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    Clinical Trial Results:
    A Phase 2b Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of MK-3655 in Individuals With Pre-cirrhotic Nonalcoholic Steatohepatitis (NASH)

    Summary
    EudraCT number
    		 2019-003048-63
    Trial protocol
    		 DE   FR   IT   SE   GR  
    Global end of trial date
    13 Apr 2023

    Results information
    Results version number
    		 v1
    This version publication date
    29 Mar 2024
    First version publication date
    29 Mar 2024
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    3655-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04583423
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme LLC
    Sponsor organisation address
    126 East Lincoln Avenue, P.O. Box 2000, Rahway, NJ, United States, 07065
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme LLC, ClinicalTrialsDisclosure@merck.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
    13 Apr 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Apr 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Apr 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This study will evaluate the effect of each dose of MK-3655 versus placebo on the percentage of individuals with NASH resolution without worsening of fibrosis after 52 weeks. The primary hypothesis of the study is that at least 1 dose of MK-3655 is superior to placebo with respect to the percentage of individuals with NASH resolution without worsening of fibrosis after 52 weeks.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Nov 2020
    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
    Argentina: 2
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    Chile: 3
    Country: Number of subjects enrolled
    China: 8
    Country: Number of subjects enrolled
    Colombia: 1
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Hong Kong: 4
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Japan: 45
    Country: Number of subjects enrolled
    Korea, Republic of: 2
    Country: Number of subjects enrolled
    Mexico: 6
    Country: Number of subjects enrolled
    New Zealand: 3
    Country: Number of subjects enrolled
    Puerto Rico: 5
    Country: Number of subjects enrolled
    Russian Federation: 6
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Taiwan: 4
    Country: Number of subjects enrolled
    Türkiye: 3
    Country: Number of subjects enrolled
    United States: 57
    Worldwide total number of subjects
    183
    EEA total number of subjects
    27
    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)
    141
    From 65 to 84 years
    42
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Males and females with pre-cirrhotic NASH aged 18 to 80 years (in Japan and Taiwan, aged 20 to 80 years were enrolled in the study

    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
    		 Investigator, Monitor, Carer, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MK-3655 50 mg
    Arm description
    		 Following a 2-week placebo run-in, participants received MK-3655 50 mg by subcutaneous (SC) injection once every 4 weeks (Q4W) for 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MK-3655
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    50-mg SC injection Q4W for 52 weeks

    Arm title
    		 MK-3655 100 mg
    Arm description
    		 Following a 2-week placebo run-in, participants received MK-3655 100 mg by SC injection Q4W for 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MK-3655
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    100-mg SC injection Q4W for 52 weeks

    Arm title
    		 MK-3655 300 mg
    Arm description
    		 Following a 2-week placebo run-in, participants received MK-3655 300 mg by SC injection Q4W for 52 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MK-3655
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    300-mg SC injection Q4W for 52 weeks

    Arm title
    		 Placebo
    Arm description
    		 Following a 2-week placebo run-in, participants received placebo by SC injection Q4W for 52 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo for MK-3655
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    SC injection Q4W for 52 weeks

    Number of subjects in period 1
    		MK-3655 50 mg MK-3655 100 mg MK-3655 300 mg Placebo
    Started
    45
    48
    46
    44
    Received 1st Dose
    45
    47
    46
    44
    Completed
    10
    11
    8
    8
    Not completed
    35
    37
    38
    36
         Consent withdrawn by subject
    3
    1
    2
    1
         Study Terminated by Sponsor
    32
    35
    36
    33
         Lost to follow-up
    -
    1
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MK-3655 50 mg
    Reporting group description
    		 Following a 2-week placebo run-in, participants received MK-3655 50 mg by subcutaneous (SC) injection once every 4 weeks (Q4W) for 52 weeks.

    Reporting group title
    MK-3655 100 mg
    Reporting group description
    		 Following a 2-week placebo run-in, participants received MK-3655 100 mg by SC injection Q4W for 52 weeks.

    Reporting group title
    MK-3655 300 mg
    Reporting group description
    		 Following a 2-week placebo run-in, participants received MK-3655 300 mg by SC injection Q4W for 52 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Following a 2-week placebo run-in, participants received placebo by SC injection Q4W for 52 weeks.

    Reporting group values
    		 MK-3655 50 mg MK-3655 100 mg MK-3655 300 mg Placebo Total
    Number of subjects
    		 45 48 46 44 183
    Age categorical
    Units: Participants
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 33 38 34 36 141
        From 65-84 years
    		 12 10 12 8 42
        85 years and over
    		 0 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 59.6 ( 8.9 ) 54.3 ( 12.3 ) 56.6 ( 11.3 ) 55.8 ( 10.1 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 25 20 23 19 87
        Male
    		 20 28 23 25 96
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 1 1
        Asian
    		 15 18 16 16 65
        Native Hawaiian or Other Pacific Islander
    		 1 0 1 0 2
        Black or African American
    		 3 2 1 1 7
        White
    		 26 28 27 26 107
        More than one race
    		 0 0 1 0 1
        Unknown or Not Reported
    		 0 0 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 12 13 17 18 60
        Not Hispanic or Latino
    		 33 34 28 25 120
        Unknown or Not Reported
    		 0 1 1 1 3
    Fibrosis Score
    Units: Subjects
        Stage 2
    		 21 22 21 21 85
        Stage 3
    		 24 26 25 23 98
    Percent Liver Fat Content
    Units: Subjects
        <20%
    		 30 23 30 31 114
        ≥ 20%
    		 15 25 16 13 69
    Type 2 Diabetes Mellitus (T2DM)
    Units: Subjects
        Yes for T2DM
    		 22 25 25 24 96
        No for T2DM
    		 23 23 21 20 87
    Region
    Units: Subjects
        Japan
    		 11 12 11 11 45
        East Asia excluding Japan
    		 6 5 5 5 21
        Other
    		 28 31 30 28 117

    End points

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    End points reporting groups
    Reporting group title
    MK-3655 50 mg
    Reporting group description
    		 Following a 2-week placebo run-in, participants received MK-3655 50 mg by subcutaneous (SC) injection once every 4 weeks (Q4W) for 52 weeks.

    Reporting group title
    MK-3655 100 mg
    Reporting group description
    		 Following a 2-week placebo run-in, participants received MK-3655 100 mg by SC injection Q4W for 52 weeks.

    Reporting group title
    MK-3655 300 mg
    Reporting group description
    		 Following a 2-week placebo run-in, participants received MK-3655 300 mg by SC injection Q4W for 52 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Following a 2-week placebo run-in, participants received placebo by SC injection Q4W for 52 weeks.

    Primary: Percentage of Participants With Nonalcoholic Steatohepatitis (NASH) Resolution Without Worsening of Fibrosis After 52 Weeks

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    End point title
    		 Percentage of Participants With Nonalcoholic Steatohepatitis (NASH) Resolution Without Worsening of Fibrosis After 52 Weeks
    End point description
    The NASH Clinical Research Network (CRN) scoring system evaluated by Blinded Independent Central Review (BICR) was used to assess treatment response. The NASH CRN scoring scales were: lobular inflammation score (0-3); hepatocyte ballooning score (0-2); steatosis score (0-3); and fibrosis score (0-4). NASH resolution was defined as a score of 0-1 for inflammation, 0 for ballooning, and any grade of steatosis. Analysis population was the Full Analysis Set (FAS), which consisted of all randomized participants who had at least 1 injection of study intervention and had at least 1 assessment.
    End point type
    Primary
    End point timeframe
    Week 52
    End point values
    		 MK-3655 50 mg MK-3655 100 mg MK-3655 300 mg Placebo
    Number of subjects analysed
    18
    21
    17
    17
    Units: Percentage of Participants
        number (not applicable)
    16.7
    14.3
    17.6
    5.9
    Statistical analysis title
    		 MK-3655 50 mg vs Placebo
    Comparison groups
    MK-3655 50 mg v Placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3504 [1]
    Method
    		 Miettinen and Nurminen's method
    Parameter type
    		 Difference in Percentages
    Point estimate
    10.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -13.4
         upper limit
    		 35.1
    Notes
    [1] - Stratified by concurrent diagnosis of T2DM at the time of randomization and fibrosis score and using Cochran-Mantel-Haenszel weighting scheme
    Statistical analysis title
    		 MK-3655 300 mg vs Placebo
    Comparison groups
    MK-3655 300 mg v Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1428 [2]
    Method
    		 Miettinen and Nurminen's method
    Parameter type
    		 Difference in Percentages
    Point estimate
    15.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.5
         upper limit
    		 42.3
    Notes
    [2] - Stratified by concurrent diagnosis of T2DM at the time of randomization and fibrosis score and using Cochran-Mantel-Haenszel weighting scheme
    Statistical analysis title
    		 MK-3655 100 mg vs Placebo
    Comparison groups
    MK-3655 100 mg v Placebo
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.373 [3]
    Method
    		 Miettinen and Nurminen's method
    Parameter type
    		 Difference in Percentages
    Point estimate
    9.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.6
         upper limit
    		 32.1
    Notes
    [3] - Stratified by concurrent diagnosis of T2DM at the time of randomization and fibrosis score and using Cochran-Mantel-Haenszel weighting scheme

    Primary: Percentage of Participants Who Experienced an Adverse Event (AE)

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    End point title
    		 Percentage of Participants Who Experienced an Adverse Event (AE) [4]
    End point description
    An AE was defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it was considered related to the medical treatment or procedure, that occurred during the course of the study. Analysis population was the All Participants as Treated (APaT) population, which included all randomized participants who received at least 1 injection of study intervention.
    End point type
    Primary
    End point timeframe
    Up to 56 weeks
    Notes
    [4] - 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 analysis was planned for the endpoint
    End point values
    		 MK-3655 50 mg MK-3655 100 mg MK-3655 300 mg Placebo
    Number of subjects analysed
    45
    47
    46
    44
    Units: Percentage of Participants
        number (not applicable)
    73.3
    70.2
    76.1
    77.3
    No statistical analyses for this end point

    Primary: Percentage of Participants Discontinuing Study Medication Due to an AE

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    End point title
    		 Percentage of Participants Discontinuing Study Medication Due to an AE [5]
    End point description
    An AE was defined as any unfavorable and unintended sign including an abnormal laboratory finding, symptom or disease associated with the use of a medical treatment or procedure, regardless of whether it was considered related to the medical treatment or procedure, that occurred during the course of the study. Analysis population was the APaT, which included all randomized participants who received at least 1 injection of study intervention.
    End point type
    Primary
    End point timeframe
    Up to 52 weeks
    Notes
    [5] - 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 analysis was planned for the endpoint
    End point values
    		 MK-3655 50 mg MK-3655 100 mg MK-3655 300 mg Placebo
    Number of subjects analysed
    45
    47
    46
    44
    Units: Percentage of Participants
        number (not applicable)
    2.2
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Mean Percent Relative Reduction from Baseline in Liver Fat Content (LFC) After 24 weeks

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    End point title
    		 Mean Percent Relative Reduction from Baseline in Liver Fat Content (LFC) After 24 weeks
    End point description
    LFC % was measured by Magnetic Resonance Imaging-Estimated Proton Density Fat Fraction (MRI-PDFF) and evaluated by BICR. MRI-PDFF is a highly accurate noninvasive measure of the proportion of fat content of a tissue. Analysis population was the FAS, which consisted of all randomized participants who had at least 1 injection of study intervention and had at least 1 assessment.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    		 MK-3655 50 mg MK-3655 100 mg MK-3655 300 mg Placebo
    Number of subjects analysed
    33
    36
    37
    31
    Units: Percentage Change
        least squares mean (confidence interval 95%)
    30.1 (17.5 to 42.7)
    30.0 (18.2 to 41.8)
    37.2 (25.5 to 48.8)
    11.0 (-0.9 to 23.0)
    Statistical analysis title
    		 MK-3655 50 mg vs Placebo
    Comparison groups
    MK-3655 50 mg v Placebo
    Number of subjects included in analysis
    64
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in Least Square (LS) Means
    Point estimate
    19.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.7
         upper limit
    		 36.4
    Statistical analysis title
    		 MK-3655 300 mg vs Placebo
    Comparison groups
    MK-3655 300 mg v Placebo
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in LS Means
    Point estimate
    26.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9.5
         upper limit
    		 42.8
    Statistical analysis title
    		 MK-3655 100 mg vs Placebo
    Comparison groups
    MK-3655 100 mg v Placebo
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in LS Means
    Point estimate
    19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.2
         upper limit
    		 35.8

    Secondary: Percentage of Participants With ≥1 Stage Improvement in Fibrosis Without Worsening of Steatohepatitis Assessed With the NASH CRN Scoring System After 52 Weeks

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    End point title
    		 Percentage of Participants With ≥1 Stage Improvement in Fibrosis Without Worsening of Steatohepatitis Assessed With the NASH CRN Scoring System After 52 Weeks
    End point description
    Participants evaluated with the NASH CRN scoring system with BICR with ≥1 stage improvement in fibrosis without worsening of steatohepatitis defined as no increase in the ballooning, inflammation, or steatosis scores. Analysis population was the FAS, which consisted of all randomized participants who had at least 1 injection of study intervention and had at least 1 assessment.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 MK-3655 50 mg MK-3655 100 mg MK-3655 300 mg Placebo
    Number of subjects analysed
    18
    21
    17
    17
    Units: Percentage of Participants
        number (not applicable)
    22.2
    38.1
    29.4
    17.6
    Statistical analysis title
    		 MK-3655 50 mg vs Placebo
    Comparison groups
    MK-3655 50 mg v Placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8978 [6]
    Method
    		 Miettinen and Nurminen's method
    Parameter type
    		 Difference in Percentages
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.5
         upper limit
    		 30.3
    Notes
    [6] - Stratified by concurrent diagnosis of T2DM at the time of randomization and fibrosis score and using Cochran-Mantel-Haenszel weighting scheme
    Statistical analysis title
    		 MK-3655 300 mg vs Placebo
    Comparison groups
    MK-3655 300 mg v Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5636 [7]
    Method
    		 Miettinen and Nurminen's method
    Parameter type
    		 Difference in Percentages
    Point estimate
    8.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.1
         upper limit
    		 38.5
    Notes
    [7] - Stratified by concurrent diagnosis of T2DM at the time of randomization and fibrosis score and using Cochran-Mantel-Haenszel weighting scheme
    Statistical analysis title
    		 MK-3655 100 mg vs Placebo
    Comparison groups
    MK-3655 100 mg v Placebo
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1869 [8]
    Method
    		 Miettinen and Nurminen's method
    Parameter type
    		 Difference in Parentages
    Point estimate
    20
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.6
         upper limit
    		 46.4
    Notes
    [8] - Stratified by concurrent diagnosis of T2DM at the time of randomization and fibrosis score and using Cochran-Mantel-Haenszel weighting scheme

    Secondary: Percentage of Participants with ≥2 Point Improvement in NAS with ≥1 Point Improvement in Inflammation or Ballooning without Worsening of Fibrosis by Histology (Evaluated by BICR) after 52 weeks

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    End point title
    		 Percentage of Participants with ≥2 Point Improvement in NAS with ≥1 Point Improvement in Inflammation or Ballooning without Worsening of Fibrosis by Histology (Evaluated by BICR) after 52 weeks
    End point description
    Participants with ≥2 point improvement in the NAS with ≥1 point improvement in inflammation or ballooning without worsening of fibrosis assessed with the NASH CRN scoring system (evaluated by BICR). The NAS was calculated as the unweighted sum of the scores and ranges from 0-8 (highest activity). Analysis population was the FAS, which consisted of all randomized participants who had at least 1 injection of study intervention and had at least 1 assessment.
    End point type
    Secondary
    End point timeframe
    Week 52
    End point values
    		 MK-3655 50 mg MK-3655 100 mg MK-3655 300 mg Placebo
    Number of subjects analysed
    18
    21
    17
    17
    Units: Percentage of Participants
        number (not applicable)
    33.3
    47.6
    35.3
    29.4
    Statistical analysis title
    		 MK-3655 50 mg vs Placebo
    Comparison groups
    MK-3655 50 mg v Placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9174 [9]
    Method
    		 Miettinen and Nurminen's method
    Parameter type
    		 Difference in Percentages
    Point estimate
    1.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -28.6
         upper limit
    		 32.6
    Notes
    [9] - Stratified by concurrent diagnosis of T2DM at the time of randomization and fibrosis score and using Cochran-Mantel-Haenszel weighting scheme
    Statistical analysis title
    		 MK-3655 100 mg vs Placebo
    Comparison groups
    MK-3655 100 mg v Placebo
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.272 [10]
    Method
    		 Miettinen and Nurminen's method
    Parameter type
    		 Difference in Percentages
    Point estimate
    18.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.5
         upper limit
    		 47.1
    Notes
    [10] - Stratified by concurrent diagnosis of T2DM at the time of randomization and fibrosis score and using Cochran-Mantel-Haenszel weighting scheme
    Statistical analysis title
    		 MK-3655 300 mg vs Placebo
    Comparison groups
    MK-3655 300 mg v Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7586 [11]
    Method
    		 Miettinen and Nurminen's method
    Parameter type
    		 Difference in Percentages
    Point estimate
    5.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.7
         upper limit
    		 37.3
    Notes
    [11] - Stratified by concurrent diagnosis of T2DM at the time of randomization and fibrosis score and using Cochran-Mantel-Haenszel weighting scheme

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 64 weeks
    Adverse event reporting additional description
    All-cause mortality population included all enrolled participants. Serious Adverse Events and non-serious AEs population included all participants who received at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    MK-3655 50 mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    MK-3655 300 mg
    Reporting group description
    		 -

    Reporting group title
    MK-3655 100 mg
    Reporting group description
    		 -

    Serious adverse events
    		 MK-3655 50 mg Placebo MK-3655 300 mg MK-3655 100 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 45 (2.22%)
    8 / 44 (18.18%)
    1 / 46 (2.17%)
    1 / 47 (2.13%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Forearm fracture
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 44 (2.27%)
    0 / 46 (0.00%)
    0 / 47 (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
    Cardiac disorders
    Sinoatrial block
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 44 (2.27%)
    0 / 46 (0.00%)
    0 / 47 (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
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 44 (2.27%)
    0 / 46 (0.00%)
    0 / 47 (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
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 44 (2.27%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 44 (2.27%)
    0 / 46 (0.00%)
    0 / 47 (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 / 45 (0.00%)
    0 / 44 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (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 / 45 (0.00%)
    1 / 44 (2.27%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 44 (2.27%)
    0 / 46 (0.00%)
    0 / 47 (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
    Renal and urinary disorders
    Calculus bladder
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 44 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         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
    Acute kidney injury
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 44 (2.27%)
    0 / 46 (0.00%)
    0 / 47 (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 / 45 (0.00%)
    1 / 44 (2.27%)
    0 / 46 (0.00%)
    0 / 47 (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
    Infections and infestations
    Pyelonephritis acute
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 44 (2.27%)
    0 / 46 (0.00%)
    0 / 47 (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
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 44 (0.00%)
    0 / 46 (0.00%)
    0 / 47 (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
    Diverticulitis
         subjects affected / exposed
    0 / 45 (0.00%)
    0 / 44 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 MK-3655 50 mg Placebo MK-3655 300 mg MK-3655 100 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 45 (42.22%)
    21 / 44 (47.73%)
    27 / 46 (58.70%)
    26 / 47 (55.32%)
    Investigations
    Weight increased
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 44 (2.27%)
    3 / 46 (6.52%)
    1 / 47 (2.13%)
         occurrences all number
    1
    1
    3
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 45 (4.44%)
    1 / 44 (2.27%)
    6 / 46 (13.04%)
    6 / 47 (12.77%)
         occurrences all number
    2
    1
    7
    8
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 45 (4.44%)
    3 / 44 (6.82%)
    5 / 46 (10.87%)
    1 / 47 (2.13%)
         occurrences all number
    2
    4
    6
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 45 (4.44%)
    4 / 44 (9.09%)
    2 / 46 (4.35%)
    2 / 47 (4.26%)
         occurrences all number
    4
    5
    2
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 45 (2.22%)
    2 / 44 (4.55%)
    3 / 46 (6.52%)
    0 / 47 (0.00%)
         occurrences all number
    1
    2
    3
    0
    Diarrhoea
         subjects affected / exposed
    4 / 45 (8.89%)
    3 / 44 (6.82%)
    5 / 46 (10.87%)
    7 / 47 (14.89%)
         occurrences all number
    5
    5
    5
    7
    Nausea
         subjects affected / exposed
    2 / 45 (4.44%)
    4 / 44 (9.09%)
    1 / 46 (2.17%)
    3 / 47 (6.38%)
         occurrences all number
    2
    4
    2
    3
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 45 (0.00%)
    3 / 44 (6.82%)
    1 / 46 (2.17%)
    1 / 47 (2.13%)
         occurrences all number
    0
    4
    1
    1
    Back pain
         subjects affected / exposed
    1 / 45 (2.22%)
    3 / 44 (6.82%)
    4 / 46 (8.70%)
    3 / 47 (6.38%)
         occurrences all number
    2
    4
    6
    3
    Arthralgia
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 44 (2.27%)
    7 / 46 (15.22%)
    1 / 47 (2.13%)
         occurrences all number
    1
    1
    11
    1
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    3 / 45 (6.67%)
    1 / 44 (2.27%)
    1 / 46 (2.17%)
    2 / 47 (4.26%)
         occurrences all number
    3
    1
    1
    2
    Nasopharyngitis
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 44 (0.00%)
    2 / 46 (4.35%)
    4 / 47 (8.51%)
         occurrences all number
    2
    0
    2
    6
    Influenza
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 44 (0.00%)
    0 / 46 (0.00%)
    3 / 47 (6.38%)
         occurrences all number
    1
    0
    0
    3
    COVID-19
         subjects affected / exposed
    4 / 45 (8.89%)
    5 / 44 (11.36%)
    5 / 46 (10.87%)
    9 / 47 (19.15%)
         occurrences all number
    4
    5
    6
    11
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 44 (0.00%)
    4 / 46 (8.70%)
    5 / 47 (10.64%)
         occurrences all number
    2
    0
    4
    5
    Decreased appetite
         subjects affected / exposed
    3 / 45 (6.67%)
    0 / 44 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
         occurrences all number
    3
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Mar 2021
    Amendment 1: Data Monitoring Committee (DMC) was changed from the Sponsor’s siDMC to an eDMC.
    24 Jun 2021
    Amendment 2: Enhanced operational efficiency of the study
    30 Nov 2021
    Amendment 3: Expanded the participant population to include premenopausal women
    24 Jun 2022
    Amendment 4: Modified the Interim Analysis (IA) futility criterion
    07 Sep 2022
    Amendment 5: Harmonized follow-up safety monitoring of all study participants through Week 64

    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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