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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 Advanced Liver Fibrosis but not Cirrhosis Secondary to Non-Alcoholic Steatohepatitis (NASH)

    Summary
    EudraCT number
    2012-002488-88
    Trial protocol
    IT   DE   GB   ES   BE  
    Global end of trial date
    29 Dec 2016

    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

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    Trial identification
    Sponsor protocol code
    GS-US-321-0105
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01672866
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Clinical Trial Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.com
    Scientific contact
    Clinical Trial Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.com
    Paediatric regulatory details
    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
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Aug 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Dec 2016
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the efficacy of simtuzumab (formerly GS-6624) at preventing the histologic progression of liver fibrosis and the clinical progression to cirrhosis in adultts with 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
    05 Dec 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 165
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Italy: 6
    Worldwide total number of subjects
    222
    EEA total number of subjects
    45
    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)
    216
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants were enrolled at study sites in Europe and North America. The first participant was screened on 05 December 2012. The last study visit occurred on 29 December 2016.

    Pre-assignment
    Screening details
    631 participants were screened.

    Period 1
    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, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    SIM 75 mg
    Arm description
    Simtuzumab (SIM) 75 mg weekly for up to 240 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    Simtuzumab 75 mg
    Investigational medicinal product code
    Other name
    GS-6624
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    75 mg subcutaneous injection

    Arm title
    SIM 125 mg
    Arm description
    Simtuzumab (SIM) 125 mg weekly for up to 240 weeks
    Arm type
    Experimental

    Investigational medicinal product name
    Simtuzumab 125 mg
    Investigational medicinal product code
    Other name
    GS-6624
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    125 mg subcutaneous injection

    Arm title
    Placebo
    Arm description
    Placebo to match Simtuzumab (SIM) weekly for up to 240 weeks
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Simtuzumab (SIM) placebo subcutaneous injection

    Number of subjects in period 1 [1]
    SIM 75 mg SIM 125 mg Placebo
    Started
    71
    74
    74
    Completed
    0
    0
    0
    Not completed
    71
    74
    74
         Study Terminated by Sponsor
    48
    57
    50
         Death
    1
    -
    1
         Investigator's Discretion
    3
    3
    2
         Withdrew Consent
    10
    8
    13
         Protocol Violation
    2
    -
    -
         Adverse Event
    3
    3
    3
         Lost to follow-up
    4
    3
    5
    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: Three participants who were enrolled but never treated were not included in the subject disposition table.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SIM 75 mg
    Reporting group description
    Simtuzumab (SIM) 75 mg weekly for up to 240 weeks

    Reporting group title
    SIM 125 mg
    Reporting group description
    Simtuzumab (SIM) 125 mg weekly for up to 240 weeks

    Reporting group title
    Placebo
    Reporting group description
    Placebo to match Simtuzumab (SIM) weekly for up to 240 weeks

    Reporting group values
    SIM 75 mg SIM 125 mg Placebo Total
    Number of subjects
    71 74 74 219
    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)
    54 ± 8.8 53 ± 9.4 53 ± 8.4 -
    Gender categorical
    Units: Subjects
        Female
    43 47 48 138
        Male
    28 27 26 81
    Race
    Units: Subjects
        American Indian or Alaska Native
    0 0 1 1
        Asian
    1 3 1 5
        Black or African American
    2 0 1 3
        Native Hawaiian or Other Pacific Islander
    0 0 1 1
        White
    66 71 69 206
        Other
    2 0 1 3
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    9 14 11 34
        Not Hispanic or Latino
    62 60 63 185
    Morphometric Quantitative Collagen (MQC)
    Full Analysis Set: enrolled participants who were randomized and received at least 1 dose of study drug.
    Units: Percentage
        arithmetic mean (standard deviation)
    7.0 ± 4.18 7.2 ± 4.62 6.7 ± 3.78 -

    End points

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    End points reporting groups
    Reporting group title
    SIM 75 mg
    Reporting group description
    Simtuzumab (SIM) 75 mg weekly for up to 240 weeks

    Reporting group title
    SIM 125 mg
    Reporting group description
    Simtuzumab (SIM) 125 mg weekly for up to 240 weeks

    Reporting group title
    Placebo
    Reporting group description
    Placebo to match Simtuzumab (SIM) weekly for up to 240 weeks

    Primary: Change From Baseline in Morphometric Quantitative Collagen (MQC) on Liver Biopsy

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    End point title
    Change From Baseline in Morphometric Quantitative Collagen (MQC) on Liver Biopsy
    End point description
    Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Primary
    End point timeframe
    Baseline to Week 96
    End point values
    SIM 75 mg SIM 125 mg Placebo
    Number of subjects analysed
    71
    74
    74
    Units: Percentage
    arithmetic mean (standard deviation)
        SIM 75mg N=46,SIM 125 mg N=49,Placebo N=55
    -3.1 ± 4.83
    -2.5 ± 5.11
    -1.9 ± 4.28
    Statistical analysis title
    MQC- 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 MQC at Week 96. With MMRM setting, all participants with available data from 3 treatment groups with change in MQC at Week 48 and/or Week 96 contributed to the overall model.
    Comparison groups
    SIM 75 mg v Placebo
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Difference in LSMeans [SIM - Placebo]
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.3
         upper limit
    1
    Statistical analysis title
    MQC- 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 MQC at Week 96. With MMRM setting, all participants with available data from 3 treatment groups with change in MQC at Week 48 and/or Week 96 contributed to the overall model.
    Comparison groups
    SIM 125 mg v Placebo
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Difference in LSMeans [SIM - Placebo]
    Point estimate
    -0.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.5
         upper limit
    0.8

    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 the time to progression to cirrhosis. Participants were considered to have become cirrhotic if they had a post-baseline biopsy consistent with cirrhosis or developed overt signs and symptoms of cirrhosis. All overt signs and symptoms went through an adjudication process and were confirmed before they were considered for the EFS analysis. Participants in the Full Analysis Set with available data were analyzed.
    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 75 mg SIM 125 mg Placebo
    Number of subjects analysed
    70
    74
    74
    Units: Percentage of participants
    number (not applicable)
        Total Participants with Events (%)
    20.0
    23.0
    23.0
    Statistical analysis title
    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 the presence or absence of diabetes at baseline.
    Comparison groups
    SIM 75 mg v Placebo
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.73
    Method
    Stratified log-rank test
    Parameter type
    Not Aapplicable
    Point estimate
    9999
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    999
         upper limit
    99999
    Statistical analysis title
    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 the presence or absence of diabetes at baseline.
    Comparison groups
    SIM 125 mg v Placebo
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.85
    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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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to the last dose date plus 30 days (average exposure: SIM 75 mg= 112.3 weeks, SIM 125 mg= 111.0 weeks, Placebo= 111.3 weeks, Open-label SIM= 51.0 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 used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    SIM 75 mg
    Reporting group description
    Simtuzimab (SIM) 75 mg weekly for up to 240 weeks

    Reporting group title
    SIM 125 mg
    Reporting group description
    Simtuzimab (SIM) 125 mg weekly for up to 240 weeks

    Reporting group title
    Placebo
    Reporting group description
    Placebo to match Simtuzimab (SIM) weekly for up to 240 weeks

    Reporting group title
    Open-label SIM 125 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) 125 mg subcutaneous injection every week for up to 240 weeks.

    Serious adverse events
    SIM 75 mg SIM 125 mg Placebo Open-label SIM 125 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 71 (23.94%)
    17 / 74 (22.97%)
    14 / 74 (18.92%)
    11 / 42 (26.19%)
         number of deaths (all causes)
    0
    0
    0
    1
         number of deaths resulting from adverse events
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 42 (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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 42 (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
    Basal cell carcinoma
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 42 (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 adenoma
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 42 (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
    Rectal adenocarcinoma
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 42 (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
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 71 (1.41%)
    3 / 74 (4.05%)
    2 / 74 (2.70%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 42 (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
    0 / 71 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 42 (2.38%)
         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
    Depression
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 42 (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
    Major depression
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 42 (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
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 42 (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
    Seroma
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 42 (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
    Upper limb fracture
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 42 (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
    Investigations
    Blood glucose increased
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 42 (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
    Weight increased
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 42 (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
    0 / 71 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 42 (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
    Coronary artery occlusion
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 42 (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
    Myocardial infarction
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 42 (2.38%)
         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
    Ventricular tachycardia
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 42 (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
    Dyspnoea exertional
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 42 (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
    Pancytopenia
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 42 (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 disorders
    Syncope
         subjects affected / exposed
    1 / 71 (1.41%)
    1 / 74 (1.35%)
    1 / 74 (1.35%)
    0 / 42 (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
    Transient ischaemic attack
         subjects affected / exposed
    1 / 71 (1.41%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 42 (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
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 42 (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
    Depressed level of consciousness
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 42 (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
    Epilepsy
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 42 (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 encephalopathy
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 42 (2.38%)
         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
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 42 (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
    Abdominal pain
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    2 / 42 (4.76%)
         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
    Abdominal pain lower
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 42 (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
    Colitis
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 42 (2.38%)
         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
    Diverticular perforation
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 42 (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
    Duodenitis
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 42 (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
    1 / 71 (1.41%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 42 (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
    Haemorrhoids
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 42 (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
    Impaired gastric emptying
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 42 (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
    Intestinal obstruction
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 42 (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
    Melaena
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 42 (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
    Nausea
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 42 (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
    Rectal haemorrhage
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 42 (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
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 42 (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
    Bladder prolapse
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 42 (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
    Proteinuria
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 42 (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
    Urinary retention
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 42 (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
    Biliary dilatation
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 42 (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 / 71 (1.41%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 42 (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
    Perforation bile duct
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 42 (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
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 42 (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
    Intervertebral disc protrusion
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 42 (2.38%)
         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
    Joint instability
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 42 (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
    Osteonecrosis
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 42 (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
    Hyperadrenocorticism
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 42 (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
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 42 (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
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 42 (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
    Hyperglycaemia
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 42 (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
    Metabolic acidosis
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic disorder
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 42 (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 / 71 (4.23%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 71 (0.00%)
    2 / 74 (2.70%)
    0 / 74 (0.00%)
    1 / 42 (2.38%)
         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 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 74 (0.00%)
    2 / 74 (2.70%)
    0 / 42 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess soft tissue
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 42 (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
    Appendicitis
         subjects affected / exposed
    0 / 71 (0.00%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    1 / 42 (2.38%)
         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
    Device related infection
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 42 (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
    1 / 71 (1.41%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 42 (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
    Gastroenteritis viral
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 42 (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
    Groin abscess
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 42 (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
    Infective exacerbation of chronic obstructive airways disease
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 74 (0.00%)
    0 / 74 (0.00%)
    0 / 42 (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
    Mastoiditis
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 74 (1.35%)
    0 / 74 (0.00%)
    0 / 42 (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 75 mg SIM 125 mg Placebo Open-label SIM 125 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    65 / 71 (91.55%)
    69 / 74 (93.24%)
    72 / 74 (97.30%)
    29 / 42 (69.05%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 71 (4.23%)
    5 / 74 (6.76%)
    7 / 74 (9.46%)
    2 / 42 (4.76%)
         occurrences all number
    3
    5
    7
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    19 / 71 (26.76%)
    19 / 74 (25.68%)
    24 / 74 (32.43%)
    4 / 42 (9.52%)
         occurrences all number
    22
    20
    27
    4
    Oedema peripheral
         subjects affected / exposed
    7 / 71 (9.86%)
    3 / 74 (4.05%)
    6 / 74 (8.11%)
    2 / 42 (4.76%)
         occurrences all number
    8
    3
    6
    2
    Pyrexia
         subjects affected / exposed
    6 / 71 (8.45%)
    6 / 74 (8.11%)
    5 / 74 (6.76%)
    1 / 42 (2.38%)
         occurrences all number
    6
    6
    5
    1
    Injection site bruising
         subjects affected / exposed
    9 / 71 (12.68%)
    3 / 74 (4.05%)
    5 / 74 (6.76%)
    0 / 42 (0.00%)
         occurrences all number
    11
    4
    6
    0
    Pain
         subjects affected / exposed
    3 / 71 (4.23%)
    5 / 74 (6.76%)
    4 / 74 (5.41%)
    1 / 42 (2.38%)
         occurrences all number
    3
    6
    4
    1
    Chest pain
         subjects affected / exposed
    1 / 71 (1.41%)
    4 / 74 (5.41%)
    6 / 74 (8.11%)
    1 / 42 (2.38%)
         occurrences all number
    1
    5
    6
    1
    Influenza like illness
         subjects affected / exposed
    2 / 71 (2.82%)
    2 / 74 (2.70%)
    4 / 74 (5.41%)
    0 / 42 (0.00%)
         occurrences all number
    2
    2
    4
    0
    Injection site erythema
         subjects affected / exposed
    3 / 71 (4.23%)
    5 / 74 (6.76%)
    0 / 74 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    3
    5
    0
    0
    Injection site pain
         subjects affected / exposed
    4 / 71 (5.63%)
    1 / 74 (1.35%)
    2 / 74 (2.70%)
    0 / 42 (0.00%)
         occurrences all number
    4
    2
    2
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    4 / 71 (5.63%)
    5 / 74 (6.76%)
    7 / 74 (9.46%)
    2 / 42 (4.76%)
         occurrences all number
    4
    5
    7
    2
    Anxiety
         subjects affected / exposed
    3 / 71 (4.23%)
    5 / 74 (6.76%)
    3 / 74 (4.05%)
    0 / 42 (0.00%)
         occurrences all number
    3
    6
    3
    0
    Insomnia
         subjects affected / exposed
    2 / 71 (2.82%)
    4 / 74 (5.41%)
    3 / 74 (4.05%)
    0 / 42 (0.00%)
         occurrences all number
    2
    4
    3
    0
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    8 / 71 (11.27%)
    6 / 74 (8.11%)
    7 / 74 (9.46%)
    0 / 42 (0.00%)
         occurrences all number
    8
    8
    8
    0
    Contusion
         subjects affected / exposed
    4 / 71 (5.63%)
    4 / 74 (5.41%)
    6 / 74 (8.11%)
    0 / 42 (0.00%)
         occurrences all number
    4
    4
    6
    0
    Fall
         subjects affected / exposed
    5 / 71 (7.04%)
    2 / 74 (2.70%)
    4 / 74 (5.41%)
    0 / 42 (0.00%)
         occurrences all number
    6
    3
    4
    0
    Ligament sprain
         subjects affected / exposed
    4 / 71 (5.63%)
    1 / 74 (1.35%)
    3 / 74 (4.05%)
    0 / 42 (0.00%)
         occurrences all number
    4
    1
    3
    0
    Laceration
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 74 (1.35%)
    4 / 74 (5.41%)
    0 / 42 (0.00%)
         occurrences all number
    0
    1
    5
    0
    Investigations
    Blood glucose increased
         subjects affected / exposed
    4 / 71 (5.63%)
    1 / 74 (1.35%)
    1 / 74 (1.35%)
    1 / 42 (2.38%)
         occurrences all number
    4
    1
    1
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 71 (2.82%)
    2 / 74 (2.70%)
    5 / 74 (6.76%)
    1 / 42 (2.38%)
         occurrences all number
    2
    2
    5
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 71 (9.86%)
    11 / 74 (14.86%)
    10 / 74 (13.51%)
    0 / 42 (0.00%)
         occurrences all number
    10
    11
    11
    0
    Oropharyngeal pain
         subjects affected / exposed
    4 / 71 (5.63%)
    8 / 74 (10.81%)
    5 / 74 (6.76%)
    1 / 42 (2.38%)
         occurrences all number
    5
    10
    5
    1
    Dyspnoea
         subjects affected / exposed
    4 / 71 (5.63%)
    1 / 74 (1.35%)
    2 / 74 (2.70%)
    0 / 42 (0.00%)
         occurrences all number
    4
    1
    2
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    12 / 71 (16.90%)
    16 / 74 (21.62%)
    16 / 74 (21.62%)
    2 / 42 (4.76%)
         occurrences all number
    15
    39
    20
    2
    Dizziness
         subjects affected / exposed
    8 / 71 (11.27%)
    6 / 74 (8.11%)
    7 / 74 (9.46%)
    2 / 42 (4.76%)
         occurrences all number
    9
    6
    8
    2
    Carpal tunnel syndrome
         subjects affected / exposed
    4 / 71 (5.63%)
    2 / 74 (2.70%)
    0 / 74 (0.00%)
    0 / 42 (0.00%)
         occurrences all number
    4
    2
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    16 / 71 (22.54%)
    20 / 74 (27.03%)
    22 / 74 (29.73%)
    5 / 42 (11.90%)
         occurrences all number
    20
    21
    30
    5
    Diarrhoea
         subjects affected / exposed
    19 / 71 (26.76%)
    19 / 74 (25.68%)
    21 / 74 (28.38%)
    1 / 42 (2.38%)
         occurrences all number
    27
    21
    21
    1
    Abdominal pain upper
         subjects affected / exposed
    11 / 71 (15.49%)
    19 / 74 (25.68%)
    17 / 74 (22.97%)
    2 / 42 (4.76%)
         occurrences all number
    13
    20
    21
    2
    Vomiting
         subjects affected / exposed
    11 / 71 (15.49%)
    14 / 74 (18.92%)
    10 / 74 (13.51%)
    2 / 42 (4.76%)
         occurrences all number
    13
    16
    10
    2
    Abdominal pain
         subjects affected / exposed
    13 / 71 (18.31%)
    8 / 74 (10.81%)
    11 / 74 (14.86%)
    3 / 42 (7.14%)
         occurrences all number
    16
    9
    13
    3
    Constipation
         subjects affected / exposed
    6 / 71 (8.45%)
    2 / 74 (2.70%)
    8 / 74 (10.81%)
    1 / 42 (2.38%)
         occurrences all number
    8
    2
    9
    1
    Abdominal distension
         subjects affected / exposed
    6 / 71 (8.45%)
    4 / 74 (5.41%)
    5 / 74 (6.76%)
    0 / 42 (0.00%)
         occurrences all number
    6
    4
    6
    0
    Abdominal pain lower
         subjects affected / exposed
    1 / 71 (1.41%)
    4 / 74 (5.41%)
    5 / 74 (6.76%)
    0 / 42 (0.00%)
         occurrences all number
    1
    4
    6
    0
    Dyspepsia
         subjects affected / exposed
    1 / 71 (1.41%)
    2 / 74 (2.70%)
    4 / 74 (5.41%)
    1 / 42 (2.38%)
         occurrences all number
    1
    2
    4
    1
    Abdominal tenderness
         subjects affected / exposed
    1 / 71 (1.41%)
    4 / 74 (5.41%)
    1 / 74 (1.35%)
    1 / 42 (2.38%)
         occurrences all number
    1
    4
    1
    1
    Dry mouth
         subjects affected / exposed
    1 / 71 (1.41%)
    4 / 74 (5.41%)
    2 / 74 (2.70%)
    0 / 42 (0.00%)
         occurrences all number
    1
    4
    2
    0
    Hepatobiliary disorders
    Hepatomegaly
         subjects affected / exposed
    2 / 71 (2.82%)
    1 / 74 (1.35%)
    4 / 74 (5.41%)
    0 / 42 (0.00%)
         occurrences all number
    2
    1
    4
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    8 / 71 (11.27%)
    7 / 74 (9.46%)
    8 / 74 (10.81%)
    0 / 42 (0.00%)
         occurrences all number
    8
    7
    9
    0
    Pruritus
         subjects affected / exposed
    7 / 71 (9.86%)
    4 / 74 (5.41%)
    7 / 74 (9.46%)
    1 / 42 (2.38%)
         occurrences all number
    8
    4
    7
    1
    Alopecia
         subjects affected / exposed
    3 / 71 (4.23%)
    4 / 74 (5.41%)
    4 / 74 (5.41%)
    1 / 42 (2.38%)
         occurrences all number
    3
    4
    4
    1
    Palmar erythema
         subjects affected / exposed
    2 / 71 (2.82%)
    4 / 74 (5.41%)
    2 / 74 (2.70%)
    0 / 42 (0.00%)
         occurrences all number
    2
    4
    2
    0
    Urticaria
         subjects affected / exposed
    4 / 71 (5.63%)
    2 / 74 (2.70%)
    0 / 74 (0.00%)
    1 / 42 (2.38%)
         occurrences all number
    6
    4
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    16 / 71 (22.54%)
    11 / 74 (14.86%)
    18 / 74 (24.32%)
    3 / 42 (7.14%)
         occurrences all number
    16
    11
    18
    3
    Back pain
         subjects affected / exposed
    11 / 71 (15.49%)
    6 / 74 (8.11%)
    20 / 74 (27.03%)
    1 / 42 (2.38%)
         occurrences all number
    12
    6
    23
    1
    Pain in extremity
         subjects affected / exposed
    13 / 71 (18.31%)
    8 / 74 (10.81%)
    8 / 74 (10.81%)
    1 / 42 (2.38%)
         occurrences all number
    13
    8
    8
    1
    Muscle spasms
         subjects affected / exposed
    5 / 71 (7.04%)
    9 / 74 (12.16%)
    5 / 74 (6.76%)
    2 / 42 (4.76%)
         occurrences all number
    5
    10
    5
    2
    Musculoskeletal pain
         subjects affected / exposed
    7 / 71 (9.86%)
    7 / 74 (9.46%)
    5 / 74 (6.76%)
    1 / 42 (2.38%)
         occurrences all number
    7
    7
    6
    1
    Myalgia
         subjects affected / exposed
    7 / 71 (9.86%)
    2 / 74 (2.70%)
    4 / 74 (5.41%)
    0 / 42 (0.00%)
         occurrences all number
    7
    2
    4
    0
    Neck pain
         subjects affected / exposed
    0 / 71 (0.00%)
    5 / 74 (6.76%)
    6 / 74 (8.11%)
    0 / 42 (0.00%)
         occurrences all number
    0
    5
    6
    0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    4 / 71 (5.63%)
    3 / 74 (4.05%)
    4 / 74 (5.41%)
    1 / 42 (2.38%)
         occurrences all number
    4
    7
    4
    1
    Decreased appetite
         subjects affected / exposed
    3 / 71 (4.23%)
    3 / 74 (4.05%)
    5 / 74 (6.76%)
    0 / 42 (0.00%)
         occurrences all number
    3
    3
    5
    0
    Diabetes mellitus
         subjects affected / exposed
    6 / 71 (8.45%)
    3 / 74 (4.05%)
    2 / 74 (2.70%)
    0 / 42 (0.00%)
         occurrences all number
    6
    3
    2
    0
    Vitamin D deficiency
         subjects affected / exposed
    2 / 71 (2.82%)
    4 / 74 (5.41%)
    2 / 74 (2.70%)
    1 / 42 (2.38%)
         occurrences all number
    2
    4
    2
    1
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    11 / 71 (15.49%)
    12 / 74 (16.22%)
    10 / 74 (13.51%)
    2 / 42 (4.76%)
         occurrences all number
    15
    17
    12
    2
    Sinusitis
         subjects affected / exposed
    10 / 71 (14.08%)
    8 / 74 (10.81%)
    14 / 74 (18.92%)
    2 / 42 (4.76%)
         occurrences all number
    12
    9
    17
    2
    Urinary tract infection
         subjects affected / exposed
    10 / 71 (14.08%)
    7 / 74 (9.46%)
    14 / 74 (18.92%)
    3 / 42 (7.14%)
         occurrences all number
    11
    8
    20
    5
    Bronchitis
         subjects affected / exposed
    16 / 71 (22.54%)
    7 / 74 (9.46%)
    8 / 74 (10.81%)
    1 / 42 (2.38%)
         occurrences all number
    20
    8
    10
    1
    Nasopharyngitis
         subjects affected / exposed
    5 / 71 (7.04%)
    8 / 74 (10.81%)
    16 / 74 (21.62%)
    1 / 42 (2.38%)
         occurrences all number
    7
    13
    26
    2
    Influenza
         subjects affected / exposed
    8 / 71 (11.27%)
    8 / 74 (10.81%)
    10 / 74 (13.51%)
    2 / 42 (4.76%)
         occurrences all number
    11
    10
    11
    2
    Tooth abscess
         subjects affected / exposed
    6 / 71 (8.45%)
    1 / 74 (1.35%)
    4 / 74 (5.41%)
    0 / 42 (0.00%)
         occurrences all number
    6
    1
    4
    0
    Cellulitis
         subjects affected / exposed
    4 / 71 (5.63%)
    2 / 74 (2.70%)
    2 / 74 (2.70%)
    0 / 42 (0.00%)
         occurrences all number
    4
    2
    2
    0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 71 (1.41%)
    5 / 74 (6.76%)
    1 / 74 (1.35%)
    1 / 42 (2.38%)
         occurrences all number
    1
    5
    1
    1
    Gastroenteritis
         subjects affected / exposed
    4 / 71 (5.63%)
    1 / 74 (1.35%)
    1 / 74 (1.35%)
    1 / 42 (2.38%)
         occurrences all number
    4
    1
    1
    1
    Localised infection
         subjects affected / exposed
    4 / 71 (5.63%)
    0 / 74 (0.00%)
    1 / 74 (1.35%)
    0 / 42 (0.00%)
         occurrences all number
    4
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Feb 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
    26 Feb 2013
    1. Additional anti-GS-6624 antibodies and pharmacokinetics testing. 2. Language added regarding Brunt/Kleiner and the NAFLD Activity Score (NAS). 3. Language added regarding the Cochran-Mantel-Haenszel test. 4. New anti-GS-6624 antibodies and pharmacokinetics testing section.
    30 Sep 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 treatment via SC injection every week with a fixed dose of simtuzumab 125 mg. 3) A clinical efficacy endpoint of event free survival (EFS) has been added, EFS will be assessed by time to progression to cirrhosis and progression to cirrhosis events will be followed up to Week 240 to assess whether simtuzumab can reduce the incidence of progression to cirrhosis. Any participant found to have a liver biopsy consistent with cirrhosis at Week 48, Week 96 or Week 240 will be considered to have met this endpoint. 4) A Progression to Cirrhosis Events Adjudication Committee has been added and participants suspected to have progressed to cirrhosis will be presented to the committee to confirm if it is progression to cirrhosis or not. 5) Inclusion/ Exclusion criteria updated.
    31 Jul 2015
    1. Updating Study Director 2. Revised liver biopsy central reading process

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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