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Clinical Trial Results:
Randomized, Double-Blind, Phase 3 Trial to Compare the Efficacy of Ipilimumab vs Placebo in Asymptomatic or Minimally Symptomatic Patients with Metastatic Chemotherapy-Naïve Castration Resistant Prostate Cancer

Summary
EudraCT number	2009-016217-23
Trial protocol	NL ES GB DE SE CZ DK HU IT GR
Global end of trial date	17 Jul 2015

Results information
Results version number	v1(current)
This version publication date	30 Jul 2016
First version publication date	30 Jul 2016
Other versions

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

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Trial information

Top of page

Sponsor protocol code

CA184-095

ISRCTN number

-

US NCT number

NCT01057810

WHO universal trial number (UTN)

-

Sponsor organisation name

Bristol-Myers Squibb

Sponsor organisation address

Bristol-Myers Squibb International Corporation, 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

17 Jul 2015

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

17 Jul 2015

Was the trial ended prematurely?

Yes

Main objective of the trial

The main objective of the study was to compare overall survival of subjects with chemotherapy-naïve castration resistant prostate cancer (CRPC) who were randomised to ipilimumab vs placebo.

Protection of trial subjects

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

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

28 Jul 2010

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

United States: 269

Country: Number of subjects enrolled

Argentina: 34

Country: Number of subjects enrolled

Brazil: 42

Country: Number of subjects enrolled

Canada: 26

Country: Number of subjects enrolled

Chile: 36

Country: Number of subjects enrolled

Colombia: 19

Country: Number of subjects enrolled

Czech Republic: 18

Country: Number of subjects enrolled

Denmark: 11

Country: Number of subjects enrolled

France: 45

Country: Number of subjects enrolled

Germany: 29

Country: Number of subjects enrolled

Greece: 1

Country: Number of subjects enrolled

Hungary: 25

Country: Number of subjects enrolled

Italy: 18

Country: Number of subjects enrolled

Mexico: 33

Country: Number of subjects enrolled

Netherlands: 41

Country: Number of subjects enrolled

Norway: 1

Country: Number of subjects enrolled

Poland: 33

Country: Number of subjects enrolled

Romania: 12

Country: Number of subjects enrolled

Spain: 48

Country: Number of subjects enrolled

Sweden: 12

Country: Number of subjects enrolled

Turkey: 7

Country: Number of subjects enrolled

United Kingdom: 12

Country: Number of subjects enrolled

Austria: 65

Worldwide total number of subjects

837

EEA total number of subjects

371

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)

217

From 65 to 84 years

602

85 years and over

18

Subject disposition

Top of page

Recruitment details

-

Screening details

837 subjects enrolled; 602 randomized; 598 treated. Of the 235 not randomized, 189 no longer met criteria, 28 withdrew consent, 2 suffered Adverse Events, 2 were non-compliant, 1 was lost to follow-up, and 13 were removed for other/unspecified reasons. Post-randomization, 4 no longer met criteria and were not treated (3 placebo, 1 ipilimumab).

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, Carer, Assessor

Are arms mutually exclusive

Yes

Placebo

Arm description

Subjects were administered with ipilimumab matching placebo infusion (normal saline or 5% dextrose) at a dose of 2 milliliter/kilogram (mL/kg) intravenously (IV) over 90 minutes. Induction dosing occurred on Days 1, 22, 43, and 64 during the Induction phase and every 12 weeks starting at Week 24 during the Maintenance phase until unacceptable toxicity, clinical deterioration, confirmed disease progression, or study closure.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects were administered with placebo 2 mg/kg IV over 90 minutes.

Ipilimumab

Arm description

Subjects were administered with ipilimumab 10 mg/kg IV over 90 minutes with a normal saline flush at the end. Induction dosing occurred on Days 1, 22, 43, and 64 during the Induction phase and every 12 weeks starting at Week 24 during the Maintenance phase until unacceptable toxicity, clinical deterioration, confirmed disease progression, or study closure.

Arm type

Experimental

Investigational medicinal product name

Ipilimumab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Subjects were administered with ipilimumab 10 mg/kg IV over 90 minutes.

Number of subjects in period 1 ^[1]	Placebo	Ipilimumab
Started	202	400
Completed	1	1
Not completed	201	399
Adverse event, serious fatal	2	12
Consent withdrawn by subject	10	25
No longer met study criteria	-	1
Disease progression	156	197
Study drug toxicity	5	114
Maximum clinical benefit	5	5
Adverse event unrelated to study drug	13	29
Randomised but not treated	3	1
Unspecified	7	14
Poor/non-compliance	-	1

Notes
[1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
Justification: Out of 837 subjects who were enrolled, 602 subjects were randomised. Reasons: 189 subjects no longer met criteria, 28 subjects withdrew consent, 2 subjects suffered Adverse Events, 2 subjects were non-compliant, 1 subject was lost to follow-up, and 13 subjects were removed for other/unspecified reasons.

Baseline characteristics

Top of page

Reporting group title

Placebo

Reporting group description

Subjects were administered with ipilimumab matching placebo infusion (normal saline or 5% dextrose) at a dose of 2 milliliter/kilogram (mL/kg) intravenously (IV) over 90 minutes. Induction dosing occurred on Days 1, 22, 43, and 64 during the Induction phase and every 12 weeks starting at Week 24 during the Maintenance phase until unacceptable toxicity, clinical deterioration, confirmed disease progression, or study closure.

Reporting group title

Ipilimumab

Reporting group description

Subjects were administered with ipilimumab 10 mg/kg IV over 90 minutes with a normal saline flush at the end. Induction dosing occurred on Days 1, 22, 43, and 64 during the Induction phase and every 12 weeks starting at Week 24 during the Maintenance phase until unacceptable toxicity, clinical deterioration, confirmed disease progression, or study closure.

Reporting group values	Placebo	Ipilimumab	Total
Number of subjects	202	400	602
Age, Customized
Units: subjects
< 65 years	65	104	169
>= 65 years	137	296	433
Age Continuous
Units: years
arithmetic mean (full range (min-max))	68.6 (42 to 92)	69.3 (44 to 91)	-
Gender, Male/Female
Units: subjects
Female	0	0	0
Male	202	400	602
Region of Enrollment
Units: Subjects
North America	79	154	233
South America	25	52	77
Europe	74	161	235
Australia	24	33	57

End points

Top of page

Reporting group title

Placebo

Reporting group description

Subjects were administered with ipilimumab matching placebo infusion (normal saline or 5% dextrose) at a dose of 2 milliliter/kilogram (mL/kg) intravenously (IV) over 90 minutes. Induction dosing occurred on Days 1, 22, 43, and 64 during the Induction phase and every 12 weeks starting at Week 24 during the Maintenance phase until unacceptable toxicity, clinical deterioration, confirmed disease progression, or study closure.

Reporting group title

Ipilimumab

Reporting group description

Subjects were administered with ipilimumab 10 mg/kg IV over 90 minutes with a normal saline flush at the end. Induction dosing occurred on Days 1, 22, 43, and 64 during the Induction phase and every 12 weeks starting at Week 24 during the Maintenance phase until unacceptable toxicity, clinical deterioration, confirmed disease progression, or study closure.

Primary: Overall Survival (OS) Time

Top of page

End point title

Overall Survival (OS) Time

End point description

OS was defined as the time from the date of randomisation until the date of death. For subjects without documentation of death, OS was censored at the last date the subject was known to be alive. The analysis was performed in all randomized subjects defined as all subjects who were randomized to a treatment arm.

End point type

Primary

End point timeframe

Randomisation up to 57 months

End point values	Placebo	Ipilimumab
Number of subjects analysed	202	400
Units: months
median (confidence interval 95%)	29.73 (26.12 to 34.17)	28.65 (24.48 to 32.46)

Overall Survival Time of Ipilimumab

Statistical analysis description

Treatment comparison was estimated by Kaplan-Meier estimation for the overall survival time based on treatment (Placebo and Ipilimumab).

Comparison groups

Ipilimumab v Placebo

Number of subjects included in analysis

602

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3667

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

1.11

Confidence interval

level

95.87%

sides

2-sided

lower limit

0.88

upper limit

1.39

Secondary: Progression-Free Survival (PFS) Time

Top of page

End point title

Progression-Free Survival (PFS) Time

End point description

Progression-free survival, as determined by the investigator, was defined as the time from randomisation to the earliest date of confirmed Prostate-Specific Antigen (PSA) progression, confirmed radiological progression, clinical deterioration, or death. The analysis was performed in all randomized subjects defined as all subjects who were randomized to a treatment arm.

End point type

Secondary

End point timeframe

Randomisation up to 57 months

End point values	Placebo	Ipilimumab
Number of subjects analysed	202	400
Units: months
median (confidence interval 95%)	3.81 (2.76 to 4.11)	5.59 (5.32 to 6.28)

Progression-Free Survival Time of Ipilimumab

Statistical analysis description

Treatment comparison was estimated by Kaplan-Meier estimation for the overall survival time based on treatment (Placebo and Ipilimumab).

Comparison groups

Placebo v Ipilimumab

Number of subjects included in analysis

602

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.67

Confidence interval

level

95%

sides

2-sided

lower limit

0.55

upper limit

0.8

Secondary: Time to subsequent non-hormonal cytotoxic therapy

Top of page

End point title

Time to subsequent non-hormonal cytotoxic therapy

End point description

For subjects who discontinued treatment or experienced disease progression while on study therapy and then received subsequent non-hormonal cytotoxic therapy, time to subsequent non-hormonal cytotoxic therapy was defined as the time from randomisation to the time of initiation of subsequent non-hormonal cytotoxic therapy. Subjects who did not receive subsequent non-hormonal cytotoxic therapy were censored on the last known alive date (for subjects who have not died) or the date of last follow-up contact at which the subjects was known alive (for subjects who died). The analysis was performed in all randomized subjects defined as all subjects who were randomized to a treatment arm.

End point type

Secondary

End point timeframe

Randomisation up to 57 months

End point values	Placebo	Ipilimumab
Number of subjects analysed	128	199
Units: months
median (confidence interval 95%)	10.91 (8.44 to 14.59)	18.04 (15.18 to 24.8)

Time to subsequent cytotoxic therapy of Ipilimumab

Comparison groups

Placebo v Ipilimumab

Number of subjects included in analysis

327

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.65

Confidence interval

level

95.87%

sides

2-sided

lower limit

0.52

upper limit

0.83

Secondary: Time to Pain Progression

Top of page

End point title

Time to Pain Progression

End point description

Time to pain progression was defined as time from randomisation to the time of the earliest date of any of the following 4 events: 1) an increase in average daily worst pain intensity of >= 2 points from baseline according to the Brief Pain Inventory - Short Form (BPI-SF), maintained over 2 consecutive time periods. 2) initiation of opioid analgesic (excluding codeine or dextropropoxyphene). 3) initiation of palliative radiotherapy for prostate cancer. 4) increase in mean Analgesic Score (AS) of >= 25% from baseline (for subjects with baseline AS > 10) or increase in mean AS >= 10 points from baseline (for subjects with baseline AS <= 10). Subjects who did not experience any of these events were censored on the earliest date among the latest BPI-SF completion date with non-missing worst pain assessment and last evaluable disease assessment date as defined in the PFS censoring mechanism.The analysis was performed in all randomized subjects. Here, '99999' represents not estimable data.

End point type

Secondary

End point timeframe

Randomisation up to 57 months

End point values	Placebo	Ipilimumab
Number of subjects analysed	202	400
Units: months
median (confidence interval 95%)	16.62 (11.53 to 99999)	21.68 (19.22 to 99999)

Time to Pain Progression of Ipilimumab

Comparison groups

Placebo v Ipilimumab

Number of subjects included in analysis

602

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.98

Confidence interval

level

95.87%

sides

2-sided

lower limit

0.71

upper limit

1.35

Secondary: Number of subjects who died or had Adverse Events (AEs), Serious Adverse Events (SAEs), immune-related AEs (irAEs), or immune-mediated adverse reactions (imARs), Drug related AEs and Grade 3-4 AEs

Top of page

End point title

Number of subjects who died or had Adverse Events (AEs), Serious Adverse Events (SAEs), immune-related AEs (irAEs), or immune-mediated adverse reactions (imARs), Drug related AEs and Grade 3-4 AEs

End point description

AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalisation. irAE=AEs consistent with an immune mediated mechanism. imAR=AEs of special interest that were adjudicated as imAR by investigator. Treatment-related=having certain, probable, possible, or missing relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling. Events were graded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. The analysis was performed in treated subjects defined as all subjects who received at least 1 dose of ipilimumab or placebo.

End point type

Secondary

End point timeframe

Day 1 of study therapy to last dose plus 70 days

End point values	Placebo	Ipilimumab
Number of subjects analysed	199	399
Units: subjects
number (not applicable)
AEs (grade 3-4) (n=0,1)	59	223
Drug-related AE (any grade)	98	325
Drug-related AE (grade 3-4)	11	158
SAEs (any grade)	53	213
SAEs (grade 3-4)	39	153
AE leading to DC (any grade)	20	139
AE leading to DC (grade 3-4)	14	103
irAEs (any grade)	57	309
irAE (grade 3-4)	3	125
imAR (grade >= 2)	14	273
Deaths	130	259

No statistical analyses for this end point

Secondary: Number of treated subjects with Grade 3 or 4 clinical laboratory abnormalities

Top of page

End point title

Number of treated subjects with Grade 3 or 4 clinical laboratory abnormalities

End point description

NCI CTC, Version 3 used to assess parameters. LLN=lower limit of normal. ULN=upper limit of normal. CTC criteria: White blood cells (WBC): Gr 3:<2.0 to 1.0*10^9/L, Gr 4:<1.0*10^9/L. Absolute neutrophil count (ANC): Gr 3:<1.0 to 0.5*10^9/L, Gr 4:<0.5*10^9/L. Platelet count: Gr 3:<50.0 to 25.0*10^9/L, Gr 4:<25.0 to 10^9/L. Hemoglobin: Gr 3:<8.0 to 6.5 g/dL, Gr 4:<6.5 g/dL. Absolute Lymphocyte Count (ALC): Gr 3: 0.2 - <0.5*10^9/L, Gr 4: <0.2*10^9/L. Lipase: Gr 3:>2.0 - 5.0*ULN; Gr 4: >5.0*ULN. Amylase: Gr 3: >2.0 - 5.0*ULN; Gr 4: >5.0*ULN. Alanine aminotransferase (ALT) Gr 3: >5.0 - 20.0*ULN; Gr 4: >20.0*ULN. Aspartate Aminotransferase (AST): Gr 3: >5.0 - 20.0*ULN; Gr 4: >20.0*ULN. Bilirubin: Gr 3: >3.0 - 10.0*ULN; Gr 4: >10.0*ULN. Alkaline Phosphatase: Gr 3: >5.0 - 20.0*ULN; Gr 4: >20.0*ULN. Creatinine: Gr 3: >3.0-6.0*ULN, Gr 4: >6.0*ULN. The analysis was performed in treated subjects defined as all subjects who received at least 1 dose of ipilimumab or placebo.

End point type

Secondary

End point timeframe

Randomisation up to 57 months

End point values	Placebo	Ipilimumab
Number of subjects analysed	199	399
Units: subjects
number (not applicable)
WBC (n=195;383)	0	3
ANC (n=195;383)	0	2
Platelet count (n=194;381)	0	2
Hemoglobin (n=195;383)	2	5
ALC (n=195;383)	4	12
Lipase (n=196;382)	4	27
Amylase (n=198;385)	2	9
ALT (n=198;386)	1	16
AST (n=196;383)	1	18
Total Bilirubin (n=198;386)	0	4
Alkaline phosphatase (n=196;383)	11	18
Creatinine (n=9;23)	0	0

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

On-Study (Day 1 of study therapy to last dose plus 70 days).

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

17.1

Reporting group title

Ipilimumab

Reporting group description

Subjects were administered with ipilimumab 10 mg/kg IV over 90 minutes with a normal saline flush at the end. Induction dosing occurred on Days 1, 22, 43, and 64 during the Induction phase and every 12 weeks starting at Week 24 during the Maintenance phase until unacceptable toxicity, clinical deterioration, confirmed disease progression, or study closure.

Reporting group title

Placebo

Reporting group description

Subjects were administered with ipilimumab matching placebo infusion (normal saline or 5% dextrose) at a dose of 2 milliliter/kilogram (mL/kg) intravenously (IV) over 90 minutes. Induction dosing occurred on Days 1, 22, 43, and 64 during the Induction phase and every 12 weeks starting at Week 24 during the Maintenance phase until unacceptable toxicity, clinical deterioration, confirmed disease progression, or study closure.

Serious adverse events	Ipilimumab	Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	213 / 399 (53.38%)	53 / 199 (26.63%)
number of deaths (all causes)	35	5
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder transitional cell carcinoma
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colorectal adenocarcinoma
subjects affected / exposed	0 / 399 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Glioblastoma
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant neoplasm progression
subjects affected / exposed	12 / 399 (3.01%)	8 / 199 (4.02%)
occurrences causally related to treatment / all	0 / 12	0 / 9
deaths causally related to treatment / all	0 / 12	0 / 4
Metastases to central nervous system
subjects affected / exposed	1 / 399 (0.25%)	2 / 199 (1.01%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Metastatic pain
subjects affected / exposed	1 / 399 (0.25%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Prostate cancer metastatic
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Rectal cancer
subjects affected / exposed	1 / 399 (0.25%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal cell carcinoma
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	0 / 399 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour pain
subjects affected / exposed	2 / 399 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Arterial thrombosis
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Circulatory collapse
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	3 / 399 (0.75%)	2 / 199 (1.01%)
occurrences causally related to treatment / all	2 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Embolism
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhagic infarction
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertension
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypotension
subjects affected / exposed	4 / 399 (1.00%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	2 / 399 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombosis
subjects affected / exposed	1 / 399 (0.25%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	4 / 399 (1.00%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Chest pain
subjects affected / exposed	2 / 399 (0.50%)	2 / 199 (1.01%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Chills
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Death
subjects affected / exposed	2 / 399 (0.50%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 2	0 / 1
Fatigue
subjects affected / exposed	11 / 399 (2.76%)	2 / 199 (1.01%)
occurrences causally related to treatment / all	7 / 12	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Fibrosis
subjects affected / exposed	0 / 399 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General physical health deterioration
subjects affected / exposed	1 / 399 (0.25%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Generalised oedema
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Impaired healing
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Malaise
subjects affected / exposed	3 / 399 (0.75%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	4 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mucosal inflammation
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Multi-Organ failure
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oedema
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	3 / 399 (0.75%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pain
subjects affected / exposed	0 / 399 (0.00%)	2 / 199 (1.01%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral swelling
subjects affected / exposed	2 / 399 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	14 / 399 (3.51%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	8 / 16	0 / 1
deaths causally related to treatment / all	1 / 1	0 / 0
Sudden death
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Immune system disorders
Hypersensitivity
subjects affected / exposed	2 / 399 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Reproductive system and breast disorders
Pelvic pain
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Aspiration
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Asthma
subjects affected / exposed	1 / 399 (0.25%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchial obstruction
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cough
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	7 / 399 (1.75%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	3 / 8	0 / 0
deaths causally related to treatment / all	2 / 3	0 / 0
Haemoptysis
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung infiltration
subjects affected / exposed	2 / 399 (0.50%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	2 / 399 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	6 / 399 (1.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	4 / 6	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Pulmonary embolism
subjects affected / exposed	1 / 399 (0.25%)	4 / 199 (2.01%)
occurrences causally related to treatment / all	0 / 1	1 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory distress
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory failure
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	1 / 399 (0.25%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Delirium
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Depressed mood
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Drug dependence
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Substance-Induced psychotic disorder
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Alanine aminotransferase increased
subjects affected / exposed	5 / 399 (1.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	6 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aspartate aminotransferase increased
subjects affected / exposed	6 / 399 (1.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	7 / 7	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood creatine phosphokinase increased
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
International normalised ratio increased
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lipase increased
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Liver function test abnormal
subjects affected / exposed	2 / 399 (0.50%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Transaminases increased
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Weight decreased
subjects affected / exposed	1 / 399 (0.25%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Ankle fracture
subjects affected / exposed	0 / 399 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Clavicle fracture
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fall
subjects affected / exposed	2 / 399 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	0 / 399 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 399 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fracture
subjects affected / exposed	2 / 399 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lumbar vertebral fracture
subjects affected / exposed	0 / 399 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Overdose
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal cord injury
subjects affected / exposed	0 / 399 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	8 / 399 (2.01%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 11	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Atrial tachycardia
subjects affected / exposed	0 / 399 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	3 / 399 (0.75%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0
deaths causally related to treatment / all	2 / 3	0 / 0
Cardiac failure
subjects affected / exposed	3 / 399 (0.75%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Cardiac failure congestive
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardio-Respiratory arrest
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cardiopulmonary failure
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Coronary artery insufficiency
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Myocardial infarction
subjects affected / exposed	3 / 399 (0.75%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Myocardial ischaemia
subjects affected / exposed	1 / 399 (0.25%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tachycardia
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ventricular tachycardia
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Brain oedema
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cauda equina syndrome
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral thrombosis
subjects affected / exposed	0 / 399 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Cerebrovascular accident
subjects affected / exposed	0 / 399 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cluster headache
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cranial nerve disorder
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Depressed level of consciousness
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dizziness
subjects affected / exposed	2 / 399 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Guillain-Barre syndrome
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage intracranial
subjects affected / exposed	2 / 399 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Headache
subjects affected / exposed	2 / 399 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoaesthesia
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ivth nerve paresis
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Mononeuropathy
subjects affected / exposed	0 / 399 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Motor dysfunction
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Myasthenia gravis crisis
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neurological symptom
subjects affected / exposed	0 / 399 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral motor neuropathy
subjects affected / exposed	2 / 399 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Peripheral sensory neuropathy
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	1 / 399 (0.25%)	2 / 199 (1.01%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Syncope
subjects affected / exposed	5 / 399 (1.25%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	2 / 5	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Viith nerve paralysis
subjects affected / exposed	2 / 399 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Agranulocytosis
subjects affected / exposed	1 / 399 (0.25%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anaemia
subjects affected / exposed	2 / 399 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	3 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bandaemia
subjects affected / exposed	2 / 399 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bone marrow disorder
subjects affected / exposed	0 / 399 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile neutropenia
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pancytopenia
subjects affected / exposed	0 / 399 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 399 (0.00%)	2 / 199 (1.01%)
occurrences causally related to treatment / all	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
White blood cell disorder
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Ear and labyrinth disorders
Deafness
subjects affected / exposed	0 / 399 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Diplopia
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorder
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	2 / 399 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	5 / 399 (1.25%)	2 / 199 (1.01%)
occurrences causally related to treatment / all	3 / 5	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	0 / 399 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Anal fistula
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Coeliac disease
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis
subjects affected / exposed	27 / 399 (6.77%)	2 / 199 (1.01%)
occurrences causally related to treatment / all	29 / 32	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis ulcerative
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Constipation
subjects affected / exposed	1 / 399 (0.25%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	47 / 399 (11.78%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	54 / 59	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Diarrhoea haemorrhagic
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulum intestinal
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enteritis
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enterocolitis
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric ulcer haemorrhage
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	3 / 399 (0.75%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal necrosis
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhoids
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hernial eventration
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus
subjects affected / exposed	3 / 399 (0.75%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ileus paralytic
subjects affected / exposed	2 / 399 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	2 / 399 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Large intestine perforation
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Megacolon
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Melaena
subjects affected / exposed	0 / 399 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	10 / 399 (2.51%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	7 / 10	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Odynophagia
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	2 / 399 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	2 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Subileus
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	6 / 399 (1.50%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	2 / 6	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Autoimmune hepatitis
subjects affected / exposed	3 / 399 (0.75%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	4 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatitis
subjects affected / exposed	3 / 399 (0.75%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	3 / 3	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Hepatocellular injury
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatotoxicity
subjects affected / exposed	2 / 399 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertransaminasaemia
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dermatitis exfoliative
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rash
subjects affected / exposed	4 / 399 (1.00%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	4 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rash morbilliform
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin disorder
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Skin ulcer
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Anuria
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bladder obstruction
subjects affected / exposed	2 / 399 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dysuria
subjects affected / exposed	1 / 399 (0.25%)	2 / 199 (1.01%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Haematuria
subjects affected / exposed	4 / 399 (1.00%)	4 / 199 (2.01%)
occurrences causally related to treatment / all	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage urinary tract
subjects affected / exposed	0 / 399 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hydronephrosis
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nephritis
subjects affected / exposed	2 / 399 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Obstructive uropathy
subjects affected / exposed	1 / 399 (0.25%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal cyst haemorrhage
subjects affected / exposed	0 / 399 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
subjects affected / exposed	4 / 399 (1.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	1 / 3	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Renal failure acute
subjects affected / exposed	8 / 399 (2.01%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	1 / 8	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Renal tubular acidosis
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ureteric obstruction
subjects affected / exposed	0 / 399 (0.00%)	2 / 199 (1.01%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 399 (0.00%)	2 / 199 (1.01%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract obstruction
subjects affected / exposed	0 / 399 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urogenital disorder
subjects affected / exposed	1 / 399 (0.25%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorders
Adrenal insufficiency
subjects affected / exposed	6 / 399 (1.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	7 / 8	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Adrenocortical insufficiency acute
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Endocrine disorder
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperthyroidism
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypophysitis
subjects affected / exposed	12 / 399 (3.01%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	12 / 12	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypopituitarism
subjects affected / exposed	4 / 399 (1.00%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	5 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypothyroidism
subjects affected / exposed	2 / 399 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Secondary adrenocortical insufficiency
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Secondary hypothyroidism
subjects affected / exposed	2 / 399 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 399 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Back pain
subjects affected / exposed	4 / 399 (1.00%)	2 / 199 (1.01%)
occurrences causally related to treatment / all	1 / 4	1 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Bone pain
subjects affected / exposed	1 / 399 (0.25%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Chondrocalcinosis pyrophosphate
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Flank pain
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	2 / 399 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	2 / 399 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	2 / 399 (0.50%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pain in jaw
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pathological fracture
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Soft tissue mass
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infections and infestations
Abscess
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abscess limb
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	0 / 399 (0.00%)	2 / 199 (1.01%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Campylobacter gastroenteritis
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	2 / 399 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	2 / 399 (0.50%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	1 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cystitis
subjects affected / exposed	0 / 399 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cytomegalovirus colitis
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cytomegalovirus infection
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Device related infection
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	4 / 399 (1.00%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	3 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enterocolitis bacterial
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Enterocolitis infectious
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Febrile infection
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	3 / 399 (0.75%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Herpes virus infection
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infected skin ulcer
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infection
subjects affected / exposed	3 / 399 (0.75%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lobar pneumonia
subjects affected / exposed	0 / 399 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Meningitis aseptic
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenic sepsis
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 399 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	13 / 399 (3.26%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 14	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Pneumonia klebsiella
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	1 / 399 (0.25%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 399 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	2 / 399 (0.50%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Septic shock
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	1 / 1	0 / 0
Sinusitis
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal cord infection
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	2 / 399 (0.50%)	6 / 199 (3.02%)
occurrences causally related to treatment / all	0 / 2	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection fungal
subjects affected / exposed	0 / 399 (0.00%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	1 / 399 (0.25%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Viral infection
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	4 / 399 (1.00%)	2 / 199 (1.01%)
occurrences causally related to treatment / all	3 / 5	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Dehydration
subjects affected / exposed	14 / 399 (3.51%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	9 / 16	0 / 1
deaths causally related to treatment / all	1 / 2	0 / 0
Diabetes mellitus
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fluid overload
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypercalcaemia
subjects affected / exposed	2 / 399 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	1 / 399 (0.25%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypocalcaemia
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	2 / 399 (0.50%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	3 / 399 (0.75%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	3 / 399 (0.75%)	1 / 199 (0.50%)
occurrences causally related to treatment / all	3 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypovolaemia
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Type 2 diabetes mellitus
subjects affected / exposed	1 / 399 (0.25%)	0 / 199 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Ipilimumab	Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	361 / 399 (90.48%)	166 / 199 (83.42%)
Vascular disorders
Hot flush
subjects affected / exposed	13 / 399 (3.26%)	10 / 199 (5.03%)
occurrences all number	13	10
Hypertension
subjects affected / exposed	24 / 399 (6.02%)	7 / 199 (3.52%)
occurrences all number	27	14
Hypotension
subjects affected / exposed	21 / 399 (5.26%)	6 / 199 (3.02%)
occurrences all number	22	7
General disorders and administration site conditions
Asthenia
subjects affected / exposed	61 / 399 (15.29%)	20 / 199 (10.05%)
occurrences all number	68	23
Fatigue
subjects affected / exposed	144 / 399 (36.09%)	55 / 199 (27.64%)
occurrences all number	169	64
Oedema peripheral
subjects affected / exposed	44 / 399 (11.03%)	9 / 199 (4.52%)
occurrences all number	45	9
Pain
subjects affected / exposed	25 / 399 (6.27%)	17 / 199 (8.54%)
occurrences all number	26	14
Pyrexia
subjects affected / exposed	63 / 399 (15.79%)	18 / 199 (9.05%)
occurrences all number	73	21
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	45 / 399 (11.28%)	17 / 199 (8.54%)
occurrences all number	47	19
Dyspnoea
subjects affected / exposed	33 / 399 (8.27%)	9 / 199 (4.52%)
occurrences all number	36	9
Psychiatric disorders
Insomnia
subjects affected / exposed	38 / 399 (9.52%)	9 / 199 (4.52%)
occurrences all number	39	8
Investigations
Alanine aminotransferase increased
subjects affected / exposed	31 / 399 (7.77%)	1 / 199 (0.50%)
occurrences all number	34	1
Aspartate aminotransferase increased
subjects affected / exposed	27 / 399 (6.77%)	2 / 199 (1.01%)
occurrences all number	34	2
Weight decreased
subjects affected / exposed	61 / 399 (15.29%)	17 / 199 (8.54%)
occurrences all number	61	16
Nervous system disorders
Dizziness
subjects affected / exposed	39 / 399 (9.77%)	17 / 199 (8.54%)
occurrences all number	43	19
Dysgeusia
subjects affected / exposed	21 / 399 (5.26%)	6 / 199 (3.02%)
occurrences all number	21	6
Headache
subjects affected / exposed	73 / 399 (18.30%)	24 / 199 (12.06%)
occurrences all number	84	24
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	31 / 399 (7.77%)	12 / 199 (6.03%)
occurrences all number	34	12
Eye disorders
Vision blurred
subjects affected / exposed	21 / 399 (5.26%)	1 / 199 (0.50%)
occurrences all number	21	1
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	50 / 399 (12.53%)	13 / 199 (6.53%)
occurrences all number	61	14
Constipation
subjects affected / exposed	84 / 399 (21.05%)	37 / 199 (18.59%)
occurrences all number	96	42
Diarrhoea
subjects affected / exposed	190 / 399 (47.62%)	48 / 199 (24.12%)
occurrences all number	312	63
Nausea
subjects affected / exposed	115 / 399 (28.82%)	36 / 199 (18.09%)
occurrences all number	144	42
Vomiting
subjects affected / exposed	75 / 399 (18.80%)	18 / 199 (9.05%)
occurrences all number	95	19
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	123 / 399 (30.83%)	21 / 199 (10.55%)
occurrences all number	146	24
Rash
subjects affected / exposed	145 / 399 (36.34%)	22 / 199 (11.06%)
occurrences all number	195	27
Renal and urinary disorders
Haematuria
subjects affected / exposed	13 / 399 (3.26%)	11 / 199 (5.53%)
occurrences all number	19	12
Pollakiuria
subjects affected / exposed	18 / 399 (4.51%)	10 / 199 (5.03%)
occurrences all number	18	10
Endocrine disorders
Hypothyroidism
subjects affected / exposed	25 / 399 (6.27%)	0 / 199 (0.00%)
occurrences all number	26	0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	51 / 399 (12.78%)	33 / 199 (16.58%)
occurrences all number	55	33
Back pain
subjects affected / exposed	69 / 399 (17.29%)	42 / 199 (21.11%)
occurrences all number	74	43
Bone pain
subjects affected / exposed	21 / 399 (5.26%)	14 / 199 (7.04%)
occurrences all number	24	14
Musculoskeletal chest pain
subjects affected / exposed	8 / 399 (2.01%)	10 / 199 (5.03%)
occurrences all number	10	10
Musculoskeletal pain
subjects affected / exposed	41 / 399 (10.28%)	27 / 199 (13.57%)
occurrences all number	47	30
Myalgia
subjects affected / exposed	24 / 399 (6.02%)	9 / 199 (4.52%)
occurrences all number	27	11
Neck pain
subjects affected / exposed	8 / 399 (2.01%)	11 / 199 (5.53%)
occurrences all number	9	11
Pain in extremity
subjects affected / exposed	45 / 399 (11.28%)	27 / 199 (13.57%)
occurrences all number	48	30
Infections and infestations
Urinary tract infection
subjects affected / exposed	31 / 399 (7.77%)	15 / 199 (7.54%)
occurrences all number	36	18
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	114 / 399 (28.57%)	30 / 199 (15.08%)
occurrences all number	124	35
Dehydration
subjects affected / exposed	31 / 399 (7.77%)	6 / 199 (3.02%)
occurrences all number	34	6
Hypokalaemia
subjects affected / exposed	25 / 399 (6.27%)	5 / 199 (2.51%)
occurrences all number	30	5

More information

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Were there any global substantial amendments to the protocol? Yes

18 Apr 2011

Added pre-dose thyroid-stimulating hormone (TSH) testing to the protocol in order to ensure consistency with the Food and Drug Administration (FDA) approved label for ipilimumab.

04 Oct 2012

Updated AE/SAE follow-up period from 70 to 90 days after the last dose of blinded study drug, and clarified on weight-based dose calculations to ensure consistency with other ipilimumab studies.

17 Apr 2014

Reordered the hierarchical order of testing for secondary endpoints, introduced radiologic Progression Free Survival (rPFS), time to pain increase, time to opioid analgesic use, and time to subsequent treatment (hormonal, non-hormonal, immunotherapy) as a pre-specified exploratory endpoints.

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.

The further developments were not pursued as study did not meet its primary endpoint of demonstrating a statistically significant prolongation of overall survival.

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