Flag of the European Union

EU Clinical Trials Register

Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:

interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC

clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
Clinical Trials Information System (CTIS).

The EU Clinical Trials Register currently displays 43871 clinical trials with a EudraCT protocol, of which 7290 are clinical trials conducted with subjects less than 18 years old. The register also displays information on 18700 older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).

Examples: Cancer AND drug name. Pneumonia AND sponsor name.
How to search [pdf]

Advanced Search:

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

< Back to search results

Clinical Trial Results:
An Open-Label, Multicenter Clinical Trial with Nivolumab (BMS-936558) Monotherapy in Subjects with Advanced or Metastatic Squamous Cell (Sq) Non-Small Cell Lung Cancer (NSCLC) who Have Received at Least One Prior Systemic Regimen for the Treatment of Stage IIIb/IV SqNSCLC

Summary
EudraCT number	2014-001285-10
Trial protocol	HU SE DE FI DK PT ES AT GB IE GR RO
Global end of trial date	27 Aug 2021

Results information
Results version number	v2(current)
This version publication date	02 Nov 2022
First version publication date	11 Sep 2022
Other versions	v1
Version creation reason

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

CA209-171

ISRCTN number

-

US NCT number

NCT02409368

WHO universal trial number (UTN)

-

Sponsor organisation name

Bristol-Myers Squibb

Sponsor organisation address

Chaussee de la Hulpe 185, Brussels, Belgium, 1170

Public contact

Bristol-Myers Squibb Study Director, Bristol-Myers Squibb, 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)

No

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

No

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

No

Analysis stage

Final

Date of interim/final analysis

14 Oct 2021

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

27 Aug 2021

Was the trial ended prematurely?

No

Main objective of the trial

To determine the incidence of high-grade (CTCAE v4.0 Grades 3-4), treatment-related, select adverse events in subjects with advanced or metastatic SqNSCLC who progressed during or after at least 1 systemic therapy.

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

29 Apr 2015

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Austria: 9

Country: Number of subjects enrolled

Denmark: 16

Country: Number of subjects enrolled

Finland: 10

Country: Number of subjects enrolled

Greece: 34

Country: Number of subjects enrolled

Hungary: 51

Country: Number of subjects enrolled

Ireland: 3

Country: Number of subjects enrolled

Poland: 81

Country: Number of subjects enrolled

Portugal: 28

Country: Number of subjects enrolled

Romania: 79

Country: Number of subjects enrolled

Russian Federation: 39

Country: Number of subjects enrolled

Spain: 232

Country: Number of subjects enrolled

Sweden: 18

Country: Number of subjects enrolled

United Kingdom: 212

Worldwide total number of subjects

812

EEA total number of subjects

561

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

331

From 65 to 84 years

480

85 years and over

1

Subject disposition

Top of page

Recruitment details

-

Screening details

1 subject was ECOG PS 3 and thus outside the scope of the protocol. There were 2 ECOG classification periods during this study. The first was used in Primary Endpoint analysis. The second was used in Baseline Characteristics, Secondary Endpoint, and AE analysis. 1 subject was lost from initial ECOG Classification but included at Study Completion.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

ECOG (PS0)

Arm description

ECOG Performance Status 0 nivolumab 3 mg/kg as a 60- minute IV infusion every 2 weeks

Arm type

Experimental

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nivolumab 3 mg/kg as a 60- minute IV infusion every 2 weeks

ECOG (PS1)

Arm description

ECOG Performance Status 1 nivolumab 3 mg/kg as a 60- minute IV infusion every 2 weeks

Arm type

Experimental

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nivolumab 3 mg/kg as a 60- minute IV infusion every 2 weeks

ECOG (PS 2)

Arm description

ECOG Performance Status 2 nivolumab 3 mg/kg as a 60- minute IV infusion every 2 weeks

Arm type

Experimental

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nivolumab 3 mg/kg as a 60- minute IV infusion every 2 weeks

ECOG (PS3)

Arm description

ECOG Performance Status 3 nivolumab 3 mg/kg as a 60- minute IV infusion every 2 weeks

Arm type

Experimental

Investigational medicinal product name

Nivolumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Nivolumab 3 mg/kg as a 60- minute IV infusion every 2 weeks

Number of subjects in period 1	ECOG (PS0)	ECOG (PS1)	ECOG (PS 2)	ECOG (PS3)
Started	172	537	102	1
Completed	0	0	0	0
Not completed	172	537	102	1
Adverse event, serious fatal	1	5	-	-
Participant withdrew consent	2	3	4	-
Study drug toxicity	17	42	7	-
Other Reasons	5	26	2	-
Maximum clinical benefit	6	5	-	-
Participant no longer meets study criteria	3	8	3	-
Adverse event unrelated to study drug	17	49	12	-
Lost to follow-up	1	5	-	-
Poor/non-compliance	-	3	2	-
Disease Progression	113	382	70	1
Participant request to discontinue study treatment	6	6	2	-
Administrative reason by sponsor	1	3	-	-

Baseline characteristics

Top of page

Reporting group title

ECOG (PS0)

Reporting group description

ECOG Performance Status 0 nivolumab 3 mg/kg as a 60- minute IV infusion every 2 weeks

Reporting group title

ECOG (PS1)

Reporting group description

ECOG Performance Status 1 nivolumab 3 mg/kg as a 60- minute IV infusion every 2 weeks

Reporting group title

ECOG (PS 2)

Reporting group description

ECOG Performance Status 2 nivolumab 3 mg/kg as a 60- minute IV infusion every 2 weeks

Reporting group title

ECOG (PS3)

Reporting group description

ECOG Performance Status 3 nivolumab 3 mg/kg as a 60- minute IV infusion every 2 weeks

Reporting group values	ECOG (PS0)	ECOG (PS1)	ECOG (PS 2)	ECOG (PS3)	Total
Number of subjects	172	537	102	1	812
Age categorical
Units: Subjects
Adults (18-64 years)	83	217	31	0	331
From 65-84 years	89	320	70	1	480
85 years and over	0	0	1	0	1
Age Continuous
"999"=N/A
Units: years
arithmetic mean (standard deviation)	63.6 ± 8.28	66.1 ± 8.27	67.9 ± 7.29	71 ± 999	-
Sex: Female, Male
Units: Participants
Female	37	111	22	1	171
Male	135	426	80	0	641
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0
Asian	0	2	0	0	2
Native Hawaiian or Other Pacific Islander	0	0	0	0	0
Black or African American	0	3	0	0	3
White	165	530	102	1	798
More than one race	0	0	0	0	0
Unknown or Not Reported	7	2	0	0	9
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	13	37	11	0	61
Not Hispanic or Latino	159	500	91	1	751
Unknown or Not Reported	0	0	0	0	0

End points

Top of page

Reporting group title

ECOG (PS0)

Reporting group description

ECOG Performance Status 0 nivolumab 3 mg/kg as a 60- minute IV infusion every 2 weeks

Reporting group title

ECOG (PS1)

Reporting group description

ECOG Performance Status 1 nivolumab 3 mg/kg as a 60- minute IV infusion every 2 weeks

Reporting group title

ECOG (PS 2)

Reporting group description

ECOG Performance Status 2 nivolumab 3 mg/kg as a 60- minute IV infusion every 2 weeks

Reporting group title

ECOG (PS3)

Reporting group description

ECOG Performance Status 3 nivolumab 3 mg/kg as a 60- minute IV infusion every 2 weeks

Primary: Number of Participants With High Grade (Grade 3, 4 and 5) Treatment Related Select Adverse Events

Top of page

End point title

Number of Participants With High Grade (Grade 3, 4 and 5) Treatment Related Select Adverse Events ^[1] ^[2]

End point description

The total number of participants with high grade treatment related select adverse events.

End point type

Primary

End point timeframe

From first dose to time of analysis of primary endpoint (approximately up to 34 months)

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 were planned for this endpoint
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only summary statistics were planned for this endpoint

End point values	ECOG (PS0)	ECOG (PS1)	ECOG (PS 2)
Number of subjects analysed	172	537	102
Units: Participants
Skin	2	7	0
Gastrointestinal	1	10	0
Endocrine	4	3	0
Hepatic	4	12	2
Pulmonary	2	6	0
Renal	0	3	1
Hypersensitivity/ Infusion reaction	0	0	0

No statistical analyses for this end point

Secondary: Number of Participants with High Grade Select Adverse Events

Top of page

End point title

Number of Participants with High Grade Select Adverse Events ^[3]

End point description

An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation subject administered study drug and that does not necessarily have a causal relationship with this treatment. Select AEs include Pulmonary toxicity, Gastrointestinal toxicity (diarrhea or colitis, Endocrinopathies, Hepatotoxicity (including asymptomatic LFT elevations), Renal toxicity, Skin toxicity, and Neurological toxicity.

End point type

Secondary

End point timeframe

From first dose up to 100 days post last dose (up to 76 months)

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

End point values	ECOG (PS0)	ECOG (PS1)	ECOG (PS 2)
Number of subjects analysed	172	537	102
Units: Participants
Skin	2	7	0
Gastrointestinal	1	11	0
Endocrine	5	4	0
Hepatic	6	19	3
Pulmonary	3	9	1
Renal	0	7	1
Hypersensitivity/ Infusion reaction	0	0	1

No statistical analyses for this end point

Secondary: Median Time to Onset of Any Grade Select Adverse Events

Top of page

End point title

Median Time to Onset of Any Grade Select Adverse Events ^[4]

End point description

Median Time to onset of any grade select adverse events reported up to 100 days after last doseMedian Time to onset of any grade select adverse events reported up to 100 days after last dose. An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation subject administered study drug and that does not necessarily have a causal relationship with this treatment. Select AEs include Pulmonary toxicity, Gastrointestinal toxicity (diarrhea or colitis, Endocrinopathies, Hepatotoxicity (including asymptomatic LFT elevations), Renal toxicity, Skin toxicity, and Neurological toxicity.

End point type

Secondary

End point timeframe

From first dose up to 100 days post last dose (up to approximately 65 months)

Notes
[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: Only summary statistics were planned for this endpoint

End point values	ECOG (PS0)	ECOG (PS1)	ECOG (PS 2)
Number of subjects analysed	172	537	102
Units: Weeks
median (full range (min-max))
Endrocrine	12.79 (4.0 to 121.6)	10.14 (1.9 to 165.1)	19.86 (6.1 to 55.4)
Gastrointestinal	11.71 (0.1 to 88.0)	8.86 (0.1 to 228.1)	6.00 (0.3 to 64.3)
Hepatic	26.64 (1.4 to 234.1)	11.43 (2.0 to 90.1)	8.14 (2.0 to 88.1)
Pulmonary	33.43 (7.4 to 169.4)	11.50 (0.6 to 166.0)	3.93 (0.1 to 26.3)
Renal	28.86 (4.1 to 129.9)	22.71 (0.1 to 246.0)	10.29 (1.4 to 52.9)
Skin	12.14 (0.1 to 92.1)	7.86 (0.1 to 200.1)	14.71 (2.1 to 81.7)
Hypersensitivity/Infusion Reaction	1.93 (1.7 to 2.1)	2.21 (0.3 to 20.3)	2.14 (2.1 to 28.6)

No statistical analyses for this end point

Secondary: Median Time to Resolution of any Grade Select Adverse Events

Top of page

End point title

Median Time to Resolution of any Grade Select Adverse Events ^[5]

End point description

Median time to resolution of any grade select adverse events reported up to 100 days after last dose. An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a preexisting medical condition in a clinical investigation subject administered study drug and that does not necessarily have a causal relationship with this treatment. Select AEs include Pulmonary toxicity, Gastrointestinal toxicity (diarrhea or colitis, Endocrinopathies, Hepatotoxicity (including asymptomatic LFT elevations), Renal toxicity, Skin toxicity, and Neurological toxicity. "99999"=N/A

End point type

Secondary

End point timeframe

From first dose to up to 100 days post last dose (up to approximately 45 months)

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only summary statistics were planned for this endpoint

End point values	ECOG (PS0)	ECOG (PS1)	ECOG (PS 2)
Number of subjects analysed	172	537	102
Units: Weeks
median (confidence interval 95%)
Endrocrine	99999 (109.00 to 99999)	169.43 (17.86 to 99999)	99999 (6.14 to 99999)
Gastrointestinal	2.86 (0.43 to 5.14)	2.00 (1.00 to 3.00)	2.00 (0.43 to 5.71)
Hepatic	4.57 (2.57 to 6.14)	7.71 (4.86 to 17.14)	3.57 (2.14 to 8.14)
Pulmonary	3.00 (1.43 to 99999)	4.29 (2.14 to 6.00)	2.29 (1.00 to 99999)
Renal	10.14 (2.14 to 99999)	6.14 (2.29 to 25.14)	59.14 (0.57 to 59.14)
Skin	99999 (13.57 to 99999)	15.43 (8.71 to 52.86)	5.71 (2.00 to 99999)
Hypersensitivity/Infusion Reaction	1.14 (0.14 to 2.14)	0.14 (0.14 to 4.43)	0.14 (0.14 to 0.71)

No statistical analyses for this end point

Secondary: Overall Survival

Top of page

End point title

Overall Survival ^[6]

End point description

Overall Survival (OS) is defined as the time from first dosing date to the date of death. A subject who has not died will be censored at last known date alive. OS will be followed continuously while subjects are on treatment and every 3 months via in-person or phone contact after subjects discontinue the study drug.

End point type

Secondary

End point timeframe

From the first dosing up to the date of death (up to approximately 76 months)

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only summary statistics were planned for this endpoint

End point values	ECOG (PS0)	ECOG (PS1)	ECOG (PS 2)
Number of subjects analysed	172	537	102
Units: Months
median (confidence interval 95%)	12.1 (9.9 to 13.4)	10.3 (9.3 to 11.3)	5.2 (3.0 to 7.6)

No statistical analyses for this end point

Secondary: Objective Response Rate (ORR)

Top of page

End point title

Objective Response Rate (ORR) ^[7]

End point description

ORR is defined as the percentage of subjects with a best overall response (BOR) of confirmed CR or PR with respect to all treated participants. ORR as assessed by the investigator will be reported.

End point type

Secondary

End point timeframe

From first dose up to last dose (up to approximately 76 months)

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Only summary statistics were planned for this endpoint

End point values	ECOG (PS0)	ECOG (PS1)	ECOG (PS 2)
Number of subjects analysed	150	456	64
Units: Percentage
number (confidence interval 95%)	8.0 (4.2 to 13.6)	11.0 (8.2 to 14.2)	1.6 (0.0 to 8.4)

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

AEs/SAEs are reported from start of the treatment until the end of treatment + 100 days

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.0

Reporting group title

ECOG Performance Status 0

Reporting group description

Nivolumab 3 mg/kg as a 60-minute IV infusion every 2 weeks

Reporting group title

ECOG Performance Status 2

Reporting group description

Nivolumab 3 mg/kg as a 60-minute IV infusion every 2 weeks

Reporting group title

ECOG Performance Status 3

Reporting group description

Nivolumab 3 mg/kg as a 60-minute IV infusion every 2 weeks

Reporting group title

ECOG Performance Status 1

Reporting group description

Nivolumab 3 mg/kg as a 60-minute IV infusion every 2 weeks

Serious adverse events	ECOG Performance Status 0	ECOG Performance Status 2	ECOG Performance Status 3	ECOG Performance Status 1
Total subjects affected by serious adverse events
subjects affected / exposed	115 / 172 (66.86%)	84 / 102 (82.35%)	1 / 1 (100.00%)	375 / 537 (69.83%)
number of deaths (all causes)	131	90	1	446
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Adenocarcinoma of colon
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bladder neoplasm
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Brain cancer metastatic
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cancer pain
subjects affected / exposed	3 / 172 (1.74%)	1 / 102 (0.98%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Follicular thyroid cancer
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Malignant neoplasm progression
subjects affected / exposed	59 / 172 (34.30%)	58 / 102 (56.86%)	0 / 1 (0.00%)	206 / 537 (38.36%)
occurrences causally related to treatment / all	0 / 60	0 / 59	0 / 0	0 / 210
deaths causally related to treatment / all	0 / 57	0 / 56	0 / 0	0 / 198
Lung neoplasm malignant
subjects affected / exposed	0 / 172 (0.00%)	1 / 102 (0.98%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Metastases to central nervous system
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	3 / 537 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to lymph nodes
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Non-small cell lung cancer metastatic
subjects affected / exposed	0 / 172 (0.00%)	1 / 102 (0.98%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oncologic complication
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic carcinoma
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Small intestine adenocarcinoma
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tumour pain
subjects affected / exposed	1 / 172 (0.58%)	2 / 102 (1.96%)	0 / 1 (0.00%)	5 / 537 (0.93%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tumour compression
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tumour associated fever
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	0 / 172 (0.00%)	1 / 102 (0.98%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Embolism
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral ischaemia
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Superior vena cava occlusion
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Superior vena cava syndrome
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	4 / 537 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Venous thrombosis limb
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Death
subjects affected / exposed	0 / 172 (0.00%)	1 / 102 (0.98%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	1 / 1
Fatigue
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	1 / 1 (100.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	1 / 172 (0.58%)	1 / 102 (0.98%)	0 / 1 (0.00%)	4 / 537 (0.74%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hernia obstructive
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	1 / 172 (0.58%)	1 / 102 (0.98%)	0 / 1 (0.00%)	4 / 537 (0.74%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 172 (0.00%)	1 / 102 (0.98%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	8 / 537 (1.49%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sudden cardiac death
subjects affected / exposed	0 / 172 (0.00%)	1 / 102 (0.98%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Sudden death
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	4 / 537 (0.74%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 4
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 4
Systemic inflammatory response syndrome
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Drug hypersensitivity
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Aspiration
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Acute respiratory failure
subjects affected / exposed	0 / 172 (0.00%)	2 / 102 (1.96%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Asthma
subjects affected / exposed	0 / 172 (0.00%)	1 / 102 (0.98%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atelectasis
subjects affected / exposed	2 / 172 (1.16%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Bronchial obstruction
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 172 (0.58%)	5 / 102 (4.90%)	0 / 1 (0.00%)	7 / 537 (1.30%)
occurrences causally related to treatment / all	0 / 1	0 / 6	0 / 0	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchopneumopathy
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	9 / 172 (5.23%)	10 / 102 (9.80%)	1 / 1 (100.00%)	28 / 537 (5.21%)
occurrences causally related to treatment / all	1 / 10	0 / 11	0 / 1	4 / 31
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 1
Epistaxis
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	7 / 172 (4.07%)	3 / 102 (2.94%)	0 / 1 (0.00%)	11 / 537 (2.05%)
occurrences causally related to treatment / all	1 / 7	0 / 4	0 / 0	0 / 11
deaths causally related to treatment / all	1 / 3	0 / 2	0 / 0	0 / 3
Hypoxia
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune-mediated lung disease
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lung consolidation
subjects affected / exposed	0 / 172 (0.00%)	1 / 102 (0.98%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophagobronchial fistula
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	3 / 172 (1.74%)	2 / 102 (1.96%)	1 / 1 (100.00%)	10 / 537 (1.86%)
occurrences causally related to treatment / all	0 / 3	0 / 5	0 / 1	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia aspiration
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Pneumonitis
subjects affected / exposed	4 / 172 (2.33%)	0 / 102 (0.00%)	0 / 1 (0.00%)	15 / 537 (2.79%)
occurrences causally related to treatment / all	3 / 5	0 / 0	0 / 0	14 / 16
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2
Pneumothorax
subjects affected / exposed	0 / 172 (0.00%)	1 / 102 (0.98%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Pulmonary embolism
subjects affected / exposed	3 / 172 (1.74%)	0 / 102 (0.00%)	0 / 1 (0.00%)	6 / 537 (1.12%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Pulmonary haemorrhage
subjects affected / exposed	1 / 172 (0.58%)	1 / 102 (0.98%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
Respiratory tract haemorrhage
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	3 / 172 (1.74%)	1 / 102 (0.98%)	0 / 1 (0.00%)	10 / 537 (1.86%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 0	0 / 12
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 3
Tracheal stenosis
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Agitation
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Confusional state
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Delirium
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mania
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gamma-glutamyltransferase increased
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Liver function test increased
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Accidental overdose
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Concussion
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	1 / 172 (0.58%)	2 / 102 (1.96%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Foreign body in gastrointestinal tract
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 172 (0.00%)	1 / 102 (0.98%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	1 / 172 (0.58%)	1 / 102 (0.98%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Overdose
subjects affected / exposed	0 / 172 (0.00%)	2 / 102 (1.96%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Radiation oesophagitis
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skull fractured base
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Rib fracture
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Splenic rupture
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Tracheal obstruction
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Tracheo-oesophageal fistula
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	2 / 172 (1.16%)	2 / 102 (1.96%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	1 / 3	0 / 2	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Atrial flutter
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Cardiac failure
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	3 / 537 (0.56%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac tamponade
subjects affected / exposed	0 / 172 (0.00%)	1 / 102 (0.98%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Cardio-respiratory arrest
subjects affected / exposed	1 / 172 (0.58%)	1 / 102 (0.98%)	0 / 1 (0.00%)	3 / 537 (0.56%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 3
Cardiomegaly
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Intracardiac thrombus
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Left ventricular failure
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mitral valve prolapse
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Myocardial infarction
subjects affected / exposed	2 / 172 (1.16%)	1 / 102 (0.98%)	0 / 1 (0.00%)	3 / 537 (0.56%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	3 / 537 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	1 / 172 (0.58%)	1 / 102 (0.98%)	0 / 1 (0.00%)	3 / 537 (0.56%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Sinus tachycardia
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Supraventricular extrasystoles
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebral haemorrhage
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Brain oedema
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	1 / 172 (0.58%)	1 / 102 (0.98%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Coma
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intracranial pressure increased
subjects affected / exposed	2 / 172 (1.16%)	0 / 102 (0.00%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Lacunar infarction
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Monoparesis
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Motor dysfunction
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neuropathy peripheral
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral sensory neuropathy
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	3 / 537 (0.56%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Status epilepticus
subjects affected / exposed	0 / 172 (0.00%)	1 / 102 (0.98%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 172 (0.00%)	3 / 102 (2.94%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tremor
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 172 (1.16%)	1 / 102 (0.98%)	0 / 1 (0.00%)	6 / 537 (1.12%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 0	1 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anal fissure
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Autoimmune colitis
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	3 / 537 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	4 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colitis microscopic
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 172 (0.58%)	1 / 102 (0.98%)	0 / 1 (0.00%)	7 / 537 (1.30%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	4 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 172 (0.00%)	1 / 102 (0.98%)	0 / 1 (0.00%)	4 / 537 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorder
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune-mediated enterocolitis
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Large intestinal obstruction
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	1 / 1 (100.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal rupture
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Oesophageal stenosis
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	3 / 537 (0.56%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Stomatitis
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Autoimmune hepatitis
subjects affected / exposed	0 / 172 (0.00%)	2 / 102 (1.96%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Biliary tract disorder
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholangitis
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Drug-induced liver injury
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic failure
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune-mediated hepatitis
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Jaundice
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Jaundice cholestatic
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Liver injury
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rash macular
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 172 (0.00%)	1 / 102 (0.98%)	0 / 1 (0.00%)	4 / 537 (0.74%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Calculus urinary
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Leukocyturia
subjects affected / exposed	0 / 172 (0.00%)	1 / 102 (0.98%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	4 / 537 (0.74%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 172 (0.00%)	1 / 102 (0.98%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract obstruction
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	2 / 172 (1.16%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypercalcaemia of malignancy
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperthyroidism
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypophysitis
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thyroiditis
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypothyroidism
subjects affected / exposed	2 / 172 (1.16%)	0 / 102 (0.00%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bone pain
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	1 / 172 (0.58%)	1 / 102 (0.98%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Patellofemoral pain syndrome
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pathological fracture
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal pain
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abscess
subjects affected / exposed	0 / 172 (0.00%)	1 / 102 (0.98%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bacterial diarrhoea
subjects affected / exposed	0 / 172 (0.00%)	1 / 102 (0.98%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anal abscess
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bacterial infection
subjects affected / exposed	0 / 172 (0.00%)	1 / 102 (0.98%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Biliary sepsis
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	4 / 172 (2.33%)	1 / 102 (0.98%)	0 / 1 (0.00%)	9 / 537 (1.68%)
occurrences causally related to treatment / all	0 / 4	0 / 1	0 / 0	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis bacterial
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19 pneumonia
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Clostridium colitis
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	0 / 172 (0.00%)	2 / 102 (1.96%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
H1N1 influenza
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infection
subjects affected / exposed	1 / 172 (0.58%)	1 / 102 (0.98%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Infective exacerbation of chronic obstructive airways disease
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	3 / 537 (0.56%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	5 / 172 (2.91%)	5 / 102 (4.90%)	0 / 1 (0.00%)	21 / 537 (3.91%)
occurrences causally related to treatment / all	0 / 6	0 / 5	0 / 0	2 / 25
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Mediastinitis
subjects affected / exposed	0 / 172 (0.00%)	1 / 102 (0.98%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
Meningitis aseptic
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Parainfluenzae virus infection
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	20 / 172 (11.63%)	10 / 102 (9.80%)	1 / 1 (100.00%)	41 / 537 (7.64%)
occurrences causally related to treatment / all	0 / 22	0 / 11	0 / 1	2 / 47
deaths causally related to treatment / all	0 / 2	0 / 2	0 / 0	0 / 10
Pneumonia cytomegaloviral
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia fungal
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia pneumococcal
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary sepsis
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	3 / 537 (0.56%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	11 / 172 (6.40%)	3 / 102 (2.94%)	0 / 1 (0.00%)	25 / 537 (4.66%)
occurrences causally related to treatment / all	2 / 14	0 / 8	0 / 0	0 / 26
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
Sepsis
subjects affected / exposed	3 / 172 (1.74%)	0 / 102 (0.00%)	0 / 1 (0.00%)	7 / 537 (1.30%)
occurrences causally related to treatment / all	0 / 5	0 / 0	0 / 0	0 / 8
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
Septic shock
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
Staphylococcal infection
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Streptococcal infection
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tracheobronchitis
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	1 / 172 (0.58%)	1 / 102 (0.98%)	0 / 1 (0.00%)	3 / 537 (0.56%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Urinary tract infection
subjects affected / exposed	1 / 172 (0.58%)	1 / 102 (0.98%)	0 / 1 (0.00%)	5 / 537 (0.93%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vulval abscess
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cachexia
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	2 / 172 (1.16%)	1 / 102 (0.98%)	0 / 1 (0.00%)	2 / 537 (0.37%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	1 / 172 (0.58%)	3 / 102 (2.94%)	0 / 1 (0.00%)	12 / 537 (2.23%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0	2 / 14
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic metabolic decompensation
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoalbuminaemia
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	1 / 172 (0.58%)	0 / 102 (0.00%)	0 / 1 (0.00%)	0 / 537 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	0 / 1 (0.00%)	1 / 537 (0.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	2 / 172 (1.16%)	2 / 102 (1.96%)	0 / 1 (0.00%)	3 / 537 (0.56%)
occurrences causally related to treatment / all	0 / 2	1 / 2	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	ECOG Performance Status 0	ECOG Performance Status 2	ECOG Performance Status 3	ECOG Performance Status 1
Total subjects affected by non serious adverse events
subjects affected / exposed	149 / 172 (86.63%)	86 / 102 (84.31%)	1 / 1 (100.00%)	472 / 537 (87.90%)
Vascular disorders
Hypertension
subjects affected / exposed	12 / 172 (6.98%)	0 / 102 (0.00%)	0 / 1 (0.00%)	19 / 537 (3.54%)
occurrences all number	15	0	0	31
General disorders and administration site conditions
Asthenia
subjects affected / exposed	30 / 172 (17.44%)	15 / 102 (14.71%)	0 / 1 (0.00%)	131 / 537 (24.39%)
occurrences all number	46	19	0	170
Fatigue
subjects affected / exposed	40 / 172 (23.26%)	25 / 102 (24.51%)	1 / 1 (100.00%)	121 / 537 (22.53%)
occurrences all number	48	32	1	160
Chest pain
subjects affected / exposed	10 / 172 (5.81%)	1 / 102 (0.98%)	0 / 1 (0.00%)	24 / 537 (4.47%)
occurrences all number	11	1	0	25
Non-cardiac chest pain
subjects affected / exposed	6 / 172 (3.49%)	5 / 102 (4.90%)	0 / 1 (0.00%)	34 / 537 (6.33%)
occurrences all number	6	8	0	37
Oedema peripheral
subjects affected / exposed	7 / 172 (4.07%)	14 / 102 (13.73%)	1 / 1 (100.00%)	30 / 537 (5.59%)
occurrences all number	8	16	1	32
Pyrexia
subjects affected / exposed	9 / 172 (5.23%)	8 / 102 (7.84%)	0 / 1 (0.00%)	49 / 537 (9.12%)
occurrences all number	11	10	0	59
Influenza like illness
subjects affected / exposed	3 / 172 (1.74%)	2 / 102 (1.96%)	1 / 1 (100.00%)	4 / 537 (0.74%)
occurrences all number	4	2	3	5
Peripheral swelling
subjects affected / exposed	2 / 172 (1.16%)	2 / 102 (1.96%)	1 / 1 (100.00%)	8 / 537 (1.49%)
occurrences all number	2	2	1	8
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	44 / 172 (25.58%)	19 / 102 (18.63%)	0 / 1 (0.00%)	134 / 537 (24.95%)
occurrences all number	54	23	0	160
Dyspnoea
subjects affected / exposed	44 / 172 (25.58%)	28 / 102 (27.45%)	1 / 1 (100.00%)	167 / 537 (31.10%)
occurrences all number	61	31	1	204
Haemoptysis
subjects affected / exposed	11 / 172 (6.40%)	10 / 102 (9.80%)	0 / 1 (0.00%)	47 / 537 (8.75%)
occurrences all number	12	12	0	59
Pneumonitis
subjects affected / exposed	10 / 172 (5.81%)	2 / 102 (1.96%)	0 / 1 (0.00%)	22 / 537 (4.10%)
occurrences all number	11	2	0	26
Productive cough
subjects affected / exposed	3 / 172 (1.74%)	6 / 102 (5.88%)	0 / 1 (0.00%)	26 / 537 (4.84%)
occurrences all number	3	7	0	30
Pleural effusion
subjects affected / exposed	2 / 172 (1.16%)	1 / 102 (0.98%)	1 / 1 (100.00%)	6 / 537 (1.12%)
occurrences all number	2	1	1	6
Psychiatric disorders
Anxiety
subjects affected / exposed	9 / 172 (5.23%)	1 / 102 (0.98%)	0 / 1 (0.00%)	12 / 537 (2.23%)
occurrences all number	9	1	0	13
Investigations
Aspartate aminotransferase increased
subjects affected / exposed	15 / 172 (8.72%)	5 / 102 (4.90%)	0 / 1 (0.00%)	28 / 537 (5.21%)
occurrences all number	23	5	0	40
Alanine aminotransferase increased
subjects affected / exposed	12 / 172 (6.98%)	5 / 102 (4.90%)	0 / 1 (0.00%)	30 / 537 (5.59%)
occurrences all number	20	5	0	41
Blood creatinine increased
subjects affected / exposed	9 / 172 (5.23%)	5 / 102 (4.90%)	0 / 1 (0.00%)	34 / 537 (6.33%)
occurrences all number	13	5	0	55
Weight decreased
subjects affected / exposed	8 / 172 (4.65%)	7 / 102 (6.86%)	0 / 1 (0.00%)	42 / 537 (7.82%)
occurrences all number	8	7	0	45
Nervous system disorders
Dizziness
subjects affected / exposed	3 / 172 (1.74%)	8 / 102 (7.84%)	0 / 1 (0.00%)	28 / 537 (5.21%)
occurrences all number	3	8	0	33
Headache
subjects affected / exposed	10 / 172 (5.81%)	3 / 102 (2.94%)	0 / 1 (0.00%)	36 / 537 (6.70%)
occurrences all number	16	3	0	42
Seizure
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	1 / 1 (100.00%)	2 / 537 (0.37%)
occurrences all number	0	0	1	2
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	23 / 172 (13.37%)	21 / 102 (20.59%)	1 / 1 (100.00%)	97 / 537 (18.06%)
occurrences all number	25	35	1	126
Eye disorders
Lacrimation increased
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	1 / 1 (100.00%)	1 / 537 (0.19%)
occurrences all number	0	0	1	1
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	2 / 172 (1.16%)	3 / 102 (2.94%)	0 / 1 (0.00%)	28 / 537 (5.21%)
occurrences all number	2	4	0	34
Constipation
subjects affected / exposed	18 / 172 (10.47%)	16 / 102 (15.69%)	0 / 1 (0.00%)	80 / 537 (14.90%)
occurrences all number	18	18	0	88
Diarrhoea
subjects affected / exposed	26 / 172 (15.12%)	16 / 102 (15.69%)	0 / 1 (0.00%)	100 / 537 (18.62%)
occurrences all number	46	27	0	164
Nausea
subjects affected / exposed	20 / 172 (11.63%)	16 / 102 (15.69%)	0 / 1 (0.00%)	71 / 537 (13.22%)
occurrences all number	27	20	0	85
Stomatitis
subjects affected / exposed	5 / 172 (2.91%)	7 / 102 (6.86%)	0 / 1 (0.00%)	14 / 537 (2.61%)
occurrences all number	9	7	0	19
Vomiting
subjects affected / exposed	9 / 172 (5.23%)	9 / 102 (8.82%)	1 / 1 (100.00%)	34 / 537 (6.33%)
occurrences all number	11	15	1	45
Skin and subcutaneous tissue disorders
Dry skin
subjects affected / exposed	7 / 172 (4.07%)	6 / 102 (5.88%)	0 / 1 (0.00%)	26 / 537 (4.84%)
occurrences all number	8	6	0	27
Pruritus
subjects affected / exposed	9 / 172 (5.23%)	10 / 102 (9.80%)	0 / 1 (0.00%)	58 / 537 (10.80%)
occurrences all number	9	12	0	76
Rash
subjects affected / exposed	10 / 172 (5.81%)	5 / 102 (4.90%)	0 / 1 (0.00%)	39 / 537 (7.26%)
occurrences all number	12	5	0	41
Endocrine disorders
Hyperthyroidism
subjects affected / exposed	13 / 172 (7.56%)	1 / 102 (0.98%)	0 / 1 (0.00%)	18 / 537 (3.35%)
occurrences all number	15	1	0	19
Hypothyroidism
subjects affected / exposed	25 / 172 (14.53%)	6 / 102 (5.88%)	0 / 1 (0.00%)	37 / 537 (6.89%)
occurrences all number	25	6	0	40
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	11 / 172 (6.40%)	7 / 102 (6.86%)	1 / 1 (100.00%)	46 / 537 (8.57%)
occurrences all number	15	8	1	56
Arthralgia
subjects affected / exposed	24 / 172 (13.95%)	7 / 102 (6.86%)	1 / 1 (100.00%)	52 / 537 (9.68%)
occurrences all number	27	7	1	63
Pain in extremity
subjects affected / exposed	4 / 172 (2.33%)	6 / 102 (5.88%)	1 / 1 (100.00%)	25 / 537 (4.66%)
occurrences all number	4	6	1	28
Musculoskeletal chest pain
subjects affected / exposed	7 / 172 (4.07%)	7 / 102 (6.86%)	0 / 1 (0.00%)	24 / 537 (4.47%)
occurrences all number	7	8	0	26
Groin pain
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	1 / 1 (100.00%)	2 / 537 (0.37%)
occurrences all number	0	0	1	2
Infections and infestations
Lower respiratory tract infection
subjects affected / exposed	18 / 172 (10.47%)	7 / 102 (6.86%)	0 / 1 (0.00%)	51 / 537 (9.50%)
occurrences all number	23	12	0	73
Nasopharyngitis
subjects affected / exposed	11 / 172 (6.40%)	1 / 102 (0.98%)	0 / 1 (0.00%)	15 / 537 (2.79%)
occurrences all number	15	1	0	21
Pneumonia
subjects affected / exposed	11 / 172 (6.40%)	5 / 102 (4.90%)	0 / 1 (0.00%)	24 / 537 (4.47%)
occurrences all number	12	6	0	31
Respiratory tract infection
subjects affected / exposed	10 / 172 (5.81%)	6 / 102 (5.88%)	0 / 1 (0.00%)	37 / 537 (6.89%)
occurrences all number	14	7	0	45
Upper respiratory tract infection
subjects affected / exposed	10 / 172 (5.81%)	2 / 102 (1.96%)	0 / 1 (0.00%)	29 / 537 (5.40%)
occurrences all number	15	2	0	38
Catheter site infection
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	1 / 1 (100.00%)	0 / 537 (0.00%)
occurrences all number	0	0	1	0
Oral candidiasis
subjects affected / exposed	4 / 172 (2.33%)	3 / 102 (2.94%)	1 / 1 (100.00%)	26 / 537 (4.84%)
occurrences all number	5	5	1	33
Tooth infection
subjects affected / exposed	2 / 172 (1.16%)	0 / 102 (0.00%)	1 / 1 (100.00%)	1 / 537 (0.19%)
occurrences all number	3	0	1	1
Oral fungal infection
subjects affected / exposed	0 / 172 (0.00%)	0 / 102 (0.00%)	1 / 1 (100.00%)	1 / 537 (0.19%)
occurrences all number	0	0	1	1
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	24 / 172 (13.95%)	24 / 102 (23.53%)	0 / 1 (0.00%)	147 / 537 (27.37%)
occurrences all number	31	32	0	173
Hypercalcaemia
subjects affected / exposed	6 / 172 (3.49%)	6 / 102 (5.88%)	0 / 1 (0.00%)	39 / 537 (7.26%)
occurrences all number	12	6	0	50
Hyperkalaemia
subjects affected / exposed	7 / 172 (4.07%)	6 / 102 (5.88%)	0 / 1 (0.00%)	20 / 537 (3.72%)
occurrences all number	12	7	0	27
Hypomagnesaemia
subjects affected / exposed	11 / 172 (6.40%)	5 / 102 (4.90%)	0 / 1 (0.00%)	27 / 537 (5.03%)
occurrences all number	28	6	0	43

More information

Top of page

Were there any global substantial amendments to the protocol? Yes

21 Nov 2014

The inclusion criteria have been expanded and the exclusion criteria have been minimized in order to expand the subject population. The background section has also been updated to reflect the most recently available data. Expanded palliative local therapy. Randomization after 1 year to subjects who are still benefitting from treatment and achieved a partial or complete response to offer insight into the optimal treatment duration of nivolumab has been added. After 1 year of therapy, subjects will be randomized to continue nivolumab monotherapy (Cohort A) or discontinue therapy with the option of retreatment disease progression (Cohort B). The requirement to have a separate assessment plan for the subjects in the Performance Status 2 (PS2) subgroup has been eliminated. The EQ-5D has been removed. Lung Cancer Symptom Survey has also been eliminated from the subject follow up and decreased while on treatment. Initial tumor assessments have also been changed to occur at Week 8 instead of Week 6. The statistical section has been reformatted. The phrase “rate and frequency” has been changed to the term “incidence” throughout the protocol. The term “Adverse Events of Special Interest” has been changed to “Select Adverse Events.” The Performance Status groups were renamed “Subgroup” (from “Cohort”) to avoid confusion with the randomized cohorts. Treatment discontinuation criteria were moved from Section 3.5 to the newly created Section 4.6.5.1 to follow the nivolumab protocol structure. The requirement for electrocardiograms has been removed as these tests are not done within the nivolumab clinical development program any more.

18 Jun 2015

The sample size was reduced from 1800 to 950 (with 15% screening failure rate, 800 will be treated); second-line lung cancer patients will now be allowed to enroll in the study; and the randomization at one year into Cohort A and Cohort B has been removed.

26 Oct 2016

Adjustment to PS 0-1 and PS 2 subgroup sample numbers. Changes to informed consent procedure for treatment beyond disease progression. Clarification of SAE reporting to within 100 days of discontinuation of drug. Clarification of LCSS and TFT assessments timepoints. Addition of CBC/ TFTs to off-treatment follow-up scheduled lab test. Addition that dose must be recalculated if weight on the day of dosing differs by > 10% from the weight used to calculate the dose.

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

For support, Contact us.

The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

European Medicines Agency © 1995-Sat May 04 17:03:15 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands