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    Clinical Trial Results:
    A Phase III, Open-Label Clinical Trial to Study the Efficacy and Safety of the Combination Regimen of MK-5172/MK-8742 versus Sofosbuvir/Pegylated Interferon/Ribavirin (PR) in Treatment-Naïve and PR Prior Treatment Failure Subjects with Chronic HCV GT1, 4 or 6 Infection

    Summary
    EudraCT number
    		 2014-003836-38
    Trial protocol
    		 CZ   LT   ES   NO   HU   DK   PL  
    Global end of trial date
    16 Feb 2016

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

    Trial information

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    Trial identification
    Sponsor protocol code
    5172-077
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02358044
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., 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
    16 Feb 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a study comparing grazoprevir (MK-5172) plus elbasvir (MK-8742) treatment with sofosbuvir (SOF) plus Pegylated Interferon plus Ribavirin (RBV) [PR] treatment in treatment-naïve and prior PR treatment failure participants with chronic Hepatitis C Virus (HCV) genotype (GT)1, GT4, or GT6 infection. The primary objectives are to compare efficacy (assessed by the percentage of participants achieving sustained virologic response 12 weeks after ending study treatment [SVR12]) and safety between grazoprevir plus elbasvir and SOF plus PR treatment arms. The primary hypothesis is that the percentage of participants achieving SVR12 in the grazoprevir plus elbasvir arm is non-inferior to that in the SOF plus PR arm.
    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
    27 Feb 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Czech Republic: 40
    Country: Number of subjects enrolled
    Denmark: 6
    Country: Number of subjects enrolled
    Hungary: 37
    Country: Number of subjects enrolled
    Lithuania: 38
    Country: Number of subjects enrolled
    Norway: 11
    Country: Number of subjects enrolled
    Poland: 45
    Country: Number of subjects enrolled
    Romania: 39
    Country: Number of subjects enrolled
    Spain: 21
    Country: Number of subjects enrolled
    Turkey: 20
    Worldwide total number of subjects
    257
    EEA total number of subjects
    237
    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)
    239
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 257 participants were randomized to treatment: 129 to Grazoprevir + Elbasvir arm and 128 to Sofosbuvir plus Pegylated Interferon/Ribavirin (SOF + PR) arm. Two participants in the SOF + PR arm withdrew from study prior to treatment.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Grazoprevir + Elbasvir
    Arm description
    		 Participants receive a fixed-dose combination (FDC) tablet of 100 mg grazoprevir and 50 mg elbasvir for 12 weeks, followed by 24 weeks of follow-up.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Grazoprevir + Elbasvir (100 mg/50 mg) Fixed Dose Combination (FDC)
    Investigational medicinal product code
    Other name
    MK-5172A
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    FDC (100 mg/50 mg) taken orally (PO) every day (QD) for 12 weeks.

    Arm title
    		 SOF + PR
    Arm description
    		 Participants receive SOF (400 mg) combined with PegIntron (1.5 mcg/kg) plus RBV (1000-1200 mg weight-based dose) for 12 weeks, followed by 24 weeks of follow-up.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sofosbuvir
    Investigational medicinal product code
    Other name
    Sovaldi
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg tablets taken PO QD for 12 weeks.

    Investigational medicinal product name
    Pegylated interferon alfa-2b
    Investigational medicinal product code
    Other name
    PegIntron™
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    PegIntron™ administered as a subcutaneous (SC) injection every week (QW) at 1.5 μg/kg for 12 weeks.

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Rebetol™
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Capsule and/or tablet administered PO twice daily (BID) based on weight (1000 - 1200 mg) for 12 weeks.

    Number of subjects in period 1
    		Grazoprevir + Elbasvir SOF + PR
    Started
    129
    128
    Treated
    129
    126
    Completed
    127
    121
    Not completed
    2
    7
         Consent withdrawn by subject
    -
    4
         Physician decision
    -
    1
         Adverse event, non-fatal
    -
    1
         Lost to follow-up
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Grazoprevir + Elbasvir
    Reporting group description
    		 Participants receive a fixed-dose combination (FDC) tablet of 100 mg grazoprevir and 50 mg elbasvir for 12 weeks, followed by 24 weeks of follow-up.

    Reporting group title
    SOF + PR
    Reporting group description
    		 Participants receive SOF (400 mg) combined with PegIntron (1.5 mcg/kg) plus RBV (1000-1200 mg weight-based dose) for 12 weeks, followed by 24 weeks of follow-up.

    Reporting group values
    		 Grazoprevir + Elbasvir SOF + PR Total
    Number of subjects
    		 129 128 257
    Age categorical
    Units: Subjects
    Age Continuous
    All Randomized Participants
    Units: years
        arithmetic mean (standard deviation)
    		 47.6 ( 12.4 ) 48.4 ( 12.4 ) -
    Gender, Male/Female
    All Randomized Participants
    Units: Subjects
        Female
    		 74 64 138
        Male
    		 55 64 119

    End points

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    End points reporting groups
    Reporting group title
    Grazoprevir + Elbasvir
    Reporting group description
    		 Participants receive a fixed-dose combination (FDC) tablet of 100 mg grazoprevir and 50 mg elbasvir for 12 weeks, followed by 24 weeks of follow-up.

    Reporting group title
    SOF + PR
    Reporting group description
    		 Participants receive SOF (400 mg) combined with PegIntron (1.5 mcg/kg) plus RBV (1000-1200 mg weight-based dose) for 12 weeks, followed by 24 weeks of follow-up.

    Primary: Primary: Percentage of participants achieving Sustained Virologic Response at 12 Weeks after the end of all treatment (SVR12)

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    End point title
    		 Primary: Percentage of participants achieving Sustained Virologic Response at 12 Weeks after the end of all treatment (SVR12)
    End point description
    Hepatitis C Virus ribonucleic acid (HCV-RNA) levels in plasma were measured using the Roche COBAS®AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 on blood samples drawn from each participant. SVR12 was defined as HCV RNA below the lower limit of quantification (<LLOQ) at 12 weeks after the end of all study therapy. The primary efficacy hypothesis for this study was that the percentage of participants achieving SVR12 in the grazoprevir plus elbasvir arm was non-inferior to the percentage in the SOF plus PR arm. A secondary statistical analysis was performed to determine whether the percentage of participants achieving SVR12 in the grazoprevir plus elbasvir arm was superior to the percentage in the SOF plus PR arm.
    End point type
    Primary
    End point timeframe
    12 weeks after end of all therapy (Study Week 24)
    End point values
    		 Grazoprevir + Elbasvir SOF + PR
    Number of subjects analysed
    129
    126 [1]
    Units: percentage of participants
        number (not applicable)
    99.2
    90.5
    Notes
    [1] - 2 participants withdrew from study prior to treatment and were excluded from analysis.
    Statistical analysis title
    		 Non-Inferiority Efficacy Analyses: SVR12
    Statistical analysis description
    Primary Analysis Approach: Non-Inferiority Analyses of the percentage of participants achieving SVR12 was conducted using the Miettinen & Nurminen (M&N) method. The analysis was adjusted for genotype (1a vs. non-1a) and fibrosis stage (cirrhotic vs. non-cirrhotic). The adjusted differences (grazoprevir+elbasvir arm minus SOF+PR arm) in percentages along with the corresponding 95% confidence intervals (CIs) and p-values were provided.
    Comparison groups
    Grazoprevir + Elbasvir v SOF + PR
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    P-value
    		 < 0.001
    Method
    		 Miettinen & Nurminen Method
    Parameter type
    		 Adjusted Difference in Percentage
    Point estimate
    8.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.6
         upper limit
    		 15.3
    Notes
    [2] - The lower bound of 95% CIs was compared to pre-specified non-inferiority margin, -10% to evaluate non-inferiority. The Missing=Failure (M=F) approach was used to handle missing values.
    Statistical analysis title
    		 Superiority Efficacy Analysis: SVR12
    Statistical analysis description
    Secondary Analysis Approach: Superiority Analyses of the percentage of participants achieving SVR12 was conducted using the M&N method. The analysis was adjusted for genotype (1a vs. non-1a) and fibrosis stage (cirrhotic vs. non-cirrhotic). The adjusted differences (grazoprevir +elbasvir arm minus SOF+PR arm) in percentages along with the corresponding 95% CIs and p-values were provided.
    Comparison groups
    Grazoprevir + Elbasvir v SOF + PR
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.001
    Method
    		 Miettinen & Nurminen Method
    Parameter type
    		 Adjusted Difference in Percentage
    Point estimate
    8.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.6
         upper limit
    		 15.3

    Primary: Percentage of participants experiencing at least one adverse event (AE) during the treatment period plus first 14 follow-up days

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    End point title
    		 Percentage of participants experiencing at least one adverse event (AE) during the treatment period plus first 14 follow-up days
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that was temporally associated with the use of the Sponsor’s product, was also an AE. The percentage of participants who experienced at least one AE was reported for each treatment arm.
    End point type
    Primary
    End point timeframe
    Treatment + First 14 days of follow-up (Up to Week 14)
    End point values
    		 Grazoprevir + Elbasvir SOF + PR
    Number of subjects analysed
    129
    126 [3]
    Units: percentage of participants
        number (not applicable)
    51.9
    93.7
    Notes
    [3] - 2 participants withdrew from study prior to treatment and were excluded from analysis.
    Statistical analysis title
    		 Primary Safety Analysis: Tier 2 AEs
    Statistical analysis description
    The percentage of participants with an event were assessed via point estimates with 95% CIs provided for between-group comparisons.
    Comparison groups
    Grazoprevir + Elbasvir v SOF + PR
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    -41.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -51.1
         upper limit
    		 -31.9

    Primary: Percentage of participants discontinuing study treatment due to an AE

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    End point title
    		 Percentage of participants discontinuing study treatment due to an AE [4]
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which did not necessarily have a causal relationship with this treatment. An AE could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that was temporally associated with the use of the Sponsor’s product, was also an AE. The percentage of participants who discontinued study treatment due to an AE was reported for each treatment arm. Participants that discontinued study drug treatment due to an AE may have still continued on trial.
    End point type
    Primary
    End point timeframe
    Up to Week 12
    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 between-group statistical comparison was planned for this endpoint.
    End point values
    		 Grazoprevir + Elbasvir SOF + PR
    Number of subjects analysed
    129
    126 [5]
    Units: percentage of participants
        number (not applicable)
    0.8
    0.8
    Notes
    [5] - 2 participants withdrew from study prior to treatment and were excluded from analysis.
    No statistical analyses for this end point

    Secondary: Percentage of participants experiencing at least one Tier 1 safety event (key safety parameter) during the treatment period and first 14 follow-up days

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    End point title
    		 Percentage of participants experiencing at least one Tier 1 safety event (key safety parameter) during the treatment period and first 14 follow-up days
    End point description
    Tier 1 safety events were pre-specified by the protocol to evaluate safety and test the safety superiority hypothesis. Tier 1 safety events were chosen to assess broad tolerability, hematological side effects and liver-related laboratory abnormalities. For this study, Tier 1 safety events included: any serious drug-related AE, any drug-related AE leading to permanent discontinuation (DC) of all study drugs, neutrophil count <0.75 x 10^9/L, hemoglobin <10 g/dL, severe depression, hepatic events of clinical interest (defined by abnormal increases in alanine aminotransferase [ALT], aspartate aminotransferase [AST], or alkaline phosphatase [ALP]), or events meeting stopping rule criteria for DC from trial (due to abnormal increases of ALT, AST, or ALP with/without pre-specified related AEs). The percentage of participants who experienced each individual event that was defined as a Tier 1 safety event during the study treatment period was reported for each treatment arm.
    End point type
    Secondary
    End point timeframe
    Treatment + First 14 days of follow-up (Up to Week 14)
    End point values
    		 Grazoprevir + Elbasvir SOF + PR
    Number of subjects analysed
    129
    126 [6]
    Units: percentage of participants
    number (not applicable)
        Total Tier 1 AEs
    0.8
    27.8
        Tier 1 AE: Serious drug-related AE
    0
    2.4
        Tier 1 AE: DC due to drug-related AE
    0
    0.8
        Tier 1 AE: Neutrophil count <0.75 x 10^9/L
    0
    12.7
        Tier 1 AE: Hemoglobin <10 g/dL
    0.8
    14.3
        Tier 1 AE: Severe depression
    0
    0
        Tier 1 AE: Hepatic event of clinical interest
    0
    0
        Tier 1 AE: Trial DC due to stopping rule
    0
    0
    Notes
    [6] - 2 participants withdrew from study prior to treatment and were excluded from analysis.
    Statistical analysis title
    		 Total Tier 1 AEs
    Statistical analysis description
    Total Tier 1 AEs: If, and only if the primary efficacy null hypothesis was rejected, the Tier 1 safety superiority hypothesis was tested at the 2-sided 5% alpha level. The safety superiority hypothesis was that the percentage of grazoprevir+elbasvir participants with ≥1 Tier 1 event is lower than the percentage of SOF+PR participants with ≥1 Tier 1 event.
    Comparison groups
    Grazoprevir + Elbasvir v SOF + PR
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001 [7]
    Method
    		 Miettinen & Nurminen Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    -27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -35.5
         upper limit
    		 -19.6
    Notes
    [7] - % of participants with ≥1 Tier 1 event = total number participants with ≥1 Tier 1 event ÷ total number ASaT participants within each treatment arm. M&N method used to calculate a 2-sided 95% CI for the treatment difference and corresponding p-value.
    Statistical analysis title
    		 Serious drug-related AEs
    Statistical analysis description
    Serious drug-related AEs: If, and only if the primary efficacy null hypothesis was rejected, the Tier 1 safety superiority hypothesis was tested at the 2-sided 5% alpha level. The safety superiority hypothesis was that the percentage of grazoprevir+elbasvir participants with ≥1 Tier 1 event is lower than the percentage of SOF+PR participants with ≥1 Tier 1 event.
    Comparison groups
    Grazoprevir + Elbasvir v SOF + PR
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.078 [8]
    Method
    		 Miettinen & Nurminen Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    -2.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.8
         upper limit
    		 0.6
    Notes
    [8] - % of participants with ≥1 Tier 1 event = total number participants with ≥1 Tier 1 event ÷ total number ASaT participants within each treatment arm. M&N method used to calculate a 2-sided 95% CI for the treatment difference and corresponding p-value.
    Statistical analysis title
    		 DC due to drug-related AE
    Statistical analysis description
    DC due to drug-related AE: If, and only if the primary efficacy null hypothesis was rejected, the Tier 1 safety superiority hypothesis was tested at the 2-sided 5% alpha level. The safety superiority hypothesis was that the percentage of grazoprevir+elbasvir participants with ≥1 Tier 1 event is lower than the percentage of SOF+PR participants with ≥1 Tier 1 event.
    Comparison groups
    Grazoprevir + Elbasvir v SOF + PR
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.312 [9]
    Method
    		 Miettinen & Nurminen Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    -0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.4
         upper limit
    		 2.1
    Notes
    [9] - % of participants with ≥1 Tier 1 event = total number participants with ≥1 Tier 1 event ÷ total number ASaT participants within each treatment arm. M&N method used to calculate a 2-sided 95% CI for the treatment difference and corresponding p-value.
    Statistical analysis title
    		 Neutrophil count <0.75 x 10^9/L
    Statistical analysis description
    Neutrophil count <0.75 x 10^9/L: If, and only if the primary efficacy null hypothesis was rejected, the Tier 1 safety superiority hypothesis was tested at the 2-sided 5% alpha level. The safety superiority hypothesis was that the percentage of grazoprevir+elbasvir participants with ≥1 Tier 1 event is lower than the percentage of SOF+PR participants with ≥1 Tier 1 event.
    Comparison groups
    Grazoprevir + Elbasvir v SOF + PR
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001 [10]
    Method
    		 Miettinen & Nurminen Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    -12.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.7
         upper limit
    		 -8
    Notes
    [10] - % of participants with ≥1 Tier 1 event = total number participants with ≥1 Tier 1 event ÷ total number ASaT participants within each treatment arm. M&N method used to calculate a 2-sided 95% CI for the treatment difference and corresponding p-value.
    Statistical analysis title
    		 Hemoglobin <10 g/dL
    Statistical analysis description
    Hemoglobin <10 g/dL: If, and only if the primary efficacy null hypothesis was rejected, the Tier 1 safety superiority hypothesis was tested at the 2-sided 5% alpha level. The safety superiority hypothesis was that the percentage of grazoprevir+elbasvir participants with ≥1 Tier 1 event is lower than the percentage of SOF+PR participants with ≥1 Tier 1 event.
    Comparison groups
    Grazoprevir + Elbasvir v SOF + PR
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.001 [11]
    Method
    		 Miettinen & Nurminen Method
    Parameter type
    		 Difference in Percentage
    Point estimate
    -13.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.8
         upper limit
    		 -7.9
    Notes
    [11] - % of participants with ≥1 Tier 1 event = total number participants with ≥1 Tier 1 event ÷ total number ASaT participants within each treatment arm. M&N method used to calculate a 2-sided 95% CI for the treatment difference and corresponding p-value.

    Secondary: Percentage of participants achieving sustained virologic response 24 weeks after ending study treatment (SVR24)

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    End point title
    		 Percentage of participants achieving sustained virologic response 24 weeks after ending study treatment (SVR24)
    End point description
    HCV-RNA levels in plasma were measured using the Roche COBAS®AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 on blood samples drawn from each participant. SVR24 was defined as HCV RNA <LLOQ at 24 weeks after the end of all study therapy.
    End point type
    Secondary
    End point timeframe
    24 weeks after end of all therapy (Study Week 36)
    End point values
    		 Grazoprevir + Elbasvir SOF + PR
    Number of subjects analysed
    129
    126 [12]
    Units: percentage of participants
        number (not applicable)
    98.4
    89.7
    Notes
    [12] - 2 participants withdrew from study prior to treatment and were excluded from analysis.
    Statistical analysis title
    		 SVR24
    Statistical analysis description
    Analyses of the percentage of participants achieving SVR24 was conducted using the Miettinen & Nurminen (M&N) method. The analysis was adjusted for genotype (1a vs. non-1a) and fibrosis stage (cirrhotic vs. non-cirrhotic). The adjusted differences (grazoprevir+elbasvir arm minus SOF+PR arm) in percentages along with the corresponding 95% confidence intervals (CIs) and p-values were provided.
    Comparison groups
    Grazoprevir + Elbasvir v SOF + PR
    Number of subjects included in analysis
    255
    Analysis specification
    Pre-specified
    Analysis type
    		 [13]
    Method
    		 Miettinen & Nurminen Method
    Parameter type
    		 Adjusted Difference in Percentage
    Point estimate
    8.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.3
         upper limit
    		 15.7
    Notes
    [13] - The lower bound of 95% CIs was compared to pre-specified non-inferiority margin, -10% to evaluate non-inferiority. The Missing=Failure (M=F) approach was used to handle missing values.

    Secondary: Percentage of participants achieving sustained virologic response 4 weeks after ending study treatment (SVR4)

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    End point title
    		 Percentage of participants achieving sustained virologic response 4 weeks after ending study treatment (SVR4)
    End point description
    HCV-RNA levels in plasma were measured using the Roche COBAS®AmpliPrep/COBAS® TaqMan® HCV Test, v2.0 on blood samples drawn from each participant. SVR4 was defined as HCV RNA <LLOQ at 4 weeks after the end of all study therapy.
    End point type
    Secondary
    End point timeframe
    4 weeks after end of all therapy (Study Week 16)
    End point values
    		 Grazoprevir + Elbasvir SOF + PR
    Number of subjects analysed
    129
    126 [14]
    Units: percentage of participants
        number (confidence interval 95%)
    99.2 (95.8 to 100)
    92.1 (85.9 to 96.1)
    Notes
    [14] - 2 participants withdrew from study prior to treatment and were excluded from analysis.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to Follow-up Week 24
    Adverse event reporting additional description
    ASaT population; all randomized participants who received at least one dose of study treatment. Two randomized participants in the SOF + PR arm withdrew from study prior to treatment and were excluded from analysis.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Grazoprevir + Elbasvir
    Reporting group description
    		 Participants receive a fixed-dose combination (FDC) tablet of 100 mg grazoprevir and 50 mg elbasvir for 12 weeks, followed by 24 weeks of follow-up.

    Reporting group title
    SOF + PR
    Reporting group description
    		 Participants receive SOF (400 mg) combined with PegIntron (1.5 mcg/kg) plus RBV (1000-1200 mg weight-based dose) for 12 weeks, followed by 24 weeks of follow-up.

    Serious adverse events
    		 Grazoprevir + Elbasvir SOF + PR
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 129 (0.78%)
    6 / 126 (4.76%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Proctitis
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Drug dependence
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infection
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proctitis infectious
         subjects affected / exposed
    0 / 129 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    1 / 129 (0.78%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Grazoprevir + Elbasvir SOF + PR
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    44 / 129 (34.11%)
    114 / 126 (90.48%)
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    0 / 129 (0.00%)
    8 / 126 (6.35%)
         occurrences all number
    0
    12
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 129 (3.10%)
    7 / 126 (5.56%)
         occurrences all number
    5
    10
    Headache
         subjects affected / exposed
    17 / 129 (13.18%)
    50 / 126 (39.68%)
         occurrences all number
    31
    97
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 129 (0.78%)
    15 / 126 (11.90%)
         occurrences all number
    1
    15
    Neutropenia
         subjects affected / exposed
    0 / 129 (0.00%)
    11 / 126 (8.73%)
         occurrences all number
    0
    15
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    8 / 129 (6.20%)
    30 / 126 (23.81%)
         occurrences all number
    10
    36
    Chills
         subjects affected / exposed
    2 / 129 (1.55%)
    21 / 126 (16.67%)
         occurrences all number
    4
    27
    Fatigue
         subjects affected / exposed
    9 / 129 (6.98%)
    32 / 126 (25.40%)
         occurrences all number
    9
    48
    Influenza like illness
         subjects affected / exposed
    1 / 129 (0.78%)
    23 / 126 (18.25%)
         occurrences all number
    1
    40
    Pyrexia
         subjects affected / exposed
    2 / 129 (1.55%)
    68 / 126 (53.97%)
         occurrences all number
    2
    191
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    1 / 129 (0.78%)
    8 / 126 (6.35%)
         occurrences all number
    1
    10
    Nausea
         subjects affected / exposed
    8 / 129 (6.20%)
    13 / 126 (10.32%)
         occurrences all number
    9
    23
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 129 (0.00%)
    13 / 126 (10.32%)
         occurrences all number
    0
    27
    Dyspnoea
         subjects affected / exposed
    3 / 129 (2.33%)
    10 / 126 (7.94%)
         occurrences all number
    3
    10
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 129 (0.78%)
    18 / 126 (14.29%)
         occurrences all number
    1
    18
    Pruritus
         subjects affected / exposed
    2 / 129 (1.55%)
    8 / 126 (6.35%)
         occurrences all number
    2
    9
    Psychiatric disorders
    Irritability
         subjects affected / exposed
    0 / 129 (0.00%)
    10 / 126 (7.94%)
         occurrences all number
    0
    11
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 129 (3.88%)
    14 / 126 (11.11%)
         occurrences all number
    5
    25
    Back pain
         subjects affected / exposed
    3 / 129 (2.33%)
    8 / 126 (6.35%)
         occurrences all number
    4
    8
    Myalgia
         subjects affected / exposed
    4 / 129 (3.10%)
    19 / 126 (15.08%)
         occurrences all number
    6
    47
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 129 (0.78%)
    16 / 126 (12.70%)
         occurrences all number
    1
    16

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Jun 2015
    Protocol amendment 1 (AM1) made several revisions to the Inclusion Criteria, Trial Design, Rationale for Dose Selection/Regimen, Trial Flow Chart footnotes, Future Biomedical Research, Assessing and Recording AEs, and Definition of Overdose sections.
    26 Nov 2015
    AM2 added language for reporting pregnancy of a male participant’s female partner and clarified a footnote to the Trial Flow Chart regarding dosing.

    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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