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    Clinical Trial Results:
    A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Safety, Tolerability, and Efficacy of GS-9674 in Subjects with Nonalcoholic Steatohepatitis (NASH).

    Summary
    EudraCT number
    2016-002496-10
    Trial protocol
    AT   GB  
    Global end of trial date
    09 Jan 2018

    Results information
    Results version number
    v2(current)
    This version publication date
    18 May 2019
    First version publication date
    23 Jan 2019
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Adding text to “Limitations and Caveats” section

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-402-1852
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02854605
    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
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com
    Scientific contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@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
    09 Jan 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Jan 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jan 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to evaluate the safety and tolerability of GS-9674 in participants with nonalcoholic 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
    26 Oct 2016
    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
    Canada: 25
    Country: Number of subjects enrolled
    Hong Kong: 10
    Country: Number of subjects enrolled
    New Zealand: 4
    Country: Number of subjects enrolled
    Switzerland: 4
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    United States: 96
    Worldwide total number of subjects
    140
    EEA total number of subjects
    1
    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)
    121
    From 65 to 84 years
    19
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants were enrolled at study sites in North America, Hong Kong, New Zealand, and Europe. The first participant was screened on 26 October 2016. The last study visit occurred on 09 January 2018.

    Pre-assignment
    Screening details
    327 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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    GS-9674 100 mg
    Arm description
    GS-9674 100 mg tablet once daily + placebo-to-match (PTM) GS-9674 30 mg tablet once daily for 24 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    GS-9674
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg administered once daily

    Investigational medicinal product name
    PTM GS-9674 30 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered once daily

    Arm title
    GS-9674 30 mg
    Arm description
    GS-9674 30 mg tablet once daily + PTM GS-9674 100 mg tablet once daily for 24 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    GS-9674
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    30 mg administered once daily

    Investigational medicinal product name
    PTM GS-9674 100 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered once daily

    Arm title
    Placebo
    Arm description
    PTM GS-9674 30 mg tablet once daily + PTM GS-9674 100 mg tablet once daily for 24 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    PTM GS-9674 30 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered once daily

    Investigational medicinal product name
    PTM GS-9674 100 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered once daily

    Number of subjects in period 1
    GS-9674 100 mg GS-9674 30 mg Placebo
    Started
    56
    56
    28
    Completed
    53
    49
    24
    Not completed
    3
    7
    4
         Protocol violation
    -
    -
    1
         Adverse event
    1
    5
    2
         Withdrew consent
    1
    -
    1
         Investigator's discretion
    1
    -
    -
         Lost to follow-up
    -
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    GS-9674 100 mg
    Reporting group description
    GS-9674 100 mg tablet once daily + placebo-to-match (PTM) GS-9674 30 mg tablet once daily for 24 weeks.

    Reporting group title
    GS-9674 30 mg
    Reporting group description
    GS-9674 30 mg tablet once daily + PTM GS-9674 100 mg tablet once daily for 24 weeks.

    Reporting group title
    Placebo
    Reporting group description
    PTM GS-9674 30 mg tablet once daily + PTM GS-9674 100 mg tablet once daily for 24 weeks.

    Reporting group values
    GS-9674 100 mg GS-9674 30 mg Placebo Total
    Number of subjects
    56 56 28 140
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    55 ( 10.5 ) 51 ( 12.8 ) 50 ( 9.9 ) -
    Gender categorical
    Units: Subjects
        Female
    35 37 15 87
        Male
    21 19 13 53
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    17 19 8 44
        Not Hispanic or Latino
    39 37 20 96
    Race
    Units: Subjects
        American Indian or Alaska Native
    0 1 1 2
        Asian
    13 5 4 22
        Native Hawaiian or Other Pacific Islander
    0 2 0 2
        Black or African American
    1 1 1 3
        White
    42 47 21 110
        Other
    0 0 1 1

    End points

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    End points reporting groups
    Reporting group title
    GS-9674 100 mg
    Reporting group description
    GS-9674 100 mg tablet once daily + placebo-to-match (PTM) GS-9674 30 mg tablet once daily for 24 weeks.

    Reporting group title
    GS-9674 30 mg
    Reporting group description
    GS-9674 30 mg tablet once daily + PTM GS-9674 100 mg tablet once daily for 24 weeks.

    Reporting group title
    Placebo
    Reporting group description
    PTM GS-9674 30 mg tablet once daily + PTM GS-9674 100 mg tablet once daily for 24 weeks.

    Primary: Overall Safety of GS-9674 as Assessed By Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    Overall Safety of GS-9674 as Assessed By Percentage of Participants Experiencing Treatment-Emergent Adverse Events (TEAEs) [1]
    End point description
    TEAEs were defined as 1 or both of the following: 1) Any AEs with an onset date on or after the study drug start date and no later than 30 days after permanent discontinuation of study drug, 2) Any AEs leading to premature discontinuation of study drug. Safety Analysis Set included all participants who took at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Up to 24 weeks plus 30 days
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses was planned for this endpoint.
    End point values
    GS-9674 100 mg GS-9674 30 mg Placebo
    Number of subjects analysed
    56
    56
    28
    Units: Percentage of participants
    number (not applicable)
        TEAEs
    89.3
    76.8
    67.9
        TEAEs leading to premature discontinuation of drug
    1.8
    8.9
    7.1
    No statistical analyses for this end point

    Primary: Overall Safety of GS-9674 as Assessed By Percentage of Participants With Treatment-Emergent Laboratory Abnormalities

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    End point title
    Overall Safety of GS-9674 as Assessed By Percentage of Participants With Treatment-Emergent Laboratory Abnormalities [2]
    End point description
    Treatment-emergent laboratory abnormalities are defined as values that increase at least 1 toxicity grade from baseline at any post-baseline time point, up to and including the date of last dose of study drug plus 30 days for participants who permanently discontinued study. Participants in the Safety Analysis Set were analyzed.
    End point type
    Primary
    End point timeframe
    Up to 24 weeks plus 30 days
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses was planned for this endpoint.
    End point values
    GS-9674 100 mg GS-9674 30 mg Placebo
    Number of subjects analysed
    56
    56
    28
    Units: Percentage of participants
    number (not applicable)
        Any Grade ≥ 1
    89.3
    92.9
    92.9
        Grade 1
    35.7
    42.9
    50.0
        Grade 2
    37.5
    37.5
    25.0
        Grade 3
    7.1
    10.7
    14.3
        Grade 4
    8.9
    1.8
    3.6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 24 weeks plus 30 days
    Adverse event reporting additional description
    Safety Analysis Set included all participants who took at least 1 dose of study drug.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    GS-9674 30 mg
    Reporting group description
    GS-9674 30 mg tablet once daily + PTM GS-9674 100 mg tablet once daily for 24 weeks.

    Reporting group title
    Placebo
    Reporting group description
    PTM GS-9674 30 mg tablet once daily + PTM GS-9674 100 mg tablet once daily for 24 weeks.

    Reporting group title
    GS-9674 100 mg
    Reporting group description
    GS-9674 100 mg tablet once daily + PTM GS-9674 30 mg tablet once daily for 24 weeks.

    Serious adverse events
    GS-9674 30 mg Placebo GS-9674 100 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 56 (3.57%)
    1 / 28 (3.57%)
    2 / 56 (3.57%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-cell lymphoma
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 28 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oesophageal carcinoma
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 28 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 28 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 28 (3.57%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 28 (0.00%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 28 (0.00%)
    1 / 56 (1.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    GS-9674 30 mg Placebo GS-9674 100 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 56 (60.71%)
    17 / 28 (60.71%)
    39 / 56 (69.64%)
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 56 (0.00%)
    2 / 28 (7.14%)
    0 / 56 (0.00%)
         occurrences all number
    0
    2
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 56 (1.79%)
    0 / 28 (0.00%)
    3 / 56 (5.36%)
         occurrences all number
    1
    0
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 56 (10.71%)
    4 / 28 (14.29%)
    4 / 56 (7.14%)
         occurrences all number
    9
    4
    5
    Dizziness
         subjects affected / exposed
    1 / 56 (1.79%)
    2 / 28 (7.14%)
    1 / 56 (1.79%)
         occurrences all number
    1
    2
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    7 / 56 (12.50%)
    1 / 28 (3.57%)
    2 / 56 (3.57%)
         occurrences all number
    7
    1
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 56 (0.00%)
    0 / 28 (0.00%)
    3 / 56 (5.36%)
         occurrences all number
    0
    0
    3
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    5 / 56 (8.93%)
    1 / 28 (3.57%)
    3 / 56 (5.36%)
         occurrences all number
    6
    1
    3
    Abdominal distension
         subjects affected / exposed
    3 / 56 (5.36%)
    3 / 28 (10.71%)
    2 / 56 (3.57%)
         occurrences all number
    3
    3
    2
    Nausea
         subjects affected / exposed
    4 / 56 (7.14%)
    2 / 28 (7.14%)
    2 / 56 (3.57%)
         occurrences all number
    6
    2
    2
    Abdominal pain
         subjects affected / exposed
    2 / 56 (3.57%)
    0 / 28 (0.00%)
    5 / 56 (8.93%)
         occurrences all number
    2
    0
    5
    Diarrhoea
         subjects affected / exposed
    3 / 56 (5.36%)
    1 / 28 (3.57%)
    3 / 56 (5.36%)
         occurrences all number
    3
    1
    4
    Constipation
         subjects affected / exposed
    3 / 56 (5.36%)
    0 / 28 (0.00%)
    1 / 56 (1.79%)
         occurrences all number
    3
    0
    1
    Dry mouth
         subjects affected / exposed
    1 / 56 (1.79%)
    2 / 28 (7.14%)
    1 / 56 (1.79%)
         occurrences all number
    1
    2
    1
    Dyspepsia
         subjects affected / exposed
    0 / 56 (0.00%)
    2 / 28 (7.14%)
    1 / 56 (1.79%)
         occurrences all number
    0
    2
    1
    Gastritis
         subjects affected / exposed
    0 / 56 (0.00%)
    2 / 28 (7.14%)
    0 / 56 (0.00%)
         occurrences all number
    0
    2
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    9 / 56 (16.07%)
    5 / 28 (17.86%)
    13 / 56 (23.21%)
         occurrences all number
    9
    6
    15
    Pruritus generalised
         subjects affected / exposed
    3 / 56 (5.36%)
    0 / 28 (0.00%)
    3 / 56 (5.36%)
         occurrences all number
    3
    0
    3
    Psychiatric disorders
    Depression
         subjects affected / exposed
    5 / 56 (8.93%)
    0 / 28 (0.00%)
    1 / 56 (1.79%)
         occurrences all number
    5
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 56 (7.14%)
    3 / 28 (10.71%)
    2 / 56 (3.57%)
         occurrences all number
    4
    3
    2
    Myalgia
         subjects affected / exposed
    1 / 56 (1.79%)
    1 / 28 (3.57%)
    3 / 56 (5.36%)
         occurrences all number
    1
    1
    3
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 56 (8.93%)
    2 / 28 (7.14%)
    6 / 56 (10.71%)
         occurrences all number
    5
    3
    7
    Nasopharyngitis
         subjects affected / exposed
    3 / 56 (5.36%)
    3 / 28 (10.71%)
    1 / 56 (1.79%)
         occurrences all number
    4
    5
    1
    Bronchitis
         subjects affected / exposed
    3 / 56 (5.36%)
    0 / 28 (0.00%)
    3 / 56 (5.36%)
         occurrences all number
    3
    0
    3
    Urinary tract infection
         subjects affected / exposed
    0 / 56 (0.00%)
    1 / 28 (3.57%)
    4 / 56 (7.14%)
         occurrences all number
    0
    1
    4
    Sinusitis
         subjects affected / exposed
    3 / 56 (5.36%)
    0 / 28 (0.00%)
    1 / 56 (1.79%)
         occurrences all number
    3
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 56 (0.00%)
    2 / 28 (7.14%)
    0 / 56 (0.00%)
         occurrences all number
    0
    2
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Oct 2016
    - Updated inclusion criteria to allow for histological evidence of fatty liver within 2 years of - screening and to ensure subjects with cirrhosis or liver disease were not enrolled in the study - Added exclusion criterion (HbA1c > 9% at screening) to ensure subjects with poorly - controlled diabetes were not enrolled in the study - Provided additional nonclinical safety data - Updated data from other clinical studies of GS-9674 - Updated the risk/benefit assessment to communicate the risk for liver injury and provide newly available safety data - Added guidance regarding concomitant use of atorvastatin - Updated the list of prohibited medications based on newly available drug-drug interaction data - Allowed subjects to rescreen once for the study - Revised drug-induced liver injury (DILI) monitoring language to update thresholds, add creatine phosphokinase testing as a requirement for DILI observation, and to clarify study drug stopping rules - Allowed hormonal contraception as a highly effective contraceptive method
    24 Jan 2017
    -Allowed for a historical liver biopsy consistent with NASH and no documented weight loss > 5% between the date of the liver biopsy and screening to determine eligibility for enrollment - Extended screening period to up to 6 weeks - Lowered screening MRI-PDFF cutoff from ≥ 10% to ≥ 8% for detection of steatosis, and lowered screening MRE cutoff from ≥ 2.90 to ≥ 2.5 kPa for detection of hepatic fibrosis - Removed creatinine clearance inclusion criterion and replaced with criterion specifying a normal serum creatinine level - Added language to clarify that subjects with FibroSURE/FibroTest ≥ 0.75 were eligible for enrollment if a liver biopsy within 12 months of screening excluded cirrhosis. Additionally, direct bilirubin was used instead of total bilirubin in FibroSURE/FibroTest calculations for subjects with Gilbert’s syndrome or hemolysis - Added nonclinical toxicology data to support dosing of subjects beyond 12 weeks - Clarified that study drug should not be administered within 4 hours of dosing with bile acid sequestrants - Provided guidance regarding retesting of exclusionary laboratory analyses during screening and allowed retesting to be performed at the principal investigator’s discretion - Clarified that subjects who failed screening but met the revised inclusion/exclusion criteria were eligible for enrollment

    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.
    An unplanned review of unblinded clinical trial data was performed in this study that was not prospectively specified in the protocol. There was no impact on the overall integrity or conclusions of the study.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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