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

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Clinical Trial Results:
A Randomized, Multi-center Phase III Study of Nivolumab Versus Sorafenib as First-Line Treatment in Patients With Advanced Hepatocellular Carcinoma (CheckMate 459: CHECKpoint Pathway and nivoluMAb Clinical Trial Evaluation 459)

Summary
EudraCT number	2015-002740-13
Trial protocol	DE AT CZ GB SE FR ES PL IT
Global end of trial date	07 Feb 2024

Results information
Results version number	v1(current)
This version publication date	09 Feb 2025
First version publication date	09 Feb 2025
Other versions

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

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

CA209-459

ISRCTN number

-

US NCT number

NCT02576509

WHO universal trial number (UTN)

-

Sponsor organisation name

Bristol-Myers Squibb

Sponsor organisation address

Chaussée de la Hulpe 185, Brussels, Belgium,

Public contact

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

Scientific contact

EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, 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 Mar 2024

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

07 Feb 2024

Was the trial ended prematurely?

No

Main objective of the trial

The purpose of this study is to determine if nivolumab or sorafenib is more effective in the treatment of Advanced Hepatocellular Carcinoma.

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

07 Dec 2015

Long term follow-up planned

Yes

Long term follow-up rationale

Efficacy, Safety

Long term follow-up duration

5 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 21

Country: Number of subjects enrolled

Austria: 14

Country: Number of subjects enrolled

Belgium: 4

Country: Number of subjects enrolled

Canada: 11

Country: Number of subjects enrolled

China: 22

Country: Number of subjects enrolled

Czechia: 12

Country: Number of subjects enrolled

France: 112

Country: Number of subjects enrolled

Germany: 59

Country: Number of subjects enrolled

Hong Kong: 42

Country: Number of subjects enrolled

Israel: 8

Country: Number of subjects enrolled

Italy: 30

Country: Number of subjects enrolled

Japan: 107

Country: Number of subjects enrolled

Poland: 28

Country: Number of subjects enrolled

Russian Federation: 12

Country: Number of subjects enrolled

Singapore: 20

Country: Number of subjects enrolled

Korea, Republic of: 75

Country: Number of subjects enrolled

Spain: 13

Country: Number of subjects enrolled

Sweden: 7

Country: Number of subjects enrolled

Switzerland: 13

Country: Number of subjects enrolled

Taiwan: 29

Country: Number of subjects enrolled

United Kingdom: 16

Country: Number of subjects enrolled

United States: 88

Worldwide total number of subjects

743

EEA total number of subjects

279

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)

361

From 65 to 84 years

377

85 years and over

5

Subject disposition

Top of page

Recruitment details

-

Screening details

Participants were enrolled in 22 countries.

Period 1 title

Pre-Treatment Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Nivolumab 240 mg

Arm description

Nivolumab 240 mg IV every 2 weeks until disease progression or unacceptable toxicity

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

240 mg every 2 weeks

Sorafenib 400 mg

Arm description

Sorafenib 400 mg PO BID until disease progression or unacceptable toxicity

Arm type

Active comparator

Investigational medicinal product name

Sorafenib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

400 mg PO twice a day

Number of subjects in period 1	Nivolumab 240 mg	Sorafenib 400 mg
Started	371	372
Completed	367	363
Not completed	4	9
Participant withdrew consent	1	5
Participant no longer meets criteria	3	2
Participant request to stop therapy	-	2

Period 2 title

Treatment Period

Is this the baseline period?

No

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Nivolumab 240 mg

Arm description

Nivolumab 240 mg IV every 2 weeks until disease progression or unacceptable toxicity

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

240 mg every 2 weeks

Sorafenib 400 mg

Arm description

Sorafenib 400 mg PO BID until disease progression or unacceptable toxicity

Arm type

Active comparator

Investigational medicinal product name

Sorafenib

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

400 mg PO twice a day

Number of subjects in period 2	Nivolumab 240 mg	Sorafenib 400 mg
Started	367	363
Completed	0	0
Not completed	367	363
Adverse event, serious fatal	1	1
Disease progression	263	244
Participant request to stop treatment	8	18
Participant withdrew consent	3	7
Maximum clinical benefit	1	-
Other reason	12	8
Participant no longer meets criteria	1	-
Study drug toxicity	37	41
NOT REPORTED	1	-
Adverse event unrelated to study drug	39	41
Lost to follow-up	-	1
Poor/non-compliance	1	1
Administrative reason by sponsor	-	1

Baseline characteristics

Top of page

Reporting group title

Nivolumab 240 mg

Reporting group description

Nivolumab 240 mg IV every 2 weeks until disease progression or unacceptable toxicity

Reporting group title

Sorafenib 400 mg

Reporting group description

Sorafenib 400 mg PO BID until disease progression or unacceptable toxicity

Reporting group values	Nivolumab 240 mg	Sorafenib 400 mg	Total
Number of subjects	371	372	743
Age Categorical
Units: Participants
<=18 years	0	0	0
Between 18 and 65 years	185	176	361
>=65 years	186	196	382
Age Continuous
Units: years
arithmetic mean (standard deviation)	63.9 ( 10.61 )	64.5 ( 10.91 )	-
Sex: Female, Male
Units: Participants
Female	57	55	112
Male	314	317	631
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	1	1
Asian	165	167	332
Native Hawaiian or Other Pacific Islander	0	0	0
Black or African American	3	2	5
White	199	196	395
More than one race	0	0	0
Unknown or Not Reported	4	6	10
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	5	10	15
Not Hispanic or Latino	180	170	350
Unknown or Not Reported	186	192	378

End points

Top of page

Reporting group title

Nivolumab 240 mg

Reporting group description

Nivolumab 240 mg IV every 2 weeks until disease progression or unacceptable toxicity

Reporting group title

Sorafenib 400 mg

Reporting group description

Sorafenib 400 mg PO BID until disease progression or unacceptable toxicity

Reporting group title

Nivolumab 240 mg

Reporting group description

Nivolumab 240 mg IV every 2 weeks until disease progression or unacceptable toxicity

Reporting group title

Sorafenib 400 mg

Reporting group description

Sorafenib 400 mg PO BID until disease progression or unacceptable toxicity

Primary: Overall Survival (OS)

Top of page

End point title

Overall Survival (OS)

End point description

OS is defined as the time from the date of randomization to the date of death due to any cause in all randomized participants. Participants who are alive will be censored at the last known alive dates. Based on Kaplan-Meier Estimates.

End point type

Primary

End point timeframe

time from the date of randomization to the date of death due to any cause, assessed up to June 2019 (approximately 41 months)

End point values	Nivolumab 240 mg	Sorafenib 400 mg
Number of subjects analysed	371	372
Units: Months
median (confidence interval 95%)	16.39 (13.93 to 18.37)	14.69 (11.89 to 17.22)

Statisitical Analysis 1

Comparison groups

Nivolumab 240 mg v Sorafenib 400 mg

Number of subjects included in analysis

743

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0752 ^[1]

Method

Logrank

Parameter type

Hazard ratio (HR)

Point estimate

0.85

Confidence interval

level

95%

sides

2-sided

lower limit

0.71

upper limit

1.02

Notes
[1] - A priori threshold for statistical significance is 0.0419

Secondary: Objective Response Rate (ORR) per BICR RECIST 1.1

Top of page

End point title

Objective Response Rate (ORR) per BICR RECIST 1.1

End point description

ORR is defined as the proportion of participants whose best overall response (BOR) is either a complete response (CR) or partial response (PR). BOR is defined as the best response designation, as determined based on BICR-assessed tumor response according to RECIST 1.1, recorded between the date of randomization and the date of first objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first. For participants without documented progression or subsequent anti-cancer therapy, all available response designations will contribute to the BOR determination. For a BOR of CR or PR, the initial response assessment must be confirmed by a consecutive assessment no less than 4 weeks (28 days) later. Estimate of (Nivolumab - Sorafenib) is based on CMH method of weighting, stratified by stratification factors

End point type

Secondary

End point timeframe

the date of randomization and the date of first objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first, assessed up to May 2019 (approximately 40 months)

End point values	Nivolumab 240 mg	Sorafenib 400 mg
Number of subjects analysed	371	372
Units: Percentage of participants
number (confidence interval 95%)	15.4 (11.8 to 19.4)	7.0 (4.6 to 10.1)

Statisitical Analysis 2

Comparison groups

Nivolumab 240 mg v Sorafenib 400 mg

Number of subjects included in analysis

743

Analysis specification

Pre-specified

Analysis type

^[2]

Method

Parameter type

Odds ratio (OR)

Point estimate

2.41

Confidence interval

level

95%

sides

2-sided

lower limit

1.48

upper limit

3.92

Notes
[2] - no test was performed due to OS p-value result above the prior threshold

Statisitical Analysis 1

Comparison groups

Nivolumab 240 mg v Sorafenib 400 mg

Number of subjects included in analysis

743

Analysis specification

Pre-specified

Analysis type

^[3]

Method

Parameter type

Difference of ORRs

Point estimate

8.3

Confidence interval

level

95%

sides

2-sided

lower limit

3.9

upper limit

12.7

Notes
[3] - no test was performed due to OS p-value result above the prior threshold

Secondary: Efficacy based on PD-L1 expression - OS and PFS

Top of page

End point title

Efficacy based on PD-L1 expression - OS and PFS

End point description

PD-L1 expression is defined as the percent of tumor cell membrane staining in a minimum of 100 evaluable tumor cells per Dako PD-L1 IHC assay unless otherwise specified. This is referred as quantifiable PD-L1 expression. If the PD-L1 staining could not be quantified, it is further classifies as: Indeterminate: Tumor cell membrane staining hampered for reasons attributed to the biology of the tumor biopsy specimen and not because of improper sample preparation or handling. Not evaluable: Tumor biopsy specimen was not optimally collected or prepared (e.g. PD-L1 expression is neither quantifiable nor indeterminate). PD-L1 status is a dichotomized variable using an X% cut-off for quantifiable PD-L1 expression: • PD-L1 > X %: ≥ X % PD-L1 expression • PD-L1 < X %: < X % PD-L1 expression where X% denotes the PD-L1 expression cut-off of 1%. Additional cut off values may also be explored. Confidence interval based on the Clopper and Pearson method.

End point type

Secondary

End point timeframe

the date of randomization and the date of first objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first, assessed up to May 2019 (approximately 40 months)

End point values	Nivolumab 240 mg	Sorafenib 400 mg
Number of subjects analysed	371	372
Units: Months
median (confidence interval 95%)
>=1%, OS	16.07 (8.41 to 22.34)	8.62 (5.72 to 16.30)
>=1%, PFS	3.84 (2.10 to 7.62)	3.58 (1.97 to 5.36)
<1%, OS	16.72 (13.93 to 18.56)	15.24 (12.58 to 18.10)
<1%, PFS	3.61 (2.43 to 3.81)	3.75 (3.71 to 5.32)
without PD-L1 quantifiable, OS	16.23 (5.82 to 99999)	22.05 (1.77 to 99999)
without PD-L1 quantifiable, PFS	2.00 (1.87 to 99999)	6.13 (1.08 to 11.17)

Statisitical Analysis 1

Comparison groups

Nivolumab 240 mg v Sorafenib 400 mg

Number of subjects included in analysis

743

Analysis specification

Pre-specified

Analysis type

^[4]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.8

Confidence interval

level

95%

sides

2-sided

lower limit

0.54

upper limit

1.19

Notes
[4] - PD-L1 >= 1%, OS; no test was performed

Statisitical Analysis 2

Comparison groups

Nivolumab 240 mg v Sorafenib 400 mg

Number of subjects included in analysis

743

Analysis specification

Pre-specified

Analysis type

^[5]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.71

Confidence interval

level

95%

sides

2-sided

lower limit

0.48

upper limit

1.03

Notes
[5] - PD-L1 >=1%, PFS; no test was performed

Statisitical Analysis 3

Comparison groups

Nivolumab 240 mg v Sorafenib 400 mg

Number of subjects included in analysis

743

Analysis specification

Pre-specified

Analysis type

^[6]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.84

Confidence interval

level

95%

sides

2-sided

lower limit

0.69

upper limit

1.02

Notes
[6] - PD-L1 <1%, OS; no test was performed

Statisitical Analysis 4

Comparison groups

Nivolumab 240 mg v Sorafenib 400 mg

Number of subjects included in analysis

743

Analysis specification

Pre-specified

Analysis type

^[7]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.98

Confidence interval

level

95%

sides

2-sided

lower limit

0.81

upper limit

1.17

Notes
[7] - PD-L1 <1%, PFS; no test was performed

Statisitical Analysis 5

Comparison groups

Nivolumab 240 mg v Sorafenib 400 mg

Number of subjects included in analysis

743

Analysis specification

Pre-specified

Analysis type

^[8]

Method

Parameter type

Hazard ratio (HR)

Point estimate

1.26

Confidence interval

level

95%

sides

2-sided

lower limit

0.34

upper limit

4.74

Notes
[8] - without PD-L1 quantifiable, OS; no test was performed

Statisitical Analysis 5

Comparison groups

Nivolumab 240 mg v Sorafenib 400 mg

Number of subjects included in analysis

743

Analysis specification

Pre-specified

Analysis type

^[9]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.98

Confidence interval

level

95%

sides

2-sided

lower limit

0.27

upper limit

3.52

Notes
[9] - without PD-L1 quantifiable, PFS; no test was performed

Secondary: Progression-Free Survival (PFS)

Top of page

End point title

Progression-Free Survival (PFS)

End point description

PFS is defined as the time from the date of randomization to the date of the first objectively documented tumor progression as assessed by BICR according to RECIST 1.1 or death due to any cause in all randomized participants. Participants who die without a reported prior progression and without initiation of subsequent anti-cancer therapy will be considered to have progressed on the date of their death. Participants who did not progress or die will be censored on the date of their last tumor assessment. Participants who did not have baseline tumor assessment will be censored on the date they were randomized. Participants who did not have any on study tumor assessments and did not die will be censored on the date they were randomized. Participants who started any subsequent anti-cancer therapy without a prior reported progression will be censored at the last tumor assessment prior to subsequent anti-cancer therapy.

End point type

Secondary

End point timeframe

time from the date of randomization to the date of the first objectively documented tumor progression or death, assessed up to May 2019 (approximately 40 months)

End point values	Nivolumab 240 mg	Sorafenib 400 mg
Number of subjects analysed	371	372
Units: Months
median (confidence interval 95%)	3.68 (3.06 to 3.88)	3.75 (3.71 to 4.47)

Statisitical Analysis 1

Comparison groups

Nivolumab 240 mg v Sorafenib 400 mg

Number of subjects included in analysis

743

Analysis specification

Pre-specified

Analysis type

^[10]

Method

Parameter type

Hazard ratio (HR)

Point estimate

0.93

Confidence interval

level

95%

sides

2-sided

lower limit

0.79

upper limit

1.1

Notes
[10] - no test was performed due to OS p-value result above the prior threshold

Secondary: Efficacy based on PD-L1 expression - ORR

Top of page

End point title

Efficacy based on PD-L1 expression - ORR

End point description

PD-L1 expression is defined as the percent of tumor cell membrane staining in a minimum of 100 evaluable tumor cells per Dako PD-L1 IHC assay unless otherwise specified. This is referred as quantifiable PD-L1 expression. If the PD-L1 staining could not be quantified, it is further classifies as: Indeterminate: Tumor cell membrane staining hampered for reasons attributed to the biology of the tumor biopsy specimen and not because of improper sample preparation or handling. Not evaluable: Tumor biopsy specimen was not optimally collected or prepared (e.g. PD-L1 expression is neither quantifiable nor indeterminate). PD-L1 status is a dichotomized variable using an X% cut-off for quantifiable PD-L1 expression: • PD-L1 > X %: ≥ X % PD-L1 expression • PD-L1 < X %: < X % PD-L1 expression where X% denotes the PD-L1 expression cut-off of 1%. Additional cut off values may also be explored. Confidence interval based on the Clopper and Pearson method.

End point type

Secondary

End point timeframe

the date of randomization and the date of first objectively documented progression or the date of subsequent anti-cancer therapy, whichever occurs first, assessed up to May 2019 (approximately 40 months)

End point values	Nivolumab 240 mg	Sorafenib 400 mg
Number of subjects analysed	371	372
Units: Percentage of participants
number (confidence interval 95%)
>=1%, ORR	28.2 (18.1 to 40.1)	9.4 (3.5 to 19.3)
<1%, ORR	12.2 (8.7 to 16.5)	6.7 (4.1 to 10.1)
without PD-L1 quantifiable, ORR	20.0 (0.5 to 71.6)	0.0 (0.0 to 36.9)

Statisitical Analysis 2

Comparison groups

Nivolumab 240 mg v Sorafenib 400 mg

Number of subjects included in analysis

743

Analysis specification

Pre-specified

Analysis type

^[11]

Method

Parameter type

Odds ratio (OR)

Point estimate

1.95

Confidence interval

level

95%

sides

2-sided

lower limit

1.1

upper limit

3.45

Notes
[11] - PD-L1 <1%, ORR; no test was performed

Statisitical Analysis 1

Comparison groups

Nivolumab 240 mg v Sorafenib 400 mg

Number of subjects included in analysis

743

Analysis specification

Pre-specified

Analysis type

^[12]

Method

Parameter type

Odds ratio (OR)

Point estimate

3.79

Confidence interval

level

95%

sides

2-sided

lower limit

1.41

upper limit

10.17

Notes
[12] - PD-L1 >=1%, ORR; no test was performed

Adverse events

Top of page

Timeframe for reporting adverse events

Serious and non-serious adverse events were collected from first dose till 100 days after last dose of study therapy (up to approximately 95 months).

Adverse event reporting additional description

All cause mortality, serious and non serious adverse events were collected for all participants who received at least one dose of the study drug.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

26.1

Reporting group title

Sorafenib 400 mg

Reporting group description

Sorafenib 400 mg PO BID until disease progression or unacceptable toxicity

Reporting group title

Nivolumab 240 mg

Reporting group description

Nivolumab 240 mg IV every 2 weeks until disease progression or unacceptable toxicity

Serious adverse events	Sorafenib 400 mg	Nivolumab 240 mg
Total subjects affected by serious adverse events
subjects affected / exposed	216 / 363 (59.50%)	216 / 367 (58.86%)
number of deaths (all causes)	329	319
number of deaths resulting from adverse events	105	99
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatocellular carcinoma
subjects affected / exposed	2 / 363 (0.55%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cancer pain
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Liver carcinoma ruptured
subjects affected / exposed	2 / 363 (0.55%)	4 / 367 (1.09%)
occurrences causally related to treatment / all	0 / 3	1 / 4
deaths causally related to treatment / all	0 / 1	0 / 1
Malignant neoplasm progression
subjects affected / exposed	70 / 363 (19.28%)	69 / 367 (18.80%)
occurrences causally related to treatment / all	0 / 71	2 / 70
deaths causally related to treatment / all	0 / 64	0 / 55
Neoplasm malignant
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metastases to liver
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metastases to spinal cord
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Metastases to bone
subjects affected / exposed	0 / 363 (0.00%)	2 / 367 (0.54%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Rectal adenocarcinoma
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	4 / 363 (1.10%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Transitional cell carcinoma
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour haemorrhage
subjects affected / exposed	1 / 363 (0.28%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour thrombosis
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tumour associated fever
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vascular disorders
Bleeding varicose vein
subjects affected / exposed	1 / 363 (0.28%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Aneurysm ruptured
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemorrhage
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (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	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hypovolaemic shock
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Surgical and medical procedures
Assisted suicide
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
General disorders and administration site conditions
Asthenia
subjects affected / exposed	3 / 363 (0.83%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Catheter site related reaction
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Death
subjects affected / exposed	2 / 363 (0.55%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 0
Chest discomfort
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypothermia
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
General physical health deterioration
subjects affected / exposed	14 / 363 (3.86%)	8 / 367 (2.18%)
occurrences causally related to treatment / all	0 / 14	0 / 8
deaths causally related to treatment / all	0 / 11	0 / 5
Fatigue
subjects affected / exposed	4 / 363 (1.10%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	1 / 4	1 / 2
deaths causally related to treatment / all	0 / 1	0 / 0
Pain
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Performance status decreased
subjects affected / exposed	1 / 363 (0.28%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Non-cardiac chest pain
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Multiple organ dysfunction syndrome
subjects affected / exposed	0 / 363 (0.00%)	3 / 367 (0.82%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 3
Pyrexia
subjects affected / exposed	7 / 363 (1.93%)	8 / 367 (2.18%)
occurrences causally related to treatment / all	3 / 8	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza like illness
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Mucosal inflammation
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sudden death
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Respiratory, thoracic and mediastinal disorders
Pleural effusion
subjects affected / exposed	1 / 363 (0.28%)	2 / 367 (0.54%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Nasal ulcer
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lung consolidation
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Interstitial lung disease
subjects affected / exposed	0 / 363 (0.00%)	2 / 367 (0.54%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Atelectasis
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Agonal respiration
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Acute pulmonary oedema
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	2 / 363 (0.55%)	2 / 367 (0.54%)
occurrences causally related to treatment / all	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 1
Respiratory failure
subjects affected / exposed	1 / 363 (0.28%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Respiratory distress
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Pulmonary oedema
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary mass
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	3 / 363 (0.83%)	2 / 367 (0.54%)
occurrences causally related to treatment / all	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonitis
subjects affected / exposed	0 / 363 (0.00%)	4 / 367 (1.09%)
occurrences causally related to treatment / all	0 / 0	6 / 7
deaths causally related to treatment / all	0 / 0	1 / 1
Pleurisy
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Psychiatric disorders
Confusional state
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Depression
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Suicide attempt
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Investigations
Blood creatinine increased
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Blood bilirubin increased
subjects affected / exposed	1 / 363 (0.28%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
General physical condition abnormal
subjects affected / exposed	0 / 363 (0.00%)	3 / 367 (0.82%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Hepatic enzyme increased
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Influenza A virus test positive
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Transaminases increased
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Liver function test increased
subjects affected / exposed	0 / 363 (0.00%)	2 / 367 (0.54%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Occult blood positive
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Liver function test abnormal
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Injury, poisoning and procedural complications
Exposure to communicable disease
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fracture
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Head injury
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Hepatic rupture
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Hip fracture
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Periprosthetic fracture
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infusion related reaction
subjects affected / exposed	0 / 363 (0.00%)	3 / 367 (0.82%)
occurrences causally related to treatment / all	0 / 0	3 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Meniscus injury
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Overdose
subjects affected / exposed	2 / 363 (0.55%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	1 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	1 / 363 (0.28%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Procedural pain
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	1 / 363 (0.28%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Subdural haemorrhage
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Upper limb fracture
subjects affected / exposed	1 / 363 (0.28%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Aortic valve incompetence
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Atrial fibrillation
subjects affected / exposed	0 / 363 (0.00%)	5 / 367 (1.36%)
occurrences causally related to treatment / all	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Cardiac failure
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cardiac failure acute
subjects affected / exposed	0 / 363 (0.00%)	2 / 367 (0.54%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Myocardial infarction
subjects affected / exposed	1 / 363 (0.28%)	3 / 367 (0.82%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Coronary artery disease
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pericardial effusion
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pericarditis
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sinus tachycardia
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nervous system disorders
Ataxia
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Altered state of consciousness
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebral haemorrhage
subjects affected / exposed	0 / 363 (0.00%)	3 / 367 (0.82%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Cerebral infarction
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	3 / 363 (0.83%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	1 / 3	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Headache
subjects affected / exposed	2 / 363 (0.55%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	4 / 363 (1.10%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	1 / 5	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Haemorrhage intracranial
subjects affected / exposed	1 / 363 (0.28%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 1
Cognitive disorder
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hemiparesis
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic encephalopathy
subjects affected / exposed	6 / 363 (1.65%)	6 / 367 (1.63%)
occurrences causally related to treatment / all	1 / 6	0 / 6
deaths causally related to treatment / all	0 / 2	0 / 2
Hypoglycaemic coma
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Loss of consciousness
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Middle cerebral artery stroke
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Neuritis
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Neuropathy peripheral
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Malignant spinal cord compression
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Subarachnoid haemorrhage
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1
Transient ischaemic attack
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Blood and lymphatic system disorders
Febrile neutropenia
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Anaemia
subjects affected / exposed	6 / 363 (1.65%)	8 / 367 (2.18%)
occurrences causally related to treatment / all	2 / 6	2 / 8
deaths causally related to treatment / all	0 / 0	0 / 0
Iron deficiency anaemia
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Neutropenia
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Eyelid function disorder
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Glaucoma
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Retinal artery occlusion
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Retinal vascular disorder
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (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	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Abdominal pain
subjects affected / exposed	11 / 363 (3.03%)	7 / 367 (1.91%)
occurrences causally related to treatment / all	1 / 11	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 1
Abdominal pain lower
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	5 / 363 (1.38%)	2 / 367 (0.54%)
occurrences causally related to treatment / all	1 / 6	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Ascites
subjects affected / exposed	7 / 363 (1.93%)	9 / 367 (2.45%)
occurrences causally related to treatment / all	0 / 9	1 / 13
deaths causally related to treatment / all	0 / 0	0 / 1
Colitis
subjects affected / exposed	0 / 363 (0.00%)	5 / 367 (1.36%)
occurrences causally related to treatment / all	0 / 0	6 / 7
deaths causally related to treatment / all	0 / 0	0 / 0
Colitis ulcerative
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diaphragmatic hernia
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 363 (0.28%)	5 / 367 (1.36%)
occurrences causally related to treatment / all	0 / 1	1 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Anal fistula
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric varices
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dysphagia
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Duodenitis haemorrhagic
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Diverticulum intestinal
subjects affected / exposed	0 / 363 (0.00%)	2 / 367 (0.54%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	2 / 363 (0.55%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastrointestinal perforation
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Gastrointestinal haemorrhage
subjects affected / exposed	6 / 363 (1.65%)	7 / 367 (1.91%)
occurrences causally related to treatment / all	2 / 8	0 / 9
deaths causally related to treatment / all	0 / 1	0 / 2
Gastrointestinal disorder
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Oesophageal varices haemorrhage
subjects affected / exposed	8 / 363 (2.20%)	4 / 367 (1.09%)
occurrences causally related to treatment / all	1 / 8	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 1
Oesophageal haemorrhage
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Nausea
subjects affected / exposed	2 / 363 (0.55%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lower gastrointestinal haemorrhage
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	1 / 363 (0.28%)	3 / 367 (0.82%)
occurrences causally related to treatment / all	0 / 1	2 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Intra-abdominal haemorrhage
subjects affected / exposed	1 / 363 (0.28%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Vomiting
subjects affected / exposed	3 / 363 (0.83%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Varices oesophageal
subjects affected / exposed	2 / 363 (0.55%)	3 / 367 (0.82%)
occurrences causally related to treatment / all	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	6 / 363 (1.65%)	3 / 367 (0.82%)
occurrences causally related to treatment / all	2 / 6	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 1
Stomatitis
subjects affected / exposed	0 / 363 (0.00%)	2 / 367 (0.54%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatobiliary disorders
Acute hepatic failure
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cholangitis
subjects affected / exposed	4 / 363 (1.10%)	4 / 367 (1.09%)
occurrences causally related to treatment / all	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Biloma
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Biliary obstruction
subjects affected / exposed	1 / 363 (0.28%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Biliary dilatation
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bile duct stenosis
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Autoimmune hepatitis
subjects affected / exposed	0 / 363 (0.00%)	2 / 367 (0.54%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	2 / 363 (0.55%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic function abnormal
subjects affected / exposed	2 / 363 (0.55%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0
Hepatic failure
subjects affected / exposed	7 / 363 (1.93%)	10 / 367 (2.72%)
occurrences causally related to treatment / all	2 / 7	2 / 11
deaths causally related to treatment / all	1 / 6	2 / 6
Hepatic cirrhosis
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haemobilia
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholestasis
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic haemorrhage
subjects affected / exposed	1 / 363 (0.28%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypertransaminasaemia
subjects affected / exposed	0 / 363 (0.00%)	2 / 367 (0.54%)
occurrences causally related to treatment / all	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Immune-mediated hepatic disorder
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Immune-mediated hepatitis
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatic lesion
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hepatocellular injury
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Hepatorenal syndrome
subjects affected / exposed	3 / 363 (0.83%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 3	0 / 0
Hepatotoxicity
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperbilirubinaemia
subjects affected / exposed	2 / 363 (0.55%)	4 / 367 (1.09%)
occurrences causally related to treatment / all	1 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Jaundice
subjects affected / exposed	0 / 363 (0.00%)	3 / 367 (0.82%)
occurrences causally related to treatment / all	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 1
Jaundice cholestatic
subjects affected / exposed	1 / 363 (0.28%)	2 / 367 (0.54%)
occurrences causally related to treatment / all	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 1	0 / 0
Liver injury
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Portal vein thrombosis
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Skin and subcutaneous tissue disorders
Blister
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Leukoplakia
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperkeratosis
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Erythema multiforme
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	2 / 363 (0.55%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	2 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Dermatitis bullous
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Purpura
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pruritus
subjects affected / exposed	1 / 363 (0.28%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Drug reaction with eosinophilia and systemic symptoms
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Skin reaction
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Stevens-Johnson syndrome
subjects affected / exposed	0 / 363 (0.00%)	2 / 367 (0.54%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Toxic epidermal necrolysis
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rash maculo-papular
subjects affected / exposed	0 / 363 (0.00%)	2 / 367 (0.54%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Rash erythematous
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rash
subjects affected / exposed	2 / 363 (0.55%)	2 / 367 (0.54%)
occurrences causally related to treatment / all	2 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	5 / 363 (1.38%)	2 / 367 (0.54%)
occurrences causally related to treatment / all	3 / 5	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic nephropathy
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Renal failure
subjects affected / exposed	1 / 363 (0.28%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	1 / 363 (0.28%)	1 / 367 (0.27%)
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	0 / 363 (0.00%)	2 / 367 (0.54%)
occurrences causally related to treatment / all	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Hypophysitis
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arthropathy
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Back pain
subjects affected / exposed	1 / 363 (0.28%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Bone pain
subjects affected / exposed	2 / 363 (0.55%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Joint swelling
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Flank pain
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Intervertebral disc compression
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Intervertebral disc degeneration
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Fistula
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 363 (0.00%)	3 / 367 (0.82%)
occurrences causally related to treatment / all	0 / 0	1 / 3
deaths causally related to treatment / all	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Rhabdomyolysis
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (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 / 363 (0.28%)	0 / 367 (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
Anal abscess
subjects affected / exposed	2 / 363 (0.55%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Abscess limb
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Arthritis bacterial
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Abdominal infection
subjects affected / exposed	2 / 363 (0.55%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
COVID-19
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Brain abscess
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Biliary tract infection
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Biliary sepsis
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Bacterial sepsis
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Bacterial infection
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
COVID-19 pneumonia
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	1 / 363 (0.28%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Escherichia bacteraemia
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 363 (0.00%)	3 / 367 (0.82%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Epididymitis
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (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	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0
Cellulitis
subjects affected / exposed	2 / 363 (0.55%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Genitourinary tract infection
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Infective exacerbation of chronic obstructive airways disease
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infection
subjects affected / exposed	1 / 363 (0.28%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Infected lymphocele
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Haematoma infection
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Klebsiella sepsis
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Liver abscess
subjects affected / exposed	2 / 363 (0.55%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	0 / 363 (0.00%)	2 / 367 (0.54%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonitis bacterial
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Peritonitis
subjects affected / exposed	2 / 363 (0.55%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Perirectal abscess
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Osteomyelitis acute
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumocystis jirovecii pneumonia
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia mycoplasmal
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia klebsiella
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	4 / 363 (1.10%)	6 / 367 (1.63%)
occurrences causally related to treatment / all	1 / 5	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary sepsis
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Rhinovirus infection
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Sepsis
subjects affected / exposed	2 / 363 (0.55%)	7 / 367 (1.91%)
occurrences causally related to treatment / all	1 / 2	0 / 7
deaths causally related to treatment / all	0 / 1	0 / 6
Tooth abscess
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Spontaneous bacterial peritonitis
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Septic shock
subjects affected / exposed	2 / 363 (0.55%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Tracheitis
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Upper respiratory tract infection
subjects affected / exposed	1 / 363 (0.28%)	2 / 367 (0.54%)
occurrences causally related to treatment / all	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	2 / 363 (0.55%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Viral pharyngitis
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Virologic failure
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Wound infection
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Metabolism and nutrition disorders
Cachexia
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Cell death
subjects affected / exposed	1 / 363 (0.28%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Decreased appetite
subjects affected / exposed	4 / 363 (1.10%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	2 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Dehydration
subjects affected / exposed	2 / 363 (0.55%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	1 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1
Failure to thrive
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Fulminant type 1 diabetes mellitus
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	0 / 363 (0.00%)	4 / 367 (1.09%)
occurrences causally related to treatment / all	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0
Diabetic metabolic decompensation
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyperlipasaemia
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hypoglycaemia
subjects affected / exposed	0 / 363 (0.00%)	2 / 367 (0.54%)
occurrences causally related to treatment / all	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 1
Hypokalaemia
subjects affected / exposed	1 / 363 (0.28%)	0 / 367 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0
Ketoacidosis
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Lactic acidosis
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Type 2 diabetes mellitus
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 363 (0.00%)	1 / 367 (0.27%)
occurrences causally related to treatment / all	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0

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

Non-serious adverse events	Sorafenib 400 mg	Nivolumab 240 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	351 / 363 (96.69%)	339 / 367 (92.37%)
Vascular disorders
Hypertension
subjects affected / exposed	85 / 363 (23.42%)	33 / 367 (8.99%)
occurrences all number	97	37
General disorders and administration site conditions
Asthenia
subjects affected / exposed	43 / 363 (11.85%)	40 / 367 (10.90%)
occurrences all number	63	52
Fatigue
subjects affected / exposed	117 / 363 (32.23%)	103 / 367 (28.07%)
occurrences all number	134	131
Pyrexia
subjects affected / exposed	58 / 363 (15.98%)	71 / 367 (19.35%)
occurrences all number	71	90
Oedema peripheral
subjects affected / exposed	41 / 363 (11.29%)	43 / 367 (11.72%)
occurrences all number	45	49
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	47 / 363 (12.95%)	45 / 367 (12.26%)
occurrences all number	53	63
Dyspnoea
subjects affected / exposed	23 / 363 (6.34%)	27 / 367 (7.36%)
occurrences all number	24	32
Dysphonia
subjects affected / exposed	49 / 363 (13.50%)	11 / 367 (3.00%)
occurrences all number	55	11
Psychiatric disorders
Insomnia
subjects affected / exposed	31 / 363 (8.54%)	32 / 367 (8.72%)
occurrences all number	31	35
Investigations
Blood alkaline phosphatase increased
subjects affected / exposed	17 / 363 (4.68%)	19 / 367 (5.18%)
occurrences all number	21	20
Aspartate aminotransferase increased
subjects affected / exposed	60 / 363 (16.53%)	84 / 367 (22.89%)
occurrences all number	74	108
Amylase increased
subjects affected / exposed	14 / 363 (3.86%)	26 / 367 (7.08%)
occurrences all number	23	65
Alanine aminotransferase increased
subjects affected / exposed	38 / 363 (10.47%)	51 / 367 (13.90%)
occurrences all number	51	57
Blood bilirubin increased
subjects affected / exposed	48 / 363 (13.22%)	41 / 367 (11.17%)
occurrences all number	62	53
Lipase increased
subjects affected / exposed	27 / 363 (7.44%)	38 / 367 (10.35%)
occurrences all number	36	80
Weight decreased
subjects affected / exposed	68 / 363 (18.73%)	34 / 367 (9.26%)
occurrences all number	78	38
Platelet count decreased
subjects affected / exposed	28 / 363 (7.71%)	17 / 367 (4.63%)
occurrences all number	42	19
Nervous system disorders
Dizziness
subjects affected / exposed	14 / 363 (3.86%)	23 / 367 (6.27%)
occurrences all number	14	25
Headache
subjects affected / exposed	33 / 363 (9.09%)	24 / 367 (6.54%)
occurrences all number	39	30
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	30 / 363 (8.26%)	35 / 367 (9.54%)
occurrences all number	37	36
Gastrointestinal disorders
Abdominal distension
subjects affected / exposed	22 / 363 (6.06%)	15 / 367 (4.09%)
occurrences all number	26	15
Abdominal pain
subjects affected / exposed	82 / 363 (22.59%)	69 / 367 (18.80%)
occurrences all number	97	86
Abdominal pain upper
subjects affected / exposed	50 / 363 (13.77%)	42 / 367 (11.44%)
occurrences all number	57	46
Ascites
subjects affected / exposed	44 / 363 (12.12%)	46 / 367 (12.53%)
occurrences all number	55	51
Constipation
subjects affected / exposed	52 / 363 (14.33%)	50 / 367 (13.62%)
occurrences all number	68	58
Diarrhoea
subjects affected / exposed	191 / 363 (52.62%)	100 / 367 (27.25%)
occurrences all number	363	140
Stomatitis
subjects affected / exposed	25 / 363 (6.89%)	16 / 367 (4.36%)
occurrences all number	29	21
Nausea
subjects affected / exposed	70 / 363 (19.28%)	62 / 367 (16.89%)
occurrences all number	90	78
Vomiting
subjects affected / exposed	40 / 363 (11.02%)	36 / 367 (9.81%)
occurrences all number	51	41
Skin and subcutaneous tissue disorders
Dry skin
subjects affected / exposed	21 / 363 (5.79%)	16 / 367 (4.36%)
occurrences all number	23	17
Alopecia
subjects affected / exposed	71 / 363 (19.56%)	6 / 367 (1.63%)
occurrences all number	72	7
Rash
subjects affected / exposed	59 / 363 (16.25%)	75 / 367 (20.44%)
occurrences all number	70	98
Erythema
subjects affected / exposed	31 / 363 (8.54%)	5 / 367 (1.36%)
occurrences all number	37	5
Palmar-plantar erythrodysaesthesia syndrome
subjects affected / exposed	181 / 363 (49.86%)	29 / 367 (7.90%)
occurrences all number	236	30
Pruritus
subjects affected / exposed	51 / 363 (14.05%)	88 / 367 (23.98%)
occurrences all number	54	115
Endocrine disorders
Hypothyroidism
subjects affected / exposed	12 / 363 (3.31%)	29 / 367 (7.90%)
occurrences all number	12	42
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	36 / 363 (9.92%)	54 / 367 (14.71%)
occurrences all number	38	64
Back pain
subjects affected / exposed	33 / 363 (9.09%)	38 / 367 (10.35%)
occurrences all number	34	95
Muscle spasms
subjects affected / exposed	29 / 363 (7.99%)	16 / 367 (4.36%)
occurrences all number	37	18
Myalgia
subjects affected / exposed	12 / 363 (3.31%)	19 / 367 (5.18%)
occurrences all number	12	22
Infections and infestations
Nasopharyngitis
subjects affected / exposed	23 / 363 (6.34%)	33 / 367 (8.99%)
occurrences all number	25	48
Upper respiratory tract infection
subjects affected / exposed	15 / 363 (4.13%)	29 / 367 (7.90%)
occurrences all number	20	42
Metabolism and nutrition disorders
Hypoalbuminaemia
subjects affected / exposed	31 / 363 (8.54%)	19 / 367 (5.18%)
occurrences all number	38	20
Hyperglycaemia
subjects affected / exposed	8 / 363 (2.20%)	21 / 367 (5.72%)
occurrences all number	8	23
Decreased appetite
subjects affected / exposed	135 / 363 (37.19%)	77 / 367 (20.98%)
occurrences all number	167	88
Hypokalaemia
subjects affected / exposed	21 / 363 (5.79%)	13 / 367 (3.54%)
occurrences all number	42	16

More information

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Were there any global substantial amendments to the protocol? Yes

01 Oct 2015

Addition of collection of peripheral blood mononuclear cells (PBMCs) and myeloid derived suppressor cells (MDSCs) collected from subjects at baseline from selected sites, reduction of frequency of HCV RNA testing for HCV infected subjects, clarification of locoregional therapy inclusion criteria

24 Aug 2016

Updated Study Director/Medical Monitor information; Co-primary endpoint and objective changed from time to progression (TTP) to objective response rate (ORR); Added requirement for confirmatory scan to be performed for CR/PR assessment of best overall response (BOR); Management algorithms updated per revised nivolumab IB

15 Aug 2017

The purpose of this amendment is to change Overall Response Rate (ORR) from a co-primary objective to a secondary objective of the study. Overall Survival (OS) will be the sole Primary Endpoint of the study.

15 Jan 2019

The primary reason for this amendment is to update several protocol sections to reflect the most recent guidance for treating study participants with nivolumab. In addition, an exploratory objective evaluating the correlation of tumor inflammation with efficacy based on recent preliminary data has been added. Several minor inconsistencies in study objectives and endpoints and minor administrative changes are also addressed.

Were there any global interruptions to the trial? No

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

None reported

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