.75%)	0 / 15 (0.00%)	4 / 287 (1.39%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	3	0	5	0	0	0
Hot flush
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	2 / 15 (13.33%)	3 / 287 (1.05%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	2	3	0	0	0
Hypertension
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	1 / 15 (6.67%)	14 / 287 (4.88%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	14	0	0	0
Hypotension
subjects affected / exposed	1 / 4 (25.00%)	0 / 16 (0.00%)	3 / 15 (20.00%)	19 / 287 (6.62%)	0 / 2 (0.00%)	1 / 3 (33.33%)	1 / 10 (10.00%)
occurrences all number	1	0	3	20	0	2	1
Lymphoedema
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	2	0	0	0
Thrombosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Varicose vein
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	43 / 287 (14.98%)	0 / 2 (0.00%)	0 / 3 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	0	0	57	0	0	2
Catheter site haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	1 / 3 (33.33%)	0 / 10 (0.00%)
occurrences all number	0	0	0	2	0	1	0
Chills
subjects affected / exposed	0 / 4 (0.00%)	5 / 16 (31.25%)	1 / 15 (6.67%)	31 / 287 (10.80%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	7	1	33	0	0	1
Device related thrombosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	1	0	0	1
Early satiety
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	1	0	0	1
Face oedema
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	15 / 287 (5.23%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1	17	0	0	1
Facial pain
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	3 / 287 (1.05%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	3	0	0	0
Fatigue
subjects affected / exposed	3 / 4 (75.00%)	6 / 16 (37.50%)	7 / 15 (46.67%)	144 / 287 (50.17%)	1 / 2 (50.00%)	2 / 3 (66.67%)	3 / 10 (30.00%)
occurrences all number	4	6	9	184	1	2	4
Influenza like illness
subjects affected / exposed	1 / 4 (25.00%)	0 / 16 (0.00%)	3 / 15 (20.00%)	6 / 287 (2.09%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	4	6	0	0	0
Injection site swelling
subjects affected / exposed	1 / 4 (25.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Localised oedema
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	5 / 287 (1.74%)	0 / 2 (0.00%)	1 / 3 (33.33%)	1 / 10 (10.00%)
occurrences all number	0	0	0	5	0	1	10
Malaise
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	1 / 15 (6.67%)	3 / 287 (1.05%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	3	0	0	0
Mass
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Mucosal inflammation
subjects affected / exposed	0 / 4 (0.00%)	2 / 16 (12.50%)	0 / 15 (0.00%)	17 / 287 (5.92%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	17	0	0	0
Nodule
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	2 / 15 (13.33%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	2	0	0	0	1
Oedema peripheral
subjects affected / exposed	0 / 4 (0.00%)	2 / 16 (12.50%)	3 / 15 (20.00%)	29 / 287 (10.10%)	0 / 2 (0.00%)	0 / 3 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	2	3	31	0	0	2
Pain
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	1 / 15 (6.67%)	8 / 287 (2.79%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	8	0	0	0
Peripheral swelling
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	3 / 287 (1.05%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	3	0	0	1
Pyrexia
subjects affected / exposed	1 / 4 (25.00%)	5 / 16 (31.25%)	2 / 15 (13.33%)	69 / 287 (24.04%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	1	7	2	103	0	0	1
Swelling face
subjects affected / exposed	0 / 4 (0.00%)	3 / 16 (18.75%)	1 / 15 (6.67%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	3	1	2	0	0	1
Xerosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	5 / 287 (1.74%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	5	0	0	0
Non-Cardiac chest pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	9 / 287 (3.14%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	3	11	0	0	0
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	3 / 287 (1.05%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	3	0	0	0
Type iv hypersensitivity reaction
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Reproductive system and breast disorders
Breast pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Menstruation irregular
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Uterine polyp
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Vaginal haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Vulva cyst
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Vulval disorder
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Respiratory, thoracic and mediastinal disorders
Atelectasis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	2	0	0	1
Cough
subjects affected / exposed	2 / 4 (50.00%)	9 / 16 (56.25%)	5 / 15 (33.33%)	62 / 287 (21.60%)	0 / 2 (0.00%)	0 / 3 (0.00%)	2 / 10 (20.00%)
occurrences all number	2	11	6	73	0	0	2
Dysphonia
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	18 / 287 (6.27%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	19	0	0	0
Dyspnoea
subjects affected / exposed	0 / 4 (0.00%)	2 / 16 (12.50%)	2 / 15 (13.33%)	47 / 287 (16.38%)	0 / 2 (0.00%)	0 / 3 (0.00%)	3 / 10 (30.00%)
occurrences all number	0	2	2	52	0	0	5
Dyspnoea exertional
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	1 / 15 (6.67%)	8 / 287 (2.79%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	10	0	0	0
Haemoptysis
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	10 / 287 (3.48%)	0 / 2 (0.00%)	1 / 3 (33.33%)	0 / 10 (0.00%)
occurrences all number	0	1	0	13	0	1	0
Lung opacity
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	2	0	0	0
Nasal congestion
subjects affected / exposed	0 / 4 (0.00%)	3 / 16 (18.75%)	4 / 15 (26.67%)	12 / 287 (4.18%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	10	6	12	0	0	0
Nasal mucosal disorder
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Oropharyngeal pain
subjects affected / exposed	1 / 4 (25.00%)	1 / 16 (6.25%)	1 / 15 (6.67%)	7 / 287 (2.44%)	1 / 2 (50.00%)	1 / 3 (33.33%)	0 / 10 (0.00%)
occurrences all number	1	1	1	8	1	1	0
Paranasal sinus hypersecretion
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	1	0	0	0
Pharyngeal disorder
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Pleural effusion
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	9 / 287 (3.14%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	10	0	0	0
Pleuritic pain
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	1	0	0	0
Pneumonia aspiration
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	5 / 287 (1.74%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	7	0	0	1
Pneumonitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	3 / 15 (20.00%)	11 / 287 (3.83%)	0 / 2 (0.00%)	1 / 3 (33.33%)	0 / 10 (0.00%)
occurrences all number	0	0	3	12	0	1	0
Productive cough
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	10 / 287 (3.48%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	15	0	0	1
Pulmonary embolism
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	4 / 287 (1.39%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	4	0	0	0
Respiratory tract congestion
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	2	0	0	0
Rhinitis allergic
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	2	0	0	0
Rhinorrhoea
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	6 / 287 (2.09%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	6	0	0	0
Wheezing
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	7 / 287 (2.44%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	2	9	0	0	0
Sinus congestion
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	2 / 15 (13.33%)	5 / 287 (1.74%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	3	7	0	0	0
Immune-Mediated pneumonitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	1
Psychiatric disorders
Anxiety
subjects affected / exposed	1 / 4 (25.00%)	0 / 16 (0.00%)	2 / 15 (13.33%)	19 / 287 (6.62%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	2	20	0	0	0
Confusional state
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	8 / 287 (2.79%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	8	0	0	2
Depressed mood
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Depression
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	1 / 15 (6.67%)	13 / 287 (4.53%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	13	0	0	0
Hallucination
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	2	0	0	0
Insomnia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	6 / 15 (40.00%)	15 / 287 (5.23%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	9	15	0	0	1
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	13 / 287 (4.53%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	19	0	0	0
Amylase increased
subjects affected / exposed	0 / 4 (0.00%)	2 / 16 (12.50%)	1 / 15 (6.67%)	19 / 287 (6.62%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	1	20	0	0	0
Aspartate aminotransferase increased
subjects affected / exposed	0 / 4 (0.00%)	3 / 16 (18.75%)	0 / 15 (0.00%)	21 / 287 (7.32%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	3	0	28	0	0	0
Blood alkaline phosphatase increased
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	13 / 287 (4.53%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	18	0	0	0
Blood bilirubin increased
subjects affected / exposed	0 / 4 (0.00%)	2 / 16 (12.50%)	0 / 15 (0.00%)	7 / 287 (2.44%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	8	0	0	0
Blood creatinine increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	2 / 15 (13.33%)	17 / 287 (5.92%)	0 / 2 (0.00%)	0 / 3 (0.00%)	3 / 10 (30.00%)
occurrences all number	0	0	2	25	0	0	4
Blood lactate dehydrogenase increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	3 / 287 (1.05%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	3	0	0	1
Blood magnesium decreased
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Blood magnesium increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Blood phosphorus decreased
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Blood pressure increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	2 / 15 (13.33%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	2	1	0	0	0
Blood testosterone decreased
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	1 / 3 (33.33%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	1	0
Heart sounds abnormal
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Intraocular pressure increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Lipase increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	21 / 287 (7.32%)	1 / 2 (50.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	2	27	1	0	1
Lymphocyte count decreased
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	5 / 287 (1.74%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	7	0	0	1
Neutrophil count decreased
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	3 / 287 (1.05%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	3	0	0	0
Prothrombin time ratio increased
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Transaminases increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	1
Troponin increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	1 / 3 (33.33%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Weight decreased
subjects affected / exposed	1 / 4 (25.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	39 / 287 (13.59%)	0 / 2 (0.00%)	3 / 3 (100.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	44	0	3	0
Weight increased
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	3 / 287 (1.05%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	3	3	0	0	0
Cd4 lymphocytes decreased
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	1
Electrocardiogram qt prolonged
subjects affected / exposed	1 / 4 (25.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Electrocardiogram t wave amplitude decreased
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	5 / 287 (1.74%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	6	0	0	0
Incision site pain
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Infusion related reaction
subjects affected / exposed	1 / 4 (25.00%)	1 / 16 (6.25%)	7 / 15 (46.67%)	22 / 287 (7.67%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	1	9	24	0	0	0
Muscle strain
subjects affected / exposed	1 / 4 (25.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Post procedural complication
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	1
Road traffic accident
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	2
Skin abrasion
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Sunburn
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Wound dehiscence
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	1
Post-Traumatic pain
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	7 / 287 (2.44%)	1 / 2 (50.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	7	1	0	0
Cardiac failure
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	1	0	0	1
Palpitations
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	5 / 287 (1.74%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	5	0	0	0
Tachycardia
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	9 / 287 (3.14%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1	0	9	0	0	1
Nervous system disorders
Burning sensation
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Cerebrovascular accident
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	2	0	0	0
Consciousness fluctuating
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Dizziness
subjects affected / exposed	0 / 4 (0.00%)	2 / 16 (12.50%)	4 / 15 (26.67%)	22 / 287 (7.67%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	2	6	28	0	0	1
Dysarthria
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	1	0	0	0
Facial paresis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Headache
subjects affected / exposed	1 / 4 (25.00%)	3 / 16 (18.75%)	4 / 15 (26.67%)	44 / 287 (15.33%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	2	7	13	52	0	0	0
Hemiplegia
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Hypoaesthesia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	2 / 15 (13.33%)	3 / 287 (1.05%)	0 / 2 (0.00%)	1 / 3 (33.33%)	0 / 10 (0.00%)
occurrences all number	0	0	6	3	0	1	0
Lethargy
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	4 / 287 (1.39%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	4	0	0	0
Memory impairment
subjects affected / exposed	1 / 4 (25.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	5 / 287 (1.74%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	1	0	0	5	0	0	1
Migraine
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Myoclonus
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Neuropathy peripheral
subjects affected / exposed	1 / 4 (25.00%)	0 / 16 (0.00%)	2 / 15 (13.33%)	6 / 287 (2.09%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	2	6	0	0	0
Paraesthesia
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	5 / 15 (33.33%)	7 / 287 (2.44%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1	7	8	0	0	1
Peripheral sensory neuropathy
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	1	0	0	0
Sciatica
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	2	0	0	0
Sinus headache
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Somnolence
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	10 / 287 (3.48%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	10	0	0	1
Taste disorder
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Visual field defect
subjects affected / exposed	1 / 4 (25.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	2	0	0	0
Vith nerve paralysis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	1 / 3 (33.33%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Blood and lymphatic system disorders
Agranulocytosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Anaemia
subjects affected / exposed	1 / 4 (25.00%)	3 / 16 (18.75%)	0 / 15 (0.00%)	70 / 287 (24.39%)	0 / 2 (0.00%)	1 / 3 (33.33%)	1 / 10 (10.00%)
occurrences all number	1	5	0	87	0	2	1
Eosinophilia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	1	0	0	1
Leukopenia
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	2 / 15 (13.33%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	2	2	0	0	0
Lymph node pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	1
Lymphadenopathy
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	1	0	0	2
Lymphopenia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	8 / 287 (2.79%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	18	0	0	1
Neutropenia
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	2	0	0	0
Thrombocytopenia
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	1 / 15 (6.67%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	1	0	0	0
Ear and labyrinth disorders
External ear pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Hypoacusis
subjects affected / exposed	1 / 4 (25.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	3 / 287 (1.05%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	1	0	3	0	0	0
Vertigo
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	4 / 287 (1.39%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	4	0	0	0
Eye disorders
Cataract
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	1 / 15 (6.67%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	1	0	0	0
Cataract nuclear
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Chorioretinal atrophy
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Chorioretinal disorder
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Diplopia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	5 / 287 (1.74%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	5	0	0	0
Dry eye
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	3 / 287 (1.05%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	3	0	0	0
Eye movement disorder
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Eye pain
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	1	0	0	0
Lagophthalmos
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	1
Meibomian gland dysfunction
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Myopia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Ocular discomfort
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	2	0	0	0
Retinal deposits
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Strabismus
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Swelling of eyelid
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Uveitis
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	1	0	0	0
Vision blurred
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	1 / 15 (6.67%)	6 / 287 (2.09%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	7	0	0	0
Visual acuity reduced
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	2	0	0	0
Visual impairment
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	1 / 287 (0.35%)	0 / 2 (0.00%)	1 / 3 (33.33%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	1	0
Vitreous detachment
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	0	0	0	0
Gastrointestinal disorders
Abdominal discomfort
subjects affected / exposed	1 / 4 (25.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	7 / 287 (2.44%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	1	0	7	0	0	0
Abdominal distension
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	3 / 15 (20.00%)	10 / 287 (3.48%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	3	10	0	0	0
Abdominal pain
subjects affected / exposed	1 / 4 (25.00%)	2 / 16 (12.50%)	5 / 15 (33.33%)	24 / 287 (8.36%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	2	6	29	0	0	0
Abdominal pain lower
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	3	1	0	0	0
Abdominal pain upper
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	2 / 15 (13.33%)	9 / 287 (3.14%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	2	9	0	0	0
Anal haemorrhage
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Colitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	3 / 287 (1.05%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	3	0	0	1
Constipation
subjects affected / exposed	0 / 4 (0.00%)	5 / 16 (31.25%)	4 / 15 (26.67%)	60 / 287 (20.91%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	6	4	69	0	0	2
Dental caries
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	3 / 287 (1.05%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	3	0	0	0
Diarrhoea
subjects affected / exposed	0 / 4 (0.00%)	2 / 16 (12.50%)	7 / 15 (46.67%)	66 / 287 (23.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	3 / 10 (30.00%)
occurrences all number	0	4	20	93	0	0	4
Dry mouth
subjects affected / exposed	0 / 4 (0.00%)	2 / 16 (12.50%)	1 / 15 (6.67%)	19 / 287 (6.62%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	1	22	0	0	0
Dyspepsia
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	5 / 287 (1.74%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	5	0	0	0
Dysphagia
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	29 / 287 (10.10%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	32	0	0	0
Epigastric discomfort
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Gastritis
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	2	0	0	0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	1 / 15 (6.67%)	10 / 287 (3.48%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	1	10	0	0	0
Hypoaesthesia oral
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Melaena
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	4 / 287 (1.39%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	4	0	0	0
Nausea
subjects affected / exposed	2 / 4 (50.00%)	3 / 16 (18.75%)	7 / 15 (46.67%)	62 / 287 (21.60%)	0 / 2 (0.00%)	1 / 3 (33.33%)	1 / 10 (10.00%)
occurrences all number	3	4	16	75	0	1	1
Odynophagia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	6 / 287 (2.09%)	0 / 2 (0.00%)	1 / 3 (33.33%)	0 / 10 (0.00%)
occurrences all number	0	0	0	6	0	1	0
Oesophagitis
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	3 / 287 (1.05%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	3	0	0	0
Oral disorder
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	1	0	0	1
Proctalgia
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	2	0	0	0
Stomatitis
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	10 / 287 (3.48%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1	0	10	0	0	1
Toothache
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	3 / 287 (1.05%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	4	0	0	1
Vomiting
subjects affected / exposed	1 / 4 (25.00%)	2 / 16 (12.50%)	5 / 15 (33.33%)	43 / 287 (14.98%)	0 / 2 (0.00%)	0 / 3 (0.00%)	2 / 10 (20.00%)
occurrences all number	2	5	6	55	0	0	2
Skin and subcutaneous tissue disorders
Alopecia
subjects affected / exposed	1 / 4 (25.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	4 / 287 (1.39%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	4	0	0	0
Dermatitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Dermatitis acneiform
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	4 / 287 (1.39%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	5	0	0	0
Ecchymosis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Dry skin
subjects affected / exposed	1 / 4 (25.00%)	0 / 16 (0.00%)	2 / 15 (13.33%)	12 / 287 (4.18%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	2	13	0	0	0
Erythema
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	2 / 15 (13.33%)	17 / 287 (5.92%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	2	17	0	0	0
Night sweats
subjects affected / exposed	0 / 4 (0.00%)	2 / 16 (12.50%)	0 / 15 (0.00%)	6 / 287 (2.09%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	7	0	0	0
Melanocytic hyperplasia
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Papule
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Parapsoriasis
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Pruritus
subjects affected / exposed	2 / 4 (50.00%)	4 / 16 (25.00%)	8 / 15 (53.33%)	48 / 287 (16.72%)	0 / 2 (0.00%)	0 / 3 (0.00%)	3 / 10 (30.00%)
occurrences all number	2	7	11	65	0	0	5
Purpura
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Rash
subjects affected / exposed	1 / 4 (25.00%)	7 / 16 (43.75%)	4 / 15 (26.67%)	42 / 287 (14.63%)	0 / 2 (0.00%)	0 / 3 (0.00%)	2 / 10 (20.00%)
occurrences all number	2	12	7	61	0	0	3
Rash erythematous
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Rash papular
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Rash maculo-papular
subjects affected / exposed	0 / 4 (0.00%)	2 / 16 (12.50%)	2 / 15 (13.33%)	13 / 287 (4.53%)	1 / 2 (50.00%)	0 / 3 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	2	3	14	1	0	2
Scab
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Rash pruritic
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	4 / 15 (26.67%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	4	2	0	0	0
Skin hyperpigmentation
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	2	0	0	0
Skin lesion
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	5 / 287 (1.74%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	6	0	0	0
Vitiligo
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	2 / 15 (13.33%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	2	2	0	0	0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Nephrolithiasis
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	1	0	0	0
Nocturia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Pollakiuria
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	2 / 15 (13.33%)	6 / 287 (2.09%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	2	6	0	0	0
Urinary incontinence
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Urinary retention
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	6 / 287 (2.09%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	6	0	0	0
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	7 / 287 (2.44%)	0 / 2 (0.00%)	1 / 3 (33.33%)	0 / 10 (0.00%)
occurrences all number	0	0	0	7	0	1	0
Hypothyroidism
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	2 / 15 (13.33%)	25 / 287 (8.71%)	1 / 2 (50.00%)	2 / 3 (66.67%)	0 / 10 (0.00%)
occurrences all number	0	1	2	31	1	2	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	1 / 4 (25.00%)	5 / 16 (31.25%)	8 / 15 (53.33%)	35 / 287 (12.20%)	0 / 2 (0.00%)	0 / 3 (0.00%)	3 / 10 (30.00%)
occurrences all number	1	8	13	39	0	0	4
Arthritis
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1	0	3	0	0	1
Back pain
subjects affected / exposed	1 / 4 (25.00%)	1 / 16 (6.25%)	3 / 15 (20.00%)	34 / 287 (11.85%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	1	5	36	0	0	0
Foot deformity
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Joint stiffness
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Joint swelling
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	2	0	0	0
Muscle spasms
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	2 / 15 (13.33%)	15 / 287 (5.23%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	2	16	0	0	0
Muscular weakness
subjects affected / exposed	0 / 4 (0.00%)	2 / 16 (12.50%)	6 / 15 (40.00%)	6 / 287 (2.09%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	7	6	0	0	0
Musculoskeletal chest pain
subjects affected / exposed	1 / 4 (25.00%)	1 / 16 (6.25%)	2 / 15 (13.33%)	9 / 287 (3.14%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	1	2	9	0	0	0
Musculoskeletal discomfort
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	3 / 287 (1.05%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	3	0	0	0
Musculoskeletal pain
subjects affected / exposed	0 / 4 (0.00%)	2 / 16 (12.50%)	2 / 15 (13.33%)	15 / 287 (5.23%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	2	17	0	0	0
Musculoskeletal stiffness
subjects affected / exposed	0 / 4 (0.00%)	2 / 16 (12.50%)	0 / 15 (0.00%)	3 / 287 (1.05%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	0	3	0	0	0
Myalgia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	4 / 15 (26.67%)	11 / 287 (3.83%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	6	11	0	0	0
Neck pain
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	3 / 15 (20.00%)	26 / 287 (9.06%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	3	27	0	0	2
Osteoarthritis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	2	0	0	0
Pain in extremity
subjects affected / exposed	0 / 4 (0.00%)	2 / 16 (12.50%)	4 / 15 (26.67%)	8 / 287 (2.79%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	2	7	8	0	0	0
Pain in jaw
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	7 / 287 (2.44%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	7	0	0	1
Plantar fasciitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	2 / 15 (13.33%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	2	0	0	0	0
Infections and infestations
Bacterial vaginosis
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Bronchitis
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	11 / 287 (3.83%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1	0	13	0	0	1
Conjunctivitis
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	2	0	0	0
Ear infection
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	2	0	0	0
Fungal disease carrier
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	1
Fungal infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0
Gastroenteritis
subjects affected / exposed	1 / 4 (25.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	1	0	0	0
Gastroenteritis viral
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	1 / 3 (33.33%)	0 / 10 (0.00%)
occurrences all number	0	0	0	0	0	1	0
Genital infection fungal
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Hordeolum
subjects affected / exposed	1 / 4 (25.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Influenza
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	2	0	0	1
Lower respiratory tract infection
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Nasopharyngitis
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	7 / 287 (2.44%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	7	0	0	0
Ophthalmic herpes zoster
subjects affected / exposed	1 / 4 (25.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	1	0	0	0	0	0	0
Oral candidiasis
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	5 / 287 (1.74%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	5	0	0	0
Pneumonia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	16 / 287 (5.57%)	1 / 2 (50.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	1	19	1	0	2
Pneumonia influenzal
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	1
Respiratory tract infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	2 / 287 (0.70%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	2	0	0	1
Sinusitis
subjects affected / exposed	0 / 4 (0.00%)	3 / 16 (18.75%)	2 / 15 (13.33%)	7 / 287 (2.44%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	4	2	7	0	0	0
Staphylococcal bacteraemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	0	0	0	0
Upper respiratory tract infection
subjects affected / exposed	1 / 4 (25.00%)	3 / 16 (18.75%)	2 / 15 (13.33%)	18 / 287 (6.27%)	0 / 2 (0.00%)	0 / 3 (0.00%)	2 / 10 (20.00%)
occurrences all number	1	3	2	21	0	0	2
Viral infection
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	1 / 287 (0.35%)	0 / 2 (0.00%)	1 / 3 (33.33%)	0 / 10 (0.00%)
occurrences all number	0	0	0	1	0	1	0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	2 / 4 (50.00%)	2 / 16 (12.50%)	4 / 15 (26.67%)	50 / 287 (17.42%)	0 / 2 (0.00%)	1 / 3 (33.33%)	2 / 10 (20.00%)
occurrences all number	3	2	4	55	0	1	2
Dehydration
subjects affected / exposed	1 / 4 (25.00%)	1 / 16 (6.25%)	2 / 15 (13.33%)	17 / 287 (5.92%)	0 / 2 (0.00%)	1 / 3 (33.33%)	1 / 10 (10.00%)
occurrences all number	1	1	2	21	0	1	1
Diabetes mellitus
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	0	0	0	1
Gout
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	0 / 287 (0.00%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	1	0	0	0	0	0
Hypercalcaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	21 / 287 (7.32%)	0 / 2 (0.00%)	1 / 3 (33.33%)	1 / 10 (10.00%)
occurrences all number	0	0	0	30	0	1	1
Hyperglycaemia
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	13 / 287 (4.53%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	1	0	16	0	0	1
Hyperkalaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	2 / 15 (13.33%)	9 / 287 (3.14%)	0 / 2 (0.00%)	1 / 3 (33.33%)	1 / 10 (10.00%)
occurrences all number	0	0	6	10	0	1	1
Hypoglycaemia
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	3 / 287 (1.05%)	0 / 2 (0.00%)	0 / 3 (0.00%)	1 / 10 (10.00%)
occurrences all number	0	0	0	3	0	0	1
Hypokalaemia
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	22 / 287 (7.67%)	0 / 2 (0.00%)	1 / 3 (33.33%)	1 / 10 (10.00%)
occurrences all number	0	1	0	27	0	1	1
Hypomagnesaemia
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	0 / 15 (0.00%)	27 / 287 (9.41%)	0 / 2 (0.00%)	0 / 3 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	1	0	44	0	0	2
Hyponatraemia
subjects affected / exposed	0 / 4 (0.00%)	1 / 16 (6.25%)	1 / 15 (6.67%)	28 / 287 (9.76%)	0 / 2 (0.00%)	0 / 3 (0.00%)	2 / 10 (20.00%)
occurrences all number	0	1	3	34	0	0	2
Hypophosphataemia
subjects affected / exposed	1 / 4 (25.00%)	0 / 16 (0.00%)	2 / 15 (13.33%)	14 / 287 (4.88%)	0 / 2 (0.00%)	1 / 3 (33.33%)	1 / 10 (10.00%)
occurrences all number	1	0	3	19	0	1	1
Iron deficiency
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	0 / 15 (0.00%)	7 / 287 (2.44%)	0 / 2 (0.00%)	1 / 3 (33.33%)	0 / 10 (0.00%)
occurrences all number	0	0	0	7	0	1	0
Vitamin d deficiency
subjects affected / exposed	0 / 4 (0.00%)	0 / 16 (0.00%)	1 / 15 (6.67%)	1 / 287 (0.35%)	0 / 2 (0.00%)	0 / 3 (0.00%)	0 / 10 (0.00%)
occurrences all number	0	0	1	1	0	0	0

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

04 Sep 2012

Revised dose escalation design 3 + 3 + 3. Revised permanent discontinuation criteria. Revised eligibility to require subjects to have normal thyroid function and at least 1 prior therapy in the advanced/metastatic setting.

06 Feb 2014

In the dose escalation cohorts, increased the number of subjects that may be enrolled at each Dose Level from 12 to 15 in order to obtain additional data. Updated safety information for nivolumab and lirilumab. Additional tumor types of SCCHN and hepatocellular carcinoma added to dose cohort expansions. The colorectal cancer cohort was modified to enroll only subjects with non-microsatellite-instability-high tumors. Gehan 2-stage approach for efficacy assessment of these tumor types added. Cohort expansions of ovarian and renal cell carcinoma deleted. Inclusion criteria for all cohort expansions updated. Increased number of subjects in non-small cell lung cancer and melanoma cohorts. Updates to vital sign assessments, clarifications of efficacy criteria, and ADA endpoints were added.

24 Jul 2014

Updated inclusion and exclusion criteria, clarification of diagnostic imaging scan criteria and collection timelines, and addition of PK collection points.

02 Nov 2015

Add additional subjects to the SCCHN cohort in order to further explore the safety and efficacy of the compound.

12 Apr 2016

Updated objectives

12 Dec 2016

Indicated that the Dose Escalation and Cohort Expansion (Part 1) and the SCCHN Cohort Expansion (Part 2) have both completed enrollment and are not applicable starting with Amendment 13 and all subsequent amendments and that their specific eligibility criteria are not applicable. Added 4 new study parts: The SCCHN Randomized Cohorts (Part 3), The Signal Detection Cohort Expansion (Part 4), The Signal Detection in SCCHN with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5), The Signal Detection in Previously Untreated MEL with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 6). Added that enrollment for the SCCHN Cohort Expansion (Part 2) will stop when the SCCHN Randomized Cohorts (Part 3) open. Safety text, eligibility criteria, study objectives, study design, discontinuation criteria, and statistical analyses updated for all new cohorts.

28 Feb 2017

Updated the cohort size and subject allocation for the Signal Detection Cohort Expansion (Part 4) and the cohort size, randomization scheme, treatment regimen, and inclusion criteria for the Signal Detection in Squamous Cell Carcinoma of the Head and Neck (SCCHN) with Lirilumab, Nivolumab, and Ipilimumab Combination (Part 5).

08 May 2018

The primary purpose of this revised protocol is to close the future enrollment in Part 3 and Part 5 and removal of Part 4 and Part 6 from the protocol study design.

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results: A Phase 1/2 Study of the Combination of Lirilumab (Anti-KIR) Plus Nivolumab (Anti-PD-1) or Lirilumab Plus Nivolumab and Ipilimumab in Advanced Refractory Solid Tumors

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of Participants with Adverse Events (AEs) - Parts 1, 2 and 5

Primary: Number of Participants with Adverse Events (AEs) - Parts 1, 2 and 5

Primary: Number of Participants with Serious Adverse Events (SAEs) - Parts 1, 2 and 5

Primary: Number of Participants with Serious Adverse Events (SAEs) - Parts 1, 2 and 5

Primary: Number of Participants with Adverse Events (AEs) Leading to Discontinuation - Parts 1, 2 and 5

Primary: Number of Participants with Adverse Events (AEs) Leading to Discontinuation - Parts 1, 2 and 5

Primary: The Number of Participant Deaths in the Study - Parts 1, 2 and 5

Primary: The Number of Participant Deaths in the Study - Parts 1, 2 and 5

Primary: Number of Participants with Clinical Laboratory Test Abnormalities - Parts 1, 2 and 5

Primary: Number of Participants with Clinical Laboratory Test Abnormalities - Parts 1, 2 and 5

Primary: Objective Response Rate (ORR)

Primary: Objective Response Rate (ORR)

Secondary: Disease Control Rate (DCR) - Part 3

Secondary: Disease Control Rate (DCR) - Part 3

Secondary: Median Duration of Response (mDOR) - Parts 3 and 5

Secondary: Median Duration of Response (mDOR) - Parts 3 and 5

Secondary: Median Time to Response (mTTR) - Part 3

Secondary: Median Time to Response (mTTR) - Part 3

Secondary: The Number of Participants with >=50% or >=80% Tumor Reduction - Parts 3 and 5

Secondary: The Number of Participants with >=50% or >=80% Tumor Reduction - Parts 3 and 5

Secondary: Overall Survival (OS) - Part 3

Secondary: Overall Survival (OS) - Part 3

Secondary: Progression Free Survival (PFS) - Part 3

Secondary: Progression Free Survival (PFS) - Part 3

Secondary: Progression Free Survival Rate (PFSR) at 6 months - Part 3

Secondary: Progression Free Survival Rate (PFSR) at 6 months - Part 3

Secondary: Number of Participants with Adverse Events (AEs) - Part 3

Secondary: Number of Participants with Adverse Events (AEs) - Part 3

Secondary: Number of Participants with Serious Adverse Events (SAEs) - Part 3

Secondary: Number of Participants with Serious Adverse Events (SAEs) - Part 3

Secondary: Number of Participants with Adverse Events (AEs) Leading to Discontinuation - Part 3

Secondary: Number of Participants with Adverse Events (AEs) Leading to Discontinuation - Part 3

Secondary: The Number of Participant Deaths in the Study - Part 3

Secondary: The Number of Participant Deaths in the Study - Part 3

Secondary: Number of Participants with Clinical Laboratory Test Abnormalities - Part 3

Secondary: Number of Participants with Clinical Laboratory Test Abnormalities - Part 3

Secondary: Number of Participants with Anti-Drug Antibodies (ADA) - Parts 1, 2 and 5

Secondary: Number of Participants with Anti-Drug Antibodies (ADA) - Parts 1, 2 and 5

Secondary: The Number of Participants with PD-L1 Status at Pretreatment - Parts 1, 2 and 5

Secondary: The Number of Participants with PD-L1 Status at Pretreatment - Parts 1, 2 and 5

Secondary: Maximum Observed Plasma Concentration (Cmax) - Parts 1, 2 and 5

Secondary: Maximum Observed Plasma Concentration (Cmax) - Parts 1, 2 and 5

Secondary: Area Under the Plasma Concentration-Time Curve from Time Zero to the Time of the Last Quantifiable Concentration [AUC(0-T)] - Parts 1, 2 and 5

Secondary: Area Under the Plasma Concentration-Time Curve from Time Zero to the Time of the Last Quantifiable Concentration [AUC(0-T)] - Parts 1, 2 and 5

Secondary: Area Under the Plasma Concentration-Time Curve in 1 Dosing Interval [AUC(TAU)] - Parts 1, 2 and 5

Secondary: Area Under the Plasma Concentration-Time Curve in 1 Dosing Interval [AUC(TAU)] - Parts 1, 2 and 5

Secondary: Time of Maximum Observed Concentration (Tmax) - Parts 1, 2 and 5

Secondary: Time of Maximum Observed Concentration (Tmax) - Parts 1, 2 and 5

Secondary: Half-life (T-HALF) - Parts 1, 2 and 5

Secondary: Half-life (T-HALF) - Parts 1, 2 and 5

Secondary: Clearance per Time (CLT) - Parts 1, 2 and 5

Secondary: Clearance per Time (CLT) - Parts 1, 2 and 5

Secondary: Trough Observed Concentration (Cmin, also known as CTAU) - Parts 1, 2 and 5

Secondary: Trough Observed Concentration (Cmin, also known as CTAU) - Parts 1, 2 and 5

Secondary: Area Under the Pasma Concentration-Time Curve from Time Zero Extrapolated to Infinite Time ([AUC(INF)] - Parts 1, 2 and 5

Secondary: Area Under the Pasma Concentration-Time Curve from Time Zero Extrapolated to Infinite Time ([AUC(INF)] - Parts 1, 2 and 5

Secondary: Apparent Volume of Distribution During Terminal Phase (Vz) - Parts 1, 2 and 5

Secondary: Apparent Volume of Distribution During Terminal Phase (Vz) - Parts 1, 2 and 5

Secondary: End of Infusion Concentration (Ceoi) - Parts 1, 2 and 5 (Liri)

Secondary: End of Infusion Concentration (Ceoi) - Parts 1, 2 and 5 (Liri)

Secondary: Ctrough - Parts 1, 2 and 5 (Liri)

Secondary: Ctrough - Parts 1, 2 and 5 (Liri)

Secondary: End of Infusion Concentration (Ceoi) - Parts 1, 2 and 5 (Nivo)

Secondary: End of Infusion Concentration (Ceoi) - Parts 1, 2 and 5 (Nivo)

Secondary: Ctrough - Parts 1, 2 and 5 (Nivo)

Secondary: Ctrough - Parts 1, 2 and 5 (Nivo)

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Clinical Trial Results:
A Phase 1/2 Study of the Combination of Lirilumab (Anti-KIR) Plus Nivolumab (Anti-PD-1) or Lirilumab Plus Nivolumab and Ipilimumab in Advanced Refractory Solid Tumors