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Clinical Trial Results:
A Phase 2b, Dose-Ranging, Randomized, Double-Blind, Placebo-Controlled Trial Evaluating the Safety and Efficacy of GS-6624, a Monoclonal Antibody Against Lysyl Oxidase-Like 2 (LOXL2), in Subjects with Compensated Cirrhosis Secondary to Non-Alcoholic Steatohepatitis (NASH)

Summary
EudraCT number	2012-002489-11
Trial protocol	DE GB ES IT
Global end of trial date	03 Jan 2017

Results information
Results version number	v1(current)
This version publication date	17 Nov 2017
First version publication date	17 Nov 2017
Other versions

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

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Trial information

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Sponsor protocol code

GS-US-321-0106

ISRCTN number

-

US NCT number

NCT01672879

WHO universal trial number (UTN)

-

Sponsor organisation name

Gilead Sciences

Sponsor organisation address

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

Public contact

Clinical Trials Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.com

Scientific contact

Clinical Trials Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@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

03 Jan 2017

Is this the analysis of the primary completion data?

Yes

Primary completion date

26 Sep 2016

Global end of trial reached?

Yes

Global end of trial date

03 Jan 2017

Was the trial ended prematurely?

Yes

Main objective of the trial

To primary objective of this study was to evaluate whether simtuzumab (formerly GS-6624) can reduce portal venous pressure and incidence of clinical events in adults with cirrhosis due to Non-Alcoholic Steatohepatitis (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

29 Oct 2012

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 9

Country: Number of subjects enrolled

United States: 211

Country: Number of subjects enrolled

Spain: 8

Country: Number of subjects enrolled

United Kingdom: 7

Country: Number of subjects enrolled

France: 13

Country: Number of subjects enrolled

Germany: 8

Country: Number of subjects enrolled

Italy: 3

Worldwide total number of subjects

259

EEA total number of subjects

39

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)

238

From 65 to 84 years

21

85 years and over

0

Subject disposition

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Recruitment details

Participants were enrolled at study sites in Europe and North America. The first participant was screened on 29 October 2012. The last study visit occurred on 03 January 2017.

Screening details

453 participants were screened.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Are arms mutually exclusive

Yes

SIM 200 mg

Arm description

Simtuzumab (SIM) 200 mg every 2 weeks for up to 240 weeks

Arm type

Experimental

Investigational medicinal product name

Simtuzumab 200 mg

Investigational medicinal product code

Other name

GS-6624

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

200 mg intravenous infusion over 30 minutes

SIM 700 mg

Arm description

Simtuzumab (SIM) 700 mg every 2 weeks for up to 240 weeks

Arm type

Experimental

Investigational medicinal product name

Simtuzumab 700 mg

Investigational medicinal product code

Other name

GS-6624

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

700 mg intravenous infusion over 30 minutes

Placebo

Arm description

Placebo to match Simtuzumab (SIM) every 2 weeks for up to 240 weeks

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Infusion

Routes of administration

Intravenous use

Dosage and administration details

Simtuzumab (SIM) placebo intravenous infusion over 30 minutes

Number of subjects in period 1 ^[1]	SIM 200 mg	SIM 700 mg	Placebo
Started	87	86	85
Completed	0	0	0
Not completed	87	86	85
Withdrew Consent	14	7	6
Adverse Event	10	3	8
Death	-	2	-
Investigator's Discretion	6	-	3
Progressive Disease	1	-	-
Study Terminated by Sponsor	51	71	67
Lost to follow-up	4	3	1
Missing	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: One participant who was enrolled but never treated was not included in the subject disposition table.

Baseline characteristics

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Reporting group title

SIM 200 mg

Reporting group description

Simtuzumab (SIM) 200 mg every 2 weeks for up to 240 weeks

Reporting group title

SIM 700 mg

Reporting group description

Simtuzumab (SIM) 700 mg every 2 weeks for up to 240 weeks

Reporting group title

Placebo

Reporting group description

Placebo to match Simtuzumab (SIM) every 2 weeks for up to 240 weeks

Reporting group values	SIM 200 mg	SIM 700 mg	Placebo	Total
Number of subjects	87	86	85	258
Age categorical
Units: Subjects
Age continuous
Safety Analysis Set: all enrolled participants who were randomized and received at least one dose of study drug.
Units: years
arithmetic mean (standard deviation)	56 ± 7.2	55 ± 7.3	56 ± 7.8	-
Gender categorical
Units: Subjects
Female	53	54	56	163
Male	34	32	29	95
Race
Units: Subjects
Asian	3	1	0	4
Black	2	3	1	6
White	80	75	83	238
Other	2	7	1	10
Ethnicity
Units: Subjects
Hispanic or Latino	12	17	10	39
Not Hispanic or Latino	75	69	75	219
Hepatic Venous Pressure Gradient (HVPG)
Full Analysis Set: all enrolled participants who were randomized and received at least 1 dose of study drug. Only 85 participants in SIM 700 mg arm and 84 participants in placebo arm with available data were analyzed.
Units: mmHg
arithmetic mean (standard deviation)	12.9 ± 5.10	12.8 ± 5.37	13.0 ± 5.25	-

End points

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Reporting group title

SIM 200 mg

Reporting group description

Simtuzumab (SIM) 200 mg every 2 weeks for up to 240 weeks

Reporting group title

SIM 700 mg

Reporting group description

Simtuzumab (SIM) 700 mg every 2 weeks for up to 240 weeks

Reporting group title

Placebo

Reporting group description

Placebo to match Simtuzumab (SIM) every 2 weeks for up to 240 weeks

Primary: Change From Baseline in Hepatic Venous Pressure Gradient (HVPG)

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End point title

Change From Baseline in Hepatic Venous Pressure Gradient (HVPG)

End point description

Participants in the Full Analysis Set with available data were analyzed. Only 85 participants from SIM 700 mg arm and 84 participants from the placebo arm with available data were analyzed at baseline.

End point type

Primary

End point timeframe

Baseline to Week 96

End point values	SIM 200 mg	SIM 700 mg	Placebo
Number of subjects analysed	87	85	84
Units: mmHg
arithmetic mean (standard deviation)
SIM 200 mg N= 63, SIM 700 mg N= 66, Placebo N=68	-0.1 ± 3.76	0.0 ± 4.23	-0.1 ± 4.01

HVPG- Comparison of Groups

Statistical analysis description

A mixed-effect model for repeated measures (MMRM) with an unstructured variance-covariance matrix for each participant was used to calculate a point estimate and a 95% confidence interval (CI) for the treatment difference between each treatment arm and placebo in least squares mean (LSMean) change from baseline in HVPG at Week 96. With MMRM setting, all participants with available data from 3 treatment groups with change in HVPG at Week 96 contributed to the overall model.

Comparison groups

SIM 200 mg v Placebo

Number of subjects included in analysis

171

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in LSMeans [SIM - Placebo]

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-1.2

upper limit

1.5

HVPG- Comparison of Groups

Statistical analysis description

A mixed-effect model for repeated measures (MMRM) with an unstructured variance-covariance matrix for each participant was used to calculate a point estimate and a 95% confidence interval (CI) for the treatment difference between each treatment arm and placebo in least squares mean (LSMean) change from baseline in HVPG at Week 96. With MMRM setting, all participants with available data from 3 treatment groups with change in HVPG at Week 96 contributed to the overall model.

Comparison groups

SIM 700 mg v Placebo

Number of subjects included in analysis

169

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in LSMeans [SIM - Placebo]

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-1.2

upper limit

1.4

Primary: Event-Free Survival (EFS)

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End point title

Event-Free Survival (EFS)

End point description

Event free survival (EFS) was the primary clinical efficacy endpoint and was assessed by time to first liver-related event or death, whichever occurs first. Liver-related events included any of the following: - Liver transplantation - Qualification for liver transplantation -- Model for End-Stage Liver Disease (MELD) ≥ 15 - Events indicative of hepatic decompensation -- Esophageal variceal bleeding -- Ascites -- Hepatic Encephalopathy -- ≥ 2 point increase in Child Pugh-Turcotte (CPT) score -- Newly diagnosed varices in a subject without prior varices The median clinical EFS was not estimable in any treatment group. So, the percent of participants were presented, where only the event(s) with the earliest onset date were included for each participant. Full Analysis Set.

End point type

Primary

End point timeframe

Baseline up to the last dose date (maximum: up to 240 weeks in randomized phase)

End point values	SIM 200 mg	SIM 700 mg	Placebo
Number of subjects analysed	87	86	85
Units: percentage of participants
number (not applicable)	18.4	26.7	15.3

Event-Free Survival- Comparison of Groups

Statistical analysis description

Differences in EFS between a given SIM group and placebo were assessed using the log-rank test stratified by HVPG category (< 10 mmHg vs ≥ 10 mmHg) and presence or absence of diabetes at baseline.

Comparison groups

SIM 200 mg v Placebo

Number of subjects included in analysis

172

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.41

Method

Stratified log-rank test

Parameter type

Not Applicable

Point estimate

9999

Confidence interval

level

95%

sides

2-sided

lower limit

999

upper limit

99999

Event-Free Survival- Comparison of Groups

Statistical analysis description

Differences in EFS between a given SIM group and placebo were assessed using the log-rank test stratified by HVPG category (< 10 mmHg vs ≥ 10 mmHg) and presence or absence of diabetes at baseline.

Comparison groups

SIM 700 mg v Placebo

Number of subjects included in analysis

171

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.065

Method

Stratified log-rank test

Parameter type

Not Applicable

Point estimate

9999

Confidence interval

level

95%

sides

2-sided

lower limit

999

upper limit

99999

Adverse events

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Timeframe for reporting adverse events

Baseline up to the last dose date plus 30 days (average exposure: SIM 200 mg= 109.3 weeks, SIM 700 mg= 115.9 weeks, Placebo= 120.2 weeks, Open-label SIM 700 mg= 46.2 weeks)

Adverse event reporting additional description

Safety Analysis Set: all enrolled participants who were randomized and received at least one dose of study drug and Open-Label Safety Analysis Set :all participants who rolled over into the open-label phase and received at least 1 dose of open-label study drug.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

19.1

Reporting group title

SIM 200 mg

Reporting group description

Simtuzumab (SIM) 200 mg every 2 week for up to 240 weeks

Reporting group title

SIM 700 mg

Reporting group description

Simtuzumab (SIM) 700 mg every 2 weeks for up to 240 weeks

Reporting group title

Placebo

Reporting group description

Placebo to match Simtuzumab (SIM) every 2 weeks for up to 240 weeks

Reporting group title

Open-Label 700 mg

Reporting group description

All participants who completed the randomized phase through the Week 240 visit, or were ongoing at the time the study stopped who had progressed cirrhosis of the liver, were offered the opportunity to receive open-label SIM for up to 240 additional weeks. Additionally, participants who developed confirmed progression to cirrhosis prior to completing the randomized phase were eligible to roll over into the open-label phase. All participants received fixed-dose open-label Simtuzumab (SIM) 700 mg intravenous infusions every 2 weeks for up to 240 weeks.

Serious adverse events	SIM 200 mg	SIM 700 mg	Placebo	Open-Label 700 mg
Total subjects affected by serious adverse events
subjects affected / exposed	37 / 87 (42.53%)	36 / 86 (41.86%)	25 / 85 (29.41%)	17 / 40 (42.50%)
number of deaths (all causes)	0	1	1	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatocellular carcinoma
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	1 / 85 (1.18%)	2 / 40 (5.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Breast cancer recurrent
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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 cancer
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Hepatic neoplasm
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Hodgkin's disease
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Prostate cancer
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Thyroid cancer
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	1 / 85 (1.18%)	0 / 40 (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
Vascular disorders
Hypotension
subjects affected / exposed	0 / 87 (0.00%)	2 / 86 (2.33%)	0 / 85 (0.00%)	0 / 40 (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
Haematoma
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	0 / 85 (0.00%)	1 / 40 (2.50%)
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
Orthostatic hypotension
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
General disorders and administration site conditions
Chest pain
subjects affected / exposed	3 / 87 (3.45%)	2 / 86 (2.33%)	2 / 85 (2.35%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 3	1 / 3	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Asthenia
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	0 / 85 (0.00%)	1 / 40 (2.50%)
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
Fatigue
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Multiple organ dysfunction syndrome
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	1 / 85 (1.18%)	0 / 40 (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 / 1	0 / 0
Non-cardiac chest pain
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Oedema peripheral
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Peripheral swelling
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Pyrexia
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Systemic inflammatory response syndrome
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Respiratory, thoracic and mediastinal disorders
Pleural effusion
subjects affected / exposed	0 / 87 (0.00%)	3 / 86 (3.49%)	0 / 85 (0.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	1 / 85 (1.18%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atelectasis
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	1 / 85 (1.18%)	0 / 40 (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
Hepatic hydrothorax
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	1 / 85 (1.18%)	1 / 40 (2.50%)
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
Acute respiratory failure
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Asthma
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Cough
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Hydrothorax
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	1 / 85 (1.18%)	0 / 40 (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
Hypoxia
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Nasal septum deviation
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Portopulmonary hypertension
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	0 / 85 (0.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory depression
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Alcohol withdrawal syndrome
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	1 / 85 (1.18%)	0 / 40 (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
Anxiety
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	1 / 85 (1.18%)	0 / 40 (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
Bipolar disorder
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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 abuse
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	1 / 85 (1.18%)	0 / 40 (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
Major depression
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Mental status changes
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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 decompensation
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	0 / 85 (0.00%)	1 / 40 (2.50%)
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
Psychotic disorder
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Suicidal ideation
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Investigations
Blood osmolarity decreased
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	0 / 85 (0.00%)	1 / 40 (2.50%)
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
Electrocardiogram T wave peaked
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	0 / 85 (0.00%)	1 / 40 (2.50%)
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
Model for end stage liver disease score abnormal
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	0 / 85 (0.00%)	1 / 40 (2.50%)
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
Model for end stage liver disease score increased
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	0 / 85 (0.00%)	1 / 40 (2.50%)
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
Injury, poisoning and procedural complications
Post procedural haematoma
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	1 / 40 (2.50%)
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
Post procedural haemorrhage
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	1 / 85 (1.18%)	0 / 40 (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
Procedural pain
subjects affected / exposed	1 / 87 (1.15%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Subarachnoid haemorrhage
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	1 / 85 (1.18%)	0 / 40 (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
Clavicle fracture
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	1 / 85 (1.18%)	0 / 40 (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
Concussion
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Hand fracture
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	1 / 85 (1.18%)	0 / 40 (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
Infusion related reaction
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Laceration
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	1 / 85 (1.18%)	0 / 40 (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
Ligament sprain
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	1 / 85 (1.18%)	0 / 40 (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
Lumbar vertebral fracture
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Post procedural discomfort
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Procedural haemorrhage
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	0 / 85 (0.00%)	1 / 40 (2.50%)
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
Procedural hypotension
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Road traffic accident
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	1 / 85 (1.18%)	0 / 40 (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 disorders
Acute myocardial infarction
subjects affected / exposed	1 / 87 (1.15%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery stenosis
subjects affected / exposed	1 / 87 (1.15%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Atrioventricular block second degree
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Bradycardia
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	0 / 85 (0.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Nervous system disorders
Hepatic encephalopathy
subjects affected / exposed	3 / 87 (3.45%)	4 / 86 (4.65%)	2 / 85 (2.35%)	5 / 40 (12.50%)
occurrences causally related to treatment / all	0 / 3	0 / 4	0 / 4	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	2 / 85 (2.35%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Altered state of consciousness
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	1 / 85 (1.18%)	0 / 40 (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
Cerebrovascular accident
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	0 / 85 (0.00%)	1 / 40 (2.50%)
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
Cervical myelopathy
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Dizziness
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	1 / 85 (1.18%)	0 / 40 (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
Hypoaesthesia
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Migraine with aura
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Nerve compression
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	1 / 85 (1.18%)	0 / 40 (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
Somnolence
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Temporal lobe epilepsy
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	0 / 85 (0.00%)	1 / 40 (2.50%)
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
Bandaemia
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Gastrointestinal disorders
Ascites
subjects affected / exposed	2 / 87 (2.30%)	3 / 86 (3.49%)	1 / 85 (1.18%)	2 / 40 (5.00%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal varices haemorrhage
subjects affected / exposed	1 / 87 (1.15%)	2 / 86 (2.33%)	2 / 85 (2.35%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 1	0 / 5	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	1 / 87 (1.15%)	1 / 86 (1.16%)	1 / 85 (1.18%)	2 / 40 (5.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	1 / 87 (1.15%)	2 / 86 (2.33%)	1 / 85 (1.18%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0
Abdominal pain upper
subjects affected / exposed	1 / 87 (1.15%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Colitis
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	1 / 85 (1.18%)	0 / 40 (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
Haematemesis
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	1 / 40 (2.50%)
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
Nausea
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	1 / 85 (1.18%)	0 / 40 (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
Pancreatitis
subjects affected / exposed	2 / 87 (2.30%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Umbilical hernia
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal discomfort
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Abdominal distension
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Abdominal hernia
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Diverticulum
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Epiploic appendagitis
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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 haemorrhage
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Gastritis
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Haematochezia
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	0 / 85 (0.00%)	1 / 40 (2.50%)
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
Hernial eventration
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Ileus
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Impaired gastric emptying
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	1 / 85 (1.18%)	0 / 40 (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
Pancreatitis acute
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	1 / 85 (1.18%)	0 / 40 (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
Small intestinal obstruction
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Upper gastrointestinal haemorrhage
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Varices oesophageal
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Hepatobiliary disorders
Haemobilia
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	1 / 85 (1.18%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholangitis
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Cholelithiasis
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	1 / 85 (1.18%)	0 / 40 (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
Gallbladder polyp
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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	0 / 87 (0.00%)	0 / 86 (0.00%)	0 / 85 (0.00%)	1 / 40 (2.50%)
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
Ischaemic hepatitis
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	1 / 85 (1.18%)	0 / 40 (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 / 1	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	2 / 87 (2.30%)	1 / 86 (1.16%)	2 / 85 (2.35%)	3 / 40 (7.50%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dysuria
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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 failure
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Ureterolithiasis
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Endocrine disorders
Basedow's disease
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Hyperparathyroidism
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Musculoskeletal and connective tissue disorders
Neck pain
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	1 / 85 (1.18%)	1 / 40 (2.50%)
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
Back pain
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Cervical spinal stenosis
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Compartment syndrome
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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 pain
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Myositis
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Osteoarthritis
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	1 / 85 (1.18%)	0 / 40 (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
Osteoporotic fracture
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	0 / 85 (0.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Urinary tract infection
subjects affected / exposed	3 / 87 (3.45%)	1 / 86 (1.16%)	2 / 85 (2.35%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	2 / 87 (2.30%)	2 / 86 (2.33%)	1 / 85 (1.18%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 87 (0.00%)	3 / 86 (3.49%)	2 / 85 (2.35%)	0 / 40 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	2 / 87 (2.30%)	1 / 86 (1.16%)	0 / 85 (0.00%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	1 / 85 (1.18%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	1 / 85 (1.18%)	0 / 40 (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
Viral infection
subjects affected / exposed	1 / 87 (1.15%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Abscess limb
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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	0 / 87 (0.00%)	0 / 86 (0.00%)	1 / 85 (1.18%)	0 / 40 (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
Bacterial pyelonephritis
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Diverticulitis
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Escherichia bacteraemia
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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 sepsis
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Gastroenteritis
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	1 / 85 (1.18%)	0 / 40 (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
Gastroenteritis bacterial
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	0 / 85 (0.00%)	1 / 40 (2.50%)
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
Kidney infection
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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	0 / 87 (0.00%)	0 / 86 (0.00%)	1 / 85 (1.18%)	0 / 40 (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
Rocky mountain spotted fever
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Hyponatraemia
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	1 / 85 (1.18%)	2 / 40 (5.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	2 / 40 (5.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetes mellitus inadequate control
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	1 / 85 (1.18%)	0 / 40 (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
Hyperkalaemia
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	1 / 85 (1.18%)	1 / 40 (2.50%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	1 / 85 (1.18%)	0 / 40 (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
Diabetic metabolic decompensation
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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
Hyperglycaemia
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	0 / 85 (0.00%)	0 / 40 (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
Lactic acidosis
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	0 / 85 (0.00%)	0 / 40 (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

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

Non-serious adverse events	SIM 200 mg	SIM 700 mg	Placebo	Open-Label 700 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	85 / 87 (97.70%)	81 / 86 (94.19%)	83 / 85 (97.65%)	32 / 40 (80.00%)
Vascular disorders
Hypertension
subjects affected / exposed	6 / 87 (6.90%)	3 / 86 (3.49%)	2 / 85 (2.35%)	0 / 40 (0.00%)
occurrences all number	6	3	2	0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	34 / 87 (39.08%)	32 / 86 (37.21%)	28 / 85 (32.94%)	6 / 40 (15.00%)
occurrences all number	42	35	32	7
Oedema peripheral
subjects affected / exposed	13 / 87 (14.94%)	14 / 86 (16.28%)	16 / 85 (18.82%)	6 / 40 (15.00%)
occurrences all number	13	15	19	6
Pyrexia
subjects affected / exposed	10 / 87 (11.49%)	9 / 86 (10.47%)	6 / 85 (7.06%)	3 / 40 (7.50%)
occurrences all number	13	13	6	4
Chest pain
subjects affected / exposed	8 / 87 (9.20%)	10 / 86 (11.63%)	6 / 85 (7.06%)	1 / 40 (2.50%)
occurrences all number	9	10	9	1
Peripheral swelling
subjects affected / exposed	8 / 87 (9.20%)	7 / 86 (8.14%)	6 / 85 (7.06%)	2 / 40 (5.00%)
occurrences all number	8	8	8	2
Pain
subjects affected / exposed	7 / 87 (8.05%)	6 / 86 (6.98%)	3 / 85 (3.53%)	1 / 40 (2.50%)
occurrences all number	8	6	3	1
Asthenia
subjects affected / exposed	3 / 87 (3.45%)	5 / 86 (5.81%)	5 / 85 (5.88%)	3 / 40 (7.50%)
occurrences all number	4	6	6	3
Chills
subjects affected / exposed	3 / 87 (3.45%)	5 / 86 (5.81%)	4 / 85 (4.71%)	1 / 40 (2.50%)
occurrences all number	3	6	4	1
Infusion site pain
subjects affected / exposed	7 / 87 (8.05%)	0 / 86 (0.00%)	6 / 85 (7.06%)	0 / 40 (0.00%)
occurrences all number	7	0	8	0
Reproductive system and breast disorders
Gynaecomastia
subjects affected / exposed	2 / 87 (2.30%)	0 / 86 (0.00%)	1 / 85 (1.18%)	3 / 40 (7.50%)
occurrences all number	2	0	1	3
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	16 / 87 (18.39%)	12 / 86 (13.95%)	13 / 85 (15.29%)	2 / 40 (5.00%)
occurrences all number	21	20	14	2
Oropharyngeal pain
subjects affected / exposed	11 / 87 (12.64%)	8 / 86 (9.30%)	9 / 85 (10.59%)	0 / 40 (0.00%)
occurrences all number	12	8	10	0
Epistaxis
subjects affected / exposed	9 / 87 (10.34%)	9 / 86 (10.47%)	6 / 85 (7.06%)	1 / 40 (2.50%)
occurrences all number	11	10	9	1
Dyspnoea
subjects affected / exposed	9 / 87 (10.34%)	6 / 86 (6.98%)	4 / 85 (4.71%)	1 / 40 (2.50%)
occurrences all number	12	6	4	1
Nasal congestion
subjects affected / exposed	3 / 87 (3.45%)	7 / 86 (8.14%)	7 / 85 (8.24%)	0 / 40 (0.00%)
occurrences all number	3	8	12	0
Pleural effusion
subjects affected / exposed	0 / 87 (0.00%)	1 / 86 (1.16%)	1 / 85 (1.18%)	2 / 40 (5.00%)
occurrences all number	0	1	1	2
Psychiatric disorders
Insomnia
subjects affected / exposed	7 / 87 (8.05%)	5 / 86 (5.81%)	9 / 85 (10.59%)	2 / 40 (5.00%)
occurrences all number	8	6	9	2
Depression
subjects affected / exposed	4 / 87 (4.60%)	7 / 86 (8.14%)	2 / 85 (2.35%)	2 / 40 (5.00%)
occurrences all number	4	7	2	2
Anxiety
subjects affected / exposed	7 / 87 (8.05%)	3 / 86 (3.49%)	3 / 85 (3.53%)	1 / 40 (2.50%)
occurrences all number	8	3	3	1
Investigations
Blood glucose increased
subjects affected / exposed	2 / 87 (2.30%)	1 / 86 (1.16%)	5 / 85 (5.88%)	2 / 40 (5.00%)
occurrences all number	2	1	5	2
Weight increased
subjects affected / exposed	4 / 87 (4.60%)	1 / 86 (1.16%)	5 / 85 (5.88%)	0 / 40 (0.00%)
occurrences all number	4	1	5	0
Blood creatinine increased
subjects affected / exposed	1 / 87 (1.15%)	1 / 86 (1.16%)	5 / 85 (5.88%)	0 / 40 (0.00%)
occurrences all number	1	1	5	0
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	10 / 87 (11.49%)	6 / 86 (6.98%)	16 / 85 (18.82%)	5 / 40 (12.50%)
occurrences all number	13	6	20	5
Fall
subjects affected / exposed	7 / 87 (8.05%)	5 / 86 (5.81%)	13 / 85 (15.29%)	4 / 40 (10.00%)
occurrences all number	19	7	18	4
Infusion related reaction
subjects affected / exposed	10 / 87 (11.49%)	7 / 86 (8.14%)	11 / 85 (12.94%)	0 / 40 (0.00%)
occurrences all number	17	9	15	0
Procedural pain
subjects affected / exposed	8 / 87 (9.20%)	7 / 86 (8.14%)	7 / 85 (8.24%)	1 / 40 (2.50%)
occurrences all number	8	8	7	1
Ligament sprain
subjects affected / exposed	5 / 87 (5.75%)	4 / 86 (4.65%)	2 / 85 (2.35%)	0 / 40 (0.00%)
occurrences all number	5	4	3	0
Muscle strain
subjects affected / exposed	5 / 87 (5.75%)	1 / 86 (1.16%)	4 / 85 (4.71%)	0 / 40 (0.00%)
occurrences all number	5	1	6	0
Skin abrasion
subjects affected / exposed	4 / 87 (4.60%)	1 / 86 (1.16%)	2 / 85 (2.35%)	2 / 40 (5.00%)
occurrences all number	5	1	2	3
Road traffic accident
subjects affected / exposed	2 / 87 (2.30%)	1 / 86 (1.16%)	0 / 85 (0.00%)	2 / 40 (5.00%)
occurrences all number	2	1	0	2
Cardiac disorders
Palpitations
subjects affected / exposed	6 / 87 (6.90%)	1 / 86 (1.16%)	3 / 85 (3.53%)	0 / 40 (0.00%)
occurrences all number	6	1	3	0
Nervous system disorders
Headache
subjects affected / exposed	26 / 87 (29.89%)	28 / 86 (32.56%)	17 / 85 (20.00%)	5 / 40 (12.50%)
occurrences all number	41	40	27	6
Dizziness
subjects affected / exposed	14 / 87 (16.09%)	8 / 86 (9.30%)	9 / 85 (10.59%)	2 / 40 (5.00%)
occurrences all number	22	13	12	2
Hepatic encephalopathy
subjects affected / exposed	7 / 87 (8.05%)	6 / 86 (6.98%)	6 / 85 (7.06%)	4 / 40 (10.00%)
occurrences all number	7	8	6	4
Tremor
subjects affected / exposed	4 / 87 (4.60%)	4 / 86 (4.65%)	5 / 85 (5.88%)	0 / 40 (0.00%)
occurrences all number	4	4	5	0
Syncope
subjects affected / exposed	4 / 87 (4.60%)	1 / 86 (1.16%)	2 / 85 (2.35%)	2 / 40 (5.00%)
occurrences all number	4	1	3	2
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	10 / 87 (11.49%)	7 / 86 (8.14%)	6 / 85 (7.06%)	3 / 40 (7.50%)
occurrences all number	11	10	6	3
Splenomegaly
subjects affected / exposed	3 / 87 (3.45%)	4 / 86 (4.65%)	6 / 85 (7.06%)	0 / 40 (0.00%)
occurrences all number	3	4	6	0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	4 / 87 (4.60%)	6 / 86 (6.98%)	5 / 85 (5.88%)	0 / 40 (0.00%)
occurrences all number	4	6	10	0
Gastrointestinal disorders
Nausea
subjects affected / exposed	29 / 87 (33.33%)	28 / 86 (32.56%)	28 / 85 (32.94%)	9 / 40 (22.50%)
occurrences all number	51	49	56	12
Diarrhoea
subjects affected / exposed	24 / 87 (27.59%)	23 / 86 (26.74%)	33 / 85 (38.82%)	7 / 40 (17.50%)
occurrences all number	35	30	42	7
Abdominal pain
subjects affected / exposed	19 / 87 (21.84%)	23 / 86 (26.74%)	14 / 85 (16.47%)	5 / 40 (12.50%)
occurrences all number	21	25	15	5
Vomiting
subjects affected / exposed	13 / 87 (14.94%)	15 / 86 (17.44%)	19 / 85 (22.35%)	6 / 40 (15.00%)
occurrences all number	24	18	26	6
Abdominal pain upper
subjects affected / exposed	15 / 87 (17.24%)	19 / 86 (22.09%)	13 / 85 (15.29%)	5 / 40 (12.50%)
occurrences all number	17	23	18	6
Constipation
subjects affected / exposed	9 / 87 (10.34%)	15 / 86 (17.44%)	10 / 85 (11.76%)	2 / 40 (5.00%)
occurrences all number	12	20	10	2
Abdominal distension
subjects affected / exposed	9 / 87 (10.34%)	10 / 86 (11.63%)	9 / 85 (10.59%)	4 / 40 (10.00%)
occurrences all number	10	11	10	4
Ascites
subjects affected / exposed	7 / 87 (8.05%)	8 / 86 (9.30%)	9 / 85 (10.59%)	7 / 40 (17.50%)
occurrences all number	11	12	10	15
Varices oesophageal
subjects affected / exposed	5 / 87 (5.75%)	10 / 86 (11.63%)	8 / 85 (9.41%)	0 / 40 (0.00%)
occurrences all number	5	15	8	0
Gastrooesophageal reflux disease
subjects affected / exposed	5 / 87 (5.75%)	4 / 86 (4.65%)	3 / 85 (3.53%)	1 / 40 (2.50%)
occurrences all number	6	4	4	1
Abdominal pain lower
subjects affected / exposed	5 / 87 (5.75%)	3 / 86 (3.49%)	4 / 85 (4.71%)	0 / 40 (0.00%)
occurrences all number	7	3	5	0
Haemorrhoids
subjects affected / exposed	3 / 87 (3.45%)	2 / 86 (2.33%)	5 / 85 (5.88%)	1 / 40 (2.50%)
occurrences all number	3	2	5	1
Portal hypertensive gastropathy
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	8 / 85 (9.41%)	1 / 40 (2.50%)
occurrences all number	1	0	8	1
Umbilical hernia
subjects affected / exposed	1 / 87 (1.15%)	1 / 86 (1.16%)	0 / 85 (0.00%)	2 / 40 (5.00%)
occurrences all number	1	1	0	2
Hepatobiliary disorders
Hepatomegaly
subjects affected / exposed	3 / 87 (3.45%)	2 / 86 (2.33%)	7 / 85 (8.24%)	0 / 40 (0.00%)
occurrences all number	3	2	7	0
Cholelithiasis
subjects affected / exposed	1 / 87 (1.15%)	2 / 86 (2.33%)	7 / 85 (8.24%)	0 / 40 (0.00%)
occurrences all number	1	2	7	0
Jaundice
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	0 / 85 (0.00%)	2 / 40 (5.00%)
occurrences all number	0	0	0	2
Skin and subcutaneous tissue disorders
Rash
subjects affected / exposed	8 / 87 (9.20%)	11 / 86 (12.79%)	15 / 85 (17.65%)	0 / 40 (0.00%)
occurrences all number	10	11	19	0
Pruritus
subjects affected / exposed	9 / 87 (10.34%)	11 / 86 (12.79%)	6 / 85 (7.06%)	3 / 40 (7.50%)
occurrences all number	11	14	7	4
Dry skin
subjects affected / exposed	6 / 87 (6.90%)	3 / 86 (3.49%)	3 / 85 (3.53%)	1 / 40 (2.50%)
occurrences all number	6	3	3	1
Alopecia
subjects affected / exposed	3 / 87 (3.45%)	7 / 86 (8.14%)	2 / 85 (2.35%)	0 / 40 (0.00%)
occurrences all number	3	7	2	0
Renal and urinary disorders
Dysuria
subjects affected / exposed	1 / 87 (1.15%)	1 / 86 (1.16%)	3 / 85 (3.53%)	3 / 40 (7.50%)
occurrences all number	1	1	3	3
Pollakiuria
subjects affected / exposed	1 / 87 (1.15%)	0 / 86 (0.00%)	2 / 85 (2.35%)	2 / 40 (5.00%)
occurrences all number	1	0	2	2
Chronic kidney disease
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	1 / 85 (1.18%)	2 / 40 (5.00%)
occurrences all number	0	0	1	2
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	27 / 87 (31.03%)	18 / 86 (20.93%)	12 / 85 (14.12%)	2 / 40 (5.00%)
occurrences all number	36	26	21	2
Arthralgia
subjects affected / exposed	17 / 87 (19.54%)	19 / 86 (22.09%)	13 / 85 (15.29%)	0 / 40 (0.00%)
occurrences all number	18	23	19	0
Muscle spasms
subjects affected / exposed	16 / 87 (18.39%)	13 / 86 (15.12%)	10 / 85 (11.76%)	5 / 40 (12.50%)
occurrences all number	23	15	11	5
Pain in extremity
subjects affected / exposed	11 / 87 (12.64%)	9 / 86 (10.47%)	9 / 85 (10.59%)	1 / 40 (2.50%)
occurrences all number	12	9	11	1
Musculoskeletal pain
subjects affected / exposed	10 / 87 (11.49%)	6 / 86 (6.98%)	7 / 85 (8.24%)	0 / 40 (0.00%)
occurrences all number	11	7	7	0
Neck pain
subjects affected / exposed	8 / 87 (9.20%)	3 / 86 (3.49%)	5 / 85 (5.88%)	2 / 40 (5.00%)
occurrences all number	9	3	6	2
Joint swelling
subjects affected / exposed	7 / 87 (8.05%)	4 / 86 (4.65%)	2 / 85 (2.35%)	1 / 40 (2.50%)
occurrences all number	7	4	2	1
Myalgia
subjects affected / exposed	3 / 87 (3.45%)	2 / 86 (2.33%)	8 / 85 (9.41%)	0 / 40 (0.00%)
occurrences all number	3	2	9	0
Flank pain
subjects affected / exposed	3 / 87 (3.45%)	5 / 86 (5.81%)	1 / 85 (1.18%)	0 / 40 (0.00%)
occurrences all number	3	6	1	0
Infections and infestations
Nasopharyngitis
subjects affected / exposed	15 / 87 (17.24%)	16 / 86 (18.60%)	19 / 85 (22.35%)	2 / 40 (5.00%)
occurrences all number	22	18	26	2
Sinusitis
subjects affected / exposed	14 / 87 (16.09%)	16 / 86 (18.60%)	17 / 85 (20.00%)	3 / 40 (7.50%)
occurrences all number	24	19	27	4
Upper respiratory tract infection
subjects affected / exposed	15 / 87 (17.24%)	19 / 86 (22.09%)	11 / 85 (12.94%)	3 / 40 (7.50%)
occurrences all number	28	21	16	3
Bronchitis
subjects affected / exposed	14 / 87 (16.09%)	14 / 86 (16.28%)	15 / 85 (17.65%)	2 / 40 (5.00%)
occurrences all number	16	17	18	2
Urinary tract infection
subjects affected / exposed	9 / 87 (10.34%)	14 / 86 (16.28%)	18 / 85 (21.18%)	3 / 40 (7.50%)
occurrences all number	25	18	25	5
Influenza
subjects affected / exposed	4 / 87 (4.60%)	6 / 86 (6.98%)	8 / 85 (9.41%)	2 / 40 (5.00%)
occurrences all number	4	8	8	2
Gastroenteritis
subjects affected / exposed	6 / 87 (6.90%)	4 / 86 (4.65%)	2 / 85 (2.35%)	1 / 40 (2.50%)
occurrences all number	8	4	2	1
Pneumonia
subjects affected / exposed	2 / 87 (2.30%)	5 / 86 (5.81%)	2 / 85 (2.35%)	2 / 40 (5.00%)
occurrences all number	2	8	2	3
Gastroenteritis viral
subjects affected / exposed	5 / 87 (5.75%)	1 / 86 (1.16%)	2 / 85 (2.35%)	1 / 40 (2.50%)
occurrences all number	7	1	2	1
Herpes zoster
subjects affected / exposed	5 / 87 (5.75%)	2 / 86 (2.33%)	1 / 85 (1.18%)	1 / 40 (2.50%)
occurrences all number	6	3	1	1
Localised infection
subjects affected / exposed	1 / 87 (1.15%)	1 / 86 (1.16%)	2 / 85 (2.35%)	2 / 40 (5.00%)
occurrences all number	1	2	2	2
Peritonitis bacterial
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	0 / 85 (0.00%)	2 / 40 (5.00%)
occurrences all number	0	0	0	2
Metabolism and nutrition disorders
Decreased appetite
subjects affected / exposed	7 / 87 (8.05%)	2 / 86 (2.33%)	11 / 85 (12.94%)	2 / 40 (5.00%)
occurrences all number	9	4	13	2
Hyperglycaemia
subjects affected / exposed	4 / 87 (4.60%)	10 / 86 (11.63%)	6 / 85 (7.06%)	0 / 40 (0.00%)
occurrences all number	5	10	6	0
Hypokalaemia
subjects affected / exposed	3 / 87 (3.45%)	3 / 86 (3.49%)	2 / 85 (2.35%)	4 / 40 (10.00%)
occurrences all number	5	3	2	4
Hyponatraemia
subjects affected / exposed	1 / 87 (1.15%)	1 / 86 (1.16%)	2 / 85 (2.35%)	4 / 40 (10.00%)
occurrences all number	1	1	2	6
Hyperkalaemia
subjects affected / exposed	1 / 87 (1.15%)	2 / 86 (2.33%)	2 / 85 (2.35%)	2 / 40 (5.00%)
occurrences all number	1	2	2	2
Hypomagnesaemia
subjects affected / exposed	0 / 87 (0.00%)	0 / 86 (0.00%)	1 / 85 (1.18%)	2 / 40 (5.00%)
occurrences all number	0	0	1	2

More information

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Were there any global substantial amendments to the protocol? Yes

10 Jan 2013

1. Female contraception requirement following last does of study drug increased from 30 days to 90 days. 2. Exclusion Criterion regarding previous history of decompensated liver disease clarified. 3. Language modified to make Study Treatment Discontinuation absolute. 4. Withdrawal criterion added for participants who develop hypersensitivity reaction to study drug infusion. 5. Language added regarding follow-up of Serious Adverse Events.

05 Mar 2013

1. Increased number of times anti-GS-6624 antibodies are assessed. 2. Addition of Pharmacokinetics (PK) testing. 3. Language added regarding Brunt/Kleiner classification and the NAFLD Activity Score (NAS). 4. Language added regarding the Cochran-Mantel-Haenszel test. 5. New anti-GS-6624 antibodies and PK testing description section added to the Research-related Procedures section.

05 Mar 2014

1. The Randomized Treatment Phase has been extended from 96 weeks to 240 weeks. 2. An optional Open Label Phase has been added. It will include 240 additional weeks of IV treatment every 2 weeks with a fixed dose of simtuzumab 700 mg 3. A Clinical Events Adjudication Committee has been added. 4. A composite clinical event endpoint has been defined. The clinical events included which will be adjudicated by the Clinical Events Adjudication Committee were included.

31 Jul 2015

1) Updating Study Director 2) Revised liver biopsy central reading process 3) Removal of the HVPG Cap

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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