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Clinical Trial Results:
A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety and Efficacy of Selonsertib in Subjects with Compensated Cirrhosis due to Nonalcoholic Steatohepatitis (NASH)

Summary
EudraCT number	2016-004148-13
Trial protocol	AT BE GB PT PL NL ES FR IT
Global end of trial date	06 May 2019

Results information
Results version number	v1(current)
This version publication date	10 May 2020
First version publication date	10 May 2020
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

GS-US-384-1944

ISRCTN number

-

US NCT number

NCT03053063

WHO universal trial number (UTN)

-

Sponsor organisation name

Gilead Sciences

Sponsor organisation address

333 Lakeside Drive, Foster City, CA, United States, 94404

Public contact

Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com

Scientific contact

Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.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

06 May 2019

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

06 May 2019

Was the trial ended prematurely?

Yes

Main objective of the trial

The primary objective of this study was to evaluate whether selonsertib (SEL; GS-4997) can cause fibrosis regression and reduce associated complications in subjects with cirrhosis due to NASH.

Protection of trial subjects

The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

30 Jan 2017

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 7

Country: Number of subjects enrolled

Spain: 20

Country: Number of subjects enrolled

United Kingdom: 13

Country: Number of subjects enrolled

Austria: 2

Country: Number of subjects enrolled

Belgium: 7

Country: Number of subjects enrolled

France: 43

Country: Number of subjects enrolled

Germany: 10

Country: Number of subjects enrolled

United States: 525

Country: Number of subjects enrolled

Japan: 58

Country: Number of subjects enrolled

Canada: 37

Country: Number of subjects enrolled

Australia: 32

Country: Number of subjects enrolled

India: 31

Country: Number of subjects enrolled

Korea, Republic of: 24

Country: Number of subjects enrolled

Israel: 17

Country: Number of subjects enrolled

Hong Kong: 15

Country: Number of subjects enrolled

Taiwan: 9

Country: Number of subjects enrolled

Mexico: 8

Country: Number of subjects enrolled

Puerto Rico: 7

Country: Number of subjects enrolled

Italy: 6

Country: Number of subjects enrolled

New Zealand: 5

Country: Number of subjects enrolled

Singapore: 5

Country: Number of subjects enrolled

Switzerland: 2

Worldwide total number of subjects

883

EEA total number of subjects

108

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)

636

From 65 to 84 years

247

85 years and over

0

Subject disposition

Top of page

Recruitment details

Participants were enrolled at study sites in North America, Asia, Australia, New Zealand, Europe and Puerto Rico. The first participant was screened on 30 January 2017. The last study visit occurred on 06 May 2019.

Screening details

2154 participants were screened. No participants completed the study. In the Subject Disposition, the number of participants reported in the Randomised Phase arms for "Completed" is the number of participants who had confirmed clinical event therefore discontinued randomised phase per protocol.

Period 1 title

Randomised Phase

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

SEL 18 mg

Arm description

Randomised Phase: SEL 18 mg tablet orally once daily + placebo for up to 240 weeks.

Arm type

Experimental

Investigational medicinal product name

Selonsertib

Investigational medicinal product code

Other name

GS-4997

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

18 mg administered once daily

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Tablets administered once daily

SEL 6 mg

Arm description

Randomised Phase : SEL 6 mg tablet orally once daily + placebo for up to 240 weeks.

Arm type

Experimental

Investigational medicinal product name

Selonsertib

Investigational medicinal product code

Other name

GS-4997

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

6 mg administered once daily

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Tablets administered once daily

Placebo

Arm description

Randomised Phase: Placebo to match SEL 18 mg and 6 mg orally once daily for up to 240 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

Placebo to match SEL 18 mg and 6 mg administered once daily

Number of subjects in period 1 ^[1]	SEL 18 mg	SEL 6 mg	Placebo
Started	354	351	172
Completed	9	11	3
Not completed	345	340	169
Study terminated by sponsor	326	317	161
Adverse event	-	1	-
Withdrew consent	8	11	5
Investigator's discretion	8	6	2
Lost to follow-up	3	5	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: 6 participants (1 in SEL 18 mg arm, 3 in SEL 6 mg arm, and 2 in Placebo arm) were randomised but did not receive study treatment.

Period 2 title

Open-Label Phase

Is this the baseline period?

No

Allocation method

Not applicable

Blinding used

Not blinded

Open-Label SEL 18 mg

Arm description

Open-Label (OL) Phase: Participants who experienced a hepatic clinical event during the randomized phase, prior to completing the Week 240 visit, were offered the option to roll over into an OL phase to receive OL SEL 18 mg daily for a total treatment duration of 240 weeks, including the treatment duration in the randomized phase.

Arm type

Experimental

Investigational medicinal product name

Selonsertib

Investigational medicinal product code

Other name

GS-4997

Pharmaceutical forms

Film-coated tablet

Routes of administration

Oral use

Dosage and administration details

18 mg administered once daily

Number of subjects in period 2	Open-Label SEL 18 mg
Started	23
Completed	0
Not completed	23
Death	2
Study terminated by sponsor	19
Investigator's discretion	2

Baseline characteristics

Top of page

Reporting group title

SEL 18 mg

Reporting group description

Randomised Phase: SEL 18 mg tablet orally once daily + placebo for up to 240 weeks.

Reporting group title

SEL 6 mg

Reporting group description

Randomised Phase : SEL 6 mg tablet orally once daily + placebo for up to 240 weeks.

Reporting group title

Placebo

Reporting group description

Randomised Phase: Placebo to match SEL 18 mg and 6 mg orally once daily for up to 240 weeks.

Reporting group values	SEL 18 mg	SEL 6 mg	Placebo	Total
Number of subjects	354	351	172	877
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	58 ( 8.5 )	57 ( 8.7 )	60 ( 8.4 )	-
Gender categorical
Units: Subjects
Female	216	230	101	547
Male	138	121	71	330
Race
Units: Subjects
American Indian or Alaska Native	3	3	0	6
Asian	73	59	33	165
Black	5	4	1	10
Native Hawaiian or Pacific Islander	1	0	0	1
White	261	279	136	676
Other	7	6	1	14
Not Permitted	4	0	1	5
Ethnicity
Units: Subjects
Not Hispanic or Latino	300	297	149	746
Hispanic or Latino	49	51	22	122
Not Permitted	5	3	1	9

End points

Top of page

Reporting group title

SEL 18 mg

Reporting group description

Randomised Phase: SEL 18 mg tablet orally once daily + placebo for up to 240 weeks.

Reporting group title

SEL 6 mg

Reporting group description

Randomised Phase : SEL 6 mg tablet orally once daily + placebo for up to 240 weeks.

Reporting group title

Placebo

Reporting group description

Randomised Phase: Placebo to match SEL 18 mg and 6 mg orally once daily for up to 240 weeks.

Reporting group title

Open-Label SEL 18 mg

Reporting group description

Open-Label (OL) Phase: Participants who experienced a hepatic clinical event during the randomized phase, prior to completing the Week 240 visit, were offered the option to roll over into an OL phase to receive OL SEL 18 mg daily for a total treatment duration of 240 weeks, including the treatment duration in the randomized phase.

Primary: Percentage of Participants Who Achieve a ≥ 1-Stage Improvement in Fibrosis According to the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network (CRN) Classification Without Worsening of NASH

Top of page

End point title

Percentage of Participants Who Achieve a ≥ 1-Stage Improvement in Fibrosis According to the Nonalcoholic Steatohepatitis (NASH) Clinical Research Network (CRN) Classification Without Worsening of NASH

End point description

Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH CRN classification. NASH CRN fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=None, 4=Cirrhosis). Worsening of NASH was defined as ≥ 1 point increase from baseline in hepatocellular ballooning or lobular inflammation according to the Non-Alcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) criteria. As defined by NAS, hepatocellular ballooning ranges from 0-2 and lobular inflammation ranges from 0-3, with higher scores indicating more severe hepatocellular ballooning or lobular inflammation. The Full Analysis Set included all participants who were randomised into the study and received at least 1 dose of study drug.

End point type

Primary

End point timeframe

Week 48

End point values	SEL 18 mg	SEL 6 mg	Placebo
Number of subjects analysed	354	351	172
Units: percentage of participants
number (confidence interval 95%)	14.4 (10.9 to 18.5)	12.8 (9.5 to 16.8)	12.8 (8.2 to 18.7)

SEL 18 mg vs Placebo

Comparison groups

SEL 18 mg v Placebo

Number of subjects included in analysis

526

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5572 ^[1]

Method

Mantel-Haenszel

Parameter type

Percentage Difference

Point estimate

1.9

Confidence interval

level

95%

sides

2-sided

lower limit

-4.4

upper limit

8.2

Notes
[1] - Difference between SEL 18 mg vs Placebo, 95% confidence interval (CI) and p-value were obtained by stratified Mantel-Haenszel method adjusting for baseline (BL) diabetes mellitus status and BL Enhanced Liver Fibrosis (ELF) score (<11.27 vs ≥11.27).

SEL 6 mg vs Placebo

Comparison groups

SEL 6 mg v Placebo

Number of subjects included in analysis

523

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9272 ^[2]

Method

Mantel-Haenszel

Parameter type

Percentage Difference

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-6

upper limit

6.5

Notes
[2] - Difference between SEL 6 mg vs Placebo, 95% CI and p-value were obtained by stratified Mantel-Haenszel method adjusting for BL diabetes mellitus status and BL ELF score (<11.27 vs ≥11.27).

Primary: Event-Free Survival (EFS) at Week 240 as Assessed by Time to First Clinical Event

Top of page

End point title

Event-Free Survival (EFS) at Week 240 as Assessed by Time to First Clinical Event ^[3]

End point description

EFS was assessed by the time to the first clinical event, including liver decompensation events, liver transplantation and all-cause mortality.

End point type

Primary

End point timeframe

Week 240

Notes
[3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: No data was analysed as the study was terminated and no participants reached the Week 240 timepoint.

End point values	SEL 18 mg	SEL 6 mg	Placebo
Number of subjects analysed	0 ^[4]	0 ^[5]	0 ^[6]
Units: months
median (inter-quartile range (Q1-Q3))	( to )	( to )	( to )

Notes
[4] - No data was analysed as the study was terminated and no participants reached the Week 240 timepoint.
[5] - No data was analysed as the study was terminated and no participants reached the Week 240 timepoint.
[6] - No data was analysed as the study was terminated and no participants reached the Week 240 timepoint.

No statistical analyses for this end point

Secondary: Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis Without Worsening of NASH at Week 240

Top of page

End point title

Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis Without Worsening of NASH at Week 240

End point description

Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH CRN classification. NASH CRN fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=None, 4=Cirrhosis). Worsening of NASH was defined as ≥ 1 point increase from baseline in hepatocellular ballooning or lobular inflammation according to the NAS criteria. As defined by NAS, hepatocellular ballooning ranges from 0-2 and lobular inflammation ranges from 0-3, with higher scores indicating more severe hepatocellular ballooning or lobular inflammation.

End point type

Secondary

End point timeframe

Week 240

End point values	SEL 18 mg	SEL 6 mg	Placebo
Number of subjects analysed	0 ^[7]	0 ^[8]	0 ^[9]
Units: percentage of participants
number (not applicable)

Notes
[7] - No data was analysed as the study was terminated and no participants reached the Week 240 timepoint.
[8] - No data was analysed as the study was terminated and no participants reached the Week 240 timepoint.
[9] - No data was analysed as the study was terminated and no participants reached the Week 240 timepoint.

No statistical analyses for this end point

Secondary: Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis at Week 48

Top of page

End point title

Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis at Week 48

End point description

Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH CRN classification. NASH CRN fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=None, 4=Cirrhosis). Participants in the Full Analysis Set were analysed.

End point type

Secondary

End point timeframe

Week 48

End point values	SEL 18 mg	SEL 6 mg	Placebo
Number of subjects analysed	354	351	172
Units: percentage of participants
number (confidence interval 95%)	18.9 (15.0 to 23.4)	16.8 (13.0 to 21.1)	15.7 (10.6 to 22.0)

SEL 18 mg vs Placebo

Comparison groups

SEL 18 mg v Placebo

Number of subjects included in analysis

526

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.285 ^[10]

Method

Mantel-Haenszel

Parameter type

Percentage Difference

Point estimate

3.8

Confidence interval

level

95%

sides

2-sided

lower limit

-3.1

upper limit

10.6

Notes
[10] - Difference between SEL 18 mg vs Placebo, 95% CI and p-value were obtained by stratified Mantel-Haenszel method adjusting for BL diabetes mellitus status and ELF score (<11.27 vs ≥11.27).

SEL 6 mg vs Placebo

Comparison groups

SEL 6 mg v Placebo

Number of subjects included in analysis

523

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6731 ^[11]

Method

Mantel-Haenszel

Parameter type

Percentage Difference

Point estimate

1.5

Confidence interval

level

95%

sides

2-sided

lower limit

-5.3

upper limit

8.2

Notes
[11] - Difference between SEL 6 mg vs Placebo, 95% CI and p-value were obtained by stratified Mantel-Haenszel method adjusting for BL diabetes mellitus status and BL ELF score (<11.27 vs ≥11.2.

Secondary: Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis at Week 240

Top of page

End point title

Percentage of Participants Who Had a ≥ 1-Stage Improvement in Fibrosis at Week 240

End point description

Fibrosis improvement was defined as ≥ 1-stage decrease from baseline in fibrosis according to the NASH CRN classification. NASH CRN fibrosis stages range from 0 to 4, with higher scores indicating greater fibrosis (0=None, 4=Cirrhosis).

End point type

Secondary

End point timeframe

Week 240

End point values	SEL 18 mg	SEL 6 mg	Placebo
Number of subjects analysed	0 ^[12]	0 ^[13]	0 ^[14]
Units: percentage of participants
number (not applicable)

Notes
[12] - No data was analysed as the study was terminated and no participants reached the Week 240 timepoint.
[13] - No data was analysed as the study was terminated and no participants reached the Week 240 timepoint.
[14] - No data was analysed as the study was terminated and no participants reached the Week 240 timepoint.

No statistical analyses for this end point

Secondary: Percentage of Participants Who Had NASH Resolution at Week 48

Top of page

End point title

Percentage of Participants Who Had NASH Resolution at Week 48

End point description

NASH resolution was defined as lobular inflammation of 0 or 1 from ≥ 1 at baseline and hepatocellular ballooning reduced to 0 from a value ≥ 1 at baseline; both criteria were necessary conditions. As defined by NAS, hepatocellular ballooning ranges from 0-2 and lobular inflammation ranges from 0-3, with higher scores indicating more severe hepatocellular ballooning or lobular inflammation. Evaluable participants had baseline lobular inflammation and hepatocellular ballooning ≥ 1. Participants in the Full Analysis Set were analysed.

End point type

Secondary

End point timeframe

Week 48

End point values	SEL 18 mg	SEL 6 mg	Placebo
Number of subjects analysed	353	351	172
Units: percentage of participants
number (confidence interval 95%)	2.3 (1.0 to 4.4)	3.7 (2.0 to 6.3)	4.1 (1.7 to 8.2)

SEL 18 mg vs Placebo

Comparison groups

SEL 18 mg v Placebo

Number of subjects included in analysis

525

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.365 ^[15]

Method

Mantel-Haenszel

Parameter type

Percentage Difference

Point estimate

-1.7

Confidence interval

level

95%

sides

2-sided

lower limit

-5.5

upper limit

2

Notes
[15] - Difference between SEL 18 mg vs Placebo, 95% CI and p-value were obtained by stratified Mantel-Haenszel method adjusting for BL diabetes mellitus status and BL ELF score (<11.27 vs ≥11.27).

SEL 6 mg vs Placebo

Comparison groups

SEL 6 mg v Placebo

Number of subjects included in analysis

523

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8557 ^[16]

Method

Mantel-Haenszel

Parameter type

Percentage Difference

Point estimate

-0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-4.3

upper limit

3.6

Notes
[16] - Difference between SEL 6 mg vs Placebo, 95% CI and p-value were obtained by stratified Mantel-Haenszel method adjusting for BL diabetes mellitus status and BL ELF score (<11.27 vs ≥11.27).

Secondary: Percentage of Participants Who Had NASH Resolution at Week 240

Top of page

End point title

Percentage of Participants Who Had NASH Resolution at Week 240

End point description

NASH resolution was defined as lobular inflammation of 0 or 1 from ≥ 1 at baseline and hepatocellular ballooning reduced to 0 from a value ≥ 1 at baseline; both criteria were necessary conditions. As defined by NAS, hepatocellular ballooning ranges from 0-2 and lobular inflammation ranges from 0-3, with higher scores indicating more severe hepatocellular ballooning or lobular inflammation. Evaluable participants had baseline lobular inflammation and hepatocellular ballooning ≥ 1.

End point type

Secondary

End point timeframe

Week 240

End point values	SEL 18 mg	SEL 6 mg	Placebo
Number of subjects analysed	0 ^[17]	0 ^[18]	0 ^[19]
Units: percentage of participants
number (not applicable)

Notes
[17] - No data was analysed as the study was terminated and no participants reached the Week 240 timepoint.
[18] - No data was analysed as the study was terminated and no participants reached the Week 240 timepoint.
[19] - No data was analysed as the study was terminated and no participants reached the Week 240 timepoint.

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

First dose date up to last dose date (maximum: 108.7 weeks) plus 30 days

Adverse event reporting additional description

The Safety Analysis Set included all participants who received at least 1 dose of study drug.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.1

Reporting group title

SEL 18 mg

Reporting group description

Randomized Phase: SEL 18 mg tablet orally once daily + placebo for up to 240 weeks.

Reporting group title

SEL 6 mg

Reporting group description

Randomized Phase: SEL 6 mg tablet orally once daily + placebo for up to 240 weeks.

Reporting group title

Placebo

Reporting group description

Randomized Phase: Placebo tablet orally once daily for up to 240 weeks.

Reporting group title

Open-Label SEL 18 mg

Reporting group description

Participants who experienced a hepatic clinical event during the randomized phase, prior to completing the Week 240 visit, were offered the option to roll over into an OL phase to receive OL SEL 18 mg daily for a total treatment duration, including the treatment duration in the randomized phase, of 240 weeks.

Serious adverse events	SEL 18 mg	SEL 6 mg	Placebo	Open-Label SEL 18 mg
Total subjects affected by serious adverse events
subjects affected / exposed	60 / 354 (16.95%)	53 / 351 (15.10%)	22 / 172 (12.79%)	7 / 23 (30.43%)
number of deaths (all causes)	0	0	0	2
number of deaths resulting from adverse events	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatocellular carcinoma
subjects affected / exposed	2 / 354 (0.56%)	1 / 351 (0.28%)	1 / 172 (0.58%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
B-cell lymphoma
subjects affected / exposed	0 / 354 (0.00%)	0 / 351 (0.00%)	0 / 172 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colon adenoma
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nasal cavity cancer
subjects affected / exposed	0 / 354 (0.00%)	0 / 351 (0.00%)	1 / 172 (0.58%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian adenoma
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Haematoma
subjects affected / exposed	0 / 354 (0.00%)	0 / 351 (0.00%)	1 / 172 (0.58%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypotension
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Shock haemorrhagic
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Non-cardiac chest pain
subjects affected / exposed	2 / 354 (0.56%)	2 / 351 (0.57%)	3 / 172 (1.74%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	3 / 354 (0.85%)	0 / 351 (0.00%)	2 / 172 (1.16%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Generalised oedema
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral swelling
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Contrast media allergy
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Drug hypersensitivity
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sarcoidosis
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Endometrial hyperplasia
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endometrial hypertrophy
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Endometrial thickening
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hydrosalpinx
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian cyst
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 354 (0.28%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cough
subjects affected / exposed	0 / 354 (0.00%)	0 / 351 (0.00%)	1 / 172 (0.58%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Epistaxis
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic hydrothorax
subjects affected / exposed	0 / 354 (0.00%)	0 / 351 (0.00%)	0 / 172 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary mass
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Mental status changes
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bipolar disorder
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Suicidal ideation
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Suicide attempt
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Blood pressure increased
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gamma-glutamyltransferase increased
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Model for end stage liver disease score increased
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Procedural pain
subjects affected / exposed	2 / 354 (0.56%)	0 / 351 (0.00%)	0 / 172 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	1 / 354 (0.28%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Toxicity to various agents
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	1 / 172 (0.58%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Perirenal haematoma
subjects affected / exposed	0 / 354 (0.00%)	0 / 351 (0.00%)	1 / 172 (0.58%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subdural haematoma
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wound secretion
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	3 / 354 (0.85%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	1 / 3	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	1 / 354 (0.28%)	1 / 351 (0.28%)	1 / 172 (0.58%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 354 (0.00%)	2 / 351 (0.57%)	0 / 172 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Angina unstable
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	1 / 172 (0.58%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	2 / 354 (0.56%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	2 / 354 (0.56%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	0 / 354 (0.00%)	0 / 351 (0.00%)	1 / 172 (0.58%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 354 (0.00%)	0 / 351 (0.00%)	1 / 172 (0.58%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Prinzmetal angina
subjects affected / exposed	0 / 354 (0.00%)	0 / 351 (0.00%)	1 / 172 (0.58%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Hepatic encephalopathy
subjects affected / exposed	1 / 354 (0.28%)	2 / 351 (0.57%)	1 / 172 (0.58%)	2 / 23 (8.70%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 354 (0.28%)	1 / 351 (0.28%)	1 / 172 (0.58%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	1 / 172 (0.58%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 354 (0.00%)	2 / 351 (0.57%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar radiculopathy
subjects affected / exposed	1 / 354 (0.28%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cervical radiculopathy
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic hyperosmolar coma
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Facial paralysis
subjects affected / exposed	0 / 354 (0.00%)	0 / 351 (0.00%)	1 / 172 (0.58%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Loss of consciousness
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolic encephalopathy
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorder
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Toxic encephalopathy
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	3 / 354 (0.85%)	3 / 351 (0.85%)	1 / 172 (0.58%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhagic anaemia
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Immune thrombocytopenic purpura
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Iron deficiency anaemia
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	4 / 354 (1.13%)	2 / 351 (0.57%)	0 / 172 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 4	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematemesis
subjects affected / exposed	1 / 354 (0.28%)	2 / 351 (0.57%)	1 / 172 (0.58%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	2 / 354 (0.56%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain upper
subjects affected / exposed	2 / 354 (0.56%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ascites
subjects affected / exposed	1 / 354 (0.28%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	1 / 172 (0.58%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	2 / 354 (0.56%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Melaena
subjects affected / exposed	1 / 354 (0.28%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal varices haemorrhage
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Appendiceal mucocoele
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 354 (0.00%)	0 / 351 (0.00%)	0 / 172 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Duodenitis
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enterocolitis
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastric polyps
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastric ulcer perforation
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastritis
subjects affected / exposed	0 / 354 (0.00%)	0 / 351 (0.00%)	1 / 172 (0.58%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal wall thickening
subjects affected / exposed	0 / 354 (0.00%)	0 / 351 (0.00%)	1 / 172 (0.58%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhoids
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Large intestine polyp
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mallory-Weiss syndrome
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Mesenteric panniculitis
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 354 (0.00%)	0 / 351 (0.00%)	1 / 172 (0.58%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Obstructive pancreatitis
subjects affected / exposed	0 / 354 (0.00%)	0 / 351 (0.00%)	0 / 172 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophagitis
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Visceral venous thrombosis
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 354 (0.00%)	0 / 351 (0.00%)	1 / 172 (0.58%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 354 (0.00%)	3 / 351 (0.85%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	1 / 172 (0.58%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic hepatic failure
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholangitis acute
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Drug-induced liver injury
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemobilia
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic cirrhosis
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatorenal syndrome
subjects affected / exposed	0 / 354 (0.00%)	0 / 351 (0.00%)	0 / 172 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intrahepatic portal hepatic venous fistula
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Jaundice
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	2 / 354 (0.56%)	0 / 351 (0.00%)	0 / 172 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	2 / 354 (0.56%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Chronic kidney disease
subjects affected / exposed	0 / 354 (0.00%)	0 / 351 (0.00%)	0 / 172 (0.00%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ureterolithiasis
subjects affected / exposed	0 / 354 (0.00%)	0 / 351 (0.00%)	1 / 172 (0.58%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Intervertebral disc protrusion
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myalgia
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Cellulitis
subjects affected / exposed	3 / 354 (0.85%)	3 / 351 (0.85%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	3 / 354 (0.85%)	1 / 351 (0.28%)	1 / 172 (0.58%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	2 / 172 (1.16%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	2 / 354 (0.56%)	0 / 351 (0.00%)	1 / 172 (0.58%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 4	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 354 (0.00%)	0 / 351 (0.00%)	1 / 172 (0.58%)	1 / 23 (4.35%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bacteraemia
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 354 (0.00%)	0 / 351 (0.00%)	1 / 172 (0.58%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Enterocolitis infectious
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia pyelonephritis
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Genital herpes
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Meningitis
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nasal abscess
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Perineal abscess
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary tuberculosis
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 354 (0.00%)	1 / 351 (0.28%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Tonsillitis
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Diabetes mellitus inadequate control
subjects affected / exposed	0 / 354 (0.00%)	2 / 351 (0.57%)	1 / 172 (0.58%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	2 / 354 (0.56%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fluid overload
subjects affected / exposed	0 / 354 (0.00%)	0 / 351 (0.00%)	1 / 172 (0.58%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperglycaemic hyperosmolar nonketotic syndrome
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyperkalaemia
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypomagnesaemia
subjects affected / exposed	0 / 354 (0.00%)	0 / 351 (0.00%)	1 / 172 (0.58%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Obesity
subjects affected / exposed	1 / 354 (0.28%)	0 / 351 (0.00%)	0 / 172 (0.00%)	0 / 23 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	SEL 18 mg	SEL 6 mg	Placebo	Open-Label SEL 18 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	251 / 354 (70.90%)	276 / 351 (78.63%)	135 / 172 (78.49%)	17 / 23 (73.91%)
Investigations
Blood creatinine increased
subjects affected / exposed	2 / 354 (0.56%)	1 / 351 (0.28%)	1 / 172 (0.58%)	3 / 23 (13.04%)
occurrences all number	2	1	1	3
Injury, poisoning and procedural complications
Procedural pain
subjects affected / exposed	20 / 354 (5.65%)	23 / 351 (6.55%)	12 / 172 (6.98%)	0 / 23 (0.00%)
occurrences all number	21	23	13	0
Nervous system disorders
Headache
subjects affected / exposed	47 / 354 (13.28%)	48 / 351 (13.68%)	21 / 172 (12.21%)	4 / 23 (17.39%)
occurrences all number	55	56	25	4
Dizziness
subjects affected / exposed	22 / 354 (6.21%)	23 / 351 (6.55%)	17 / 172 (9.88%)	1 / 23 (4.35%)
occurrences all number	25	26	19	1
Hepatic encephalopathy
subjects affected / exposed	7 / 354 (1.98%)	5 / 351 (1.42%)	2 / 172 (1.16%)	4 / 23 (17.39%)
occurrences all number	7	5	2	4
General disorders and administration site conditions
Fatigue
subjects affected / exposed	42 / 354 (11.86%)	51 / 351 (14.53%)	20 / 172 (11.63%)	0 / 23 (0.00%)
occurrences all number	45	53	21	0
Oedema peripheral
subjects affected / exposed	20 / 354 (5.65%)	23 / 351 (6.55%)	10 / 172 (5.81%)	1 / 23 (4.35%)
occurrences all number	20	25	13	1
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	51 / 354 (14.41%)	60 / 351 (17.09%)	40 / 172 (23.26%)	2 / 23 (8.70%)
occurrences all number	59	73	46	2
Nausea
subjects affected / exposed	47 / 354 (13.28%)	59 / 351 (16.81%)	17 / 172 (9.88%)	2 / 23 (8.70%)
occurrences all number	53	73	23	3
Constipation
subjects affected / exposed	46 / 354 (12.99%)	47 / 351 (13.39%)	18 / 172 (10.47%)	0 / 23 (0.00%)
occurrences all number	50	51	18	0
Abdominal pain upper
subjects affected / exposed	42 / 354 (11.86%)	37 / 351 (10.54%)	21 / 172 (12.21%)	3 / 23 (13.04%)
occurrences all number	45	46	22	3
Abdominal pain
subjects affected / exposed	34 / 354 (9.60%)	33 / 351 (9.40%)	19 / 172 (11.05%)	2 / 23 (8.70%)
occurrences all number	36	34	20	2
Vomiting
subjects affected / exposed	24 / 354 (6.78%)	28 / 351 (7.98%)	7 / 172 (4.07%)	3 / 23 (13.04%)
occurrences all number	27	32	9	3
Abdominal distension
subjects affected / exposed	22 / 354 (6.21%)	22 / 351 (6.27%)	12 / 172 (6.98%)	3 / 23 (13.04%)
occurrences all number	22	23	12	3
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	27 / 354 (7.63%)	33 / 351 (9.40%)	14 / 172 (8.14%)	1 / 23 (4.35%)
occurrences all number	32	35	14	1
Epistaxis
subjects affected / exposed	7 / 354 (1.98%)	8 / 351 (2.28%)	2 / 172 (1.16%)	2 / 23 (8.70%)
occurrences all number	7	10	2	2
Skin and subcutaneous tissue disorders
Pruritus
subjects affected / exposed	29 / 354 (8.19%)	27 / 351 (7.69%)	11 / 172 (6.40%)	2 / 23 (8.70%)
occurrences all number	29	29	12	2
Rash
subjects affected / exposed	19 / 354 (5.37%)	13 / 351 (3.70%)	10 / 172 (5.81%)	1 / 23 (4.35%)
occurrences all number	20	17	12	1
Psychiatric disorders
Insomnia
subjects affected / exposed	24 / 354 (6.78%)	28 / 351 (7.98%)	7 / 172 (4.07%)	2 / 23 (8.70%)
occurrences all number	24	28	8	2
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	34 / 354 (9.60%)	30 / 351 (8.55%)	16 / 172 (9.30%)	1 / 23 (4.35%)
occurrences all number	37	32	17	1
Arthralgia
subjects affected / exposed	19 / 354 (5.37%)	28 / 351 (7.98%)	15 / 172 (8.72%)	3 / 23 (13.04%)
occurrences all number	20	30	18	4
Muscle spasms
subjects affected / exposed	14 / 354 (3.95%)	25 / 351 (7.12%)	10 / 172 (5.81%)	3 / 23 (13.04%)
occurrences all number	14	26	11	3
Musculoskeletal pain
subjects affected / exposed	15 / 354 (4.24%)	19 / 351 (5.41%)	9 / 172 (5.23%)	0 / 23 (0.00%)
occurrences all number	15	21	9	0
Pain in extremity
subjects affected / exposed	16 / 354 (4.52%)	19 / 351 (5.41%)	5 / 172 (2.91%)	1 / 23 (4.35%)
occurrences all number	16	20	5	1
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	43 / 354 (12.15%)	52 / 351 (14.81%)	15 / 172 (8.72%)	1 / 23 (4.35%)
occurrences all number	47	65	17	1
Nasopharyngitis
subjects affected / exposed	42 / 354 (11.86%)	33 / 351 (9.40%)	28 / 172 (16.28%)	0 / 23 (0.00%)
occurrences all number	52	40	36	0
Urinary tract infection
subjects affected / exposed	33 / 354 (9.32%)	39 / 351 (11.11%)	11 / 172 (6.40%)	0 / 23 (0.00%)
occurrences all number	49	50	13	0
Sinusitis
subjects affected / exposed	25 / 354 (7.06%)	27 / 351 (7.69%)	11 / 172 (6.40%)	1 / 23 (4.35%)
occurrences all number	32	32	11	1
Influenza
subjects affected / exposed	27 / 354 (7.63%)	24 / 351 (6.84%)	8 / 172 (4.65%)	1 / 23 (4.35%)
occurrences all number	28	25	8	1
Bronchitis
subjects affected / exposed	16 / 354 (4.52%)	27 / 351 (7.69%)	10 / 172 (5.81%)	0 / 23 (0.00%)
occurrences all number	16	30	13	0

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Were there any global substantial amendments to the protocol? Yes

24 May 2017

1. Clarified that events of hepatic decompensation included portal hypertension-related bleeding that required endoscopy and hospitalization (ie, bleeding from esophageal varices, gastric varices, and portal hypertensive gastropathy) and would be adjudicated by the Hepatic Events/Drug-Induced Liver Injury (DILI) Adjudication Committee. 2. Hepatocellular carcinoma (HCC) was removed as a component of the clinical efficacy endpoint. 3. The outcome of “death” was changed to “all-cause mortality” to clarify that all deaths would be included in the EFS analysis. 4. References to a HepQuant substudy were removed. Only subjects enrolled at participating US sites could participate concurrently in a HepQuant-sponsored study with approval by the applicable IRB/IEC. 5. Laboratory parameters and assessments at screening were clarified; international normalised ratio (INR) ≤ 1.4 and platelet count ≥100,000/μL were added as inclusion criteria, and optional measurement of liver stiffness at screening using transient elastography was included. 6. Stool frequency assessment was added to the study procedures at all visits, beginning with baseline/Day 1. 7. EFS assessed as time to the first clinical event, including HCC, as well as liver decompensation events, liver transplantation, and all-cause mortality, was added as an exploratory efficacy endpoint. 8. Clarified that a sensitivity analysis of EFS that included hepatic clinical events and liver-related death (rather than all-cause mortality) would be performed. 9. Clarified that all clinical events except all-cause mortality and liver transplantation required confirmation by the Hepatic Events Adjudication Committee and that the Committee would also review any case of HCC as an event of special interest. 10. A stratified log-rank test was added to the exploratory endpoint analysis to compare between-group differences (SEL 18 mg, SEL 6 mg, Placebo) in time to the first clinical events, including HCC.

24 May 2017

11. Estimated glomerular filtration rate (eGFR) calculation was included at all visits to identify subjects with severe renal insufficiency. 12. Specified that single PK sampling would be performed at all study visits for subjects who entered the OL phase and had severe hepatic impairment (CP Class C) and renal impairment (eGFR < 30 mL/min). 13. Clarified that subjects in the OL phase who completed study treatment should complete the Week 240/end of treatment (EOT) visit. 14. A telephone follow-up visit to occur 12 weeks after the Week 240 visit was added.

31 May 2018

1. An early termination visit that was to be completed within 30 days after the last dose of study drug and the list of assessments to be performed at the visit was clarified for subjects who prematurely discontinued the study. 2. Clarified that hepatic clinical events would be adjudicated and deaths would be reviewed by the Hepatic Events/Drug-induced liver injury (DILI) Adjudication Committee during the randomized phase of the study; DILI events and cardiovascular events, including deaths, were to be adjudicated in the OL phase of the study by the hepatic events/DILI and cardiovascular Adjudication Committees, as appropriate. 3. Clinical trial information was updated, based on updates to the SEL Investigator’s Brochure, including the numbers of SEL studies conducted and subjects dosed, updated safety data, final study data, and completion of studies.

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.

Based on the results of the Week 48 analysis, the study was terminated early for lack of efficacy as prespecified in the clinical study protocol.

http://www.ncbi.nlm.nih.gov/pubmed/32147362
http://www.ncbi.nlm.nih.gov/pubmed/31271665
http://www.ncbi.nlm.nih.gov/pubmed/30779990

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