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    Clinical Trial Results:
    A Multi-Site, Open-Label, Partially Randomized Trial of the Efficacy and Safety of Fixed Dose Elbasvir/Grazoprevir (EBR/GZR) Based Regimens in French Subjects with Chronic Hepatitis C Virus (HCV) Genotype 4 Infection

    Summary
    EudraCT number
    		 2016-001159-37
    Trial protocol
    		 FR  
    Global end of trial date
    15 Oct 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    29 Nov 2019
    First version publication date
    04 Oct 2019
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    MK-5172-096
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03111108
    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
    15 Oct 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study was to evaluate the efficacy of 8 and 12 weeks of treatment with a fixed dose combination (FDC) of elbasvir (EBR) 50 mg + grazoprevir (GZR) 100 mg (i.e., MK-5172A) as assessed by the percentage of participants with hepatitis C virus (HCV) genotype (GT) 4 infection that achieve sustained virologic response (HCV ribonucleic acid [RNA] < Lower Limit of Quantification [LLOQ]) 12 weeks after the end of study therapy (SVR12). This study also evaluated the safety and tolerability of EBR/GZR.
    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
    20 Jun 2017
    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
    France: 117
    Worldwide total number of subjects
    117
    EEA total number of subjects
    117
    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)
    102
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Adult male and female participants with chronic hepatitis C virus (HCV) genotype 4 (GT4) infection were enrolled at 12 study centers in France.

    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
    		 Arm 1: EBR/GZR for 8 Weeks
    Arm description
    		 Treatment-naïve HCV GT4 participants with stage 0-2 fibrosis (F0-F2) received elbasvir/grazoprevir (EBR/GZR) fixed dose combination (FDC) [50 mg/100 mg] for 8 weeks, followed by 24 weeks of follow-up.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Elbasvir/Grazoprevir 50 mg/100 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
    One EBR/GZR FDC tablet taken by mouth once daily.

    Arm title
    		 Arm 2: EBR/GZR for 12 Weeks
    Arm description
    		 Treatment-naïve HCV GT4 participants with F0-F2 stage fibrosis, treatment-naïve participants with F3-F4 stage fibrosis, and treatment-experienced participants with F0-F4 stage fibrosis received EBR/GZR FDC (50 mg/100 mg) for 12 weeks, followed by 24 weeks of follow-up.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Elbasvir/Grazoprevir 50 mg/100 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
    One EBR/GZR FDC tablet taken by mouth once daily.

    Number of subjects in period 1
    		Arm 1: EBR/GZR for 8 Weeks Arm 2: EBR/GZR for 12 Weeks
    Started
    53
    64
    Completed
    52
    63
    Not completed
    1
    1
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm 1: EBR/GZR for 8 Weeks
    Reporting group description
    		 Treatment-naïve HCV GT4 participants with stage 0-2 fibrosis (F0-F2) received elbasvir/grazoprevir (EBR/GZR) fixed dose combination (FDC) [50 mg/100 mg] for 8 weeks, followed by 24 weeks of follow-up.

    Reporting group title
    Arm 2: EBR/GZR for 12 Weeks
    Reporting group description
    		 Treatment-naïve HCV GT4 participants with F0-F2 stage fibrosis, treatment-naïve participants with F3-F4 stage fibrosis, and treatment-experienced participants with F0-F4 stage fibrosis received EBR/GZR FDC (50 mg/100 mg) for 12 weeks, followed by 24 weeks of follow-up.

    Reporting group values
    		 Arm 1: EBR/GZR for 8 Weeks Arm 2: EBR/GZR for 12 Weeks Total
    Number of subjects
    		 53 64 117
    Age categorical
    Units: Subjects
        Im Utero
    		 0 0 0
        Pre-term newborn - gestational age <37 weeks
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adults (18-64 years)
    		 46 56 102
        From 65-84 years
    		 7 8 15
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 51.5 ( 12.9 ) 56.0 ( 9.7 ) -
    Sex: Female, Male
    Units: Subjects
        Female
    		 29 32 61
        Male
    		 24 32 56
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 1 0 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 20 29 49
        White
    		 28 29 57
        More than one race
    		 1 0 1
        Unknown or Not Reported
    		 3 6 9

    End points

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    End points reporting groups
    Reporting group title
    Arm 1: EBR/GZR for 8 Weeks
    Reporting group description
    		 Treatment-naïve HCV GT4 participants with stage 0-2 fibrosis (F0-F2) received elbasvir/grazoprevir (EBR/GZR) fixed dose combination (FDC) [50 mg/100 mg] for 8 weeks, followed by 24 weeks of follow-up.

    Reporting group title
    Arm 2: EBR/GZR for 12 Weeks
    Reporting group description
    		 Treatment-naïve HCV GT4 participants with F0-F2 stage fibrosis, treatment-naïve participants with F3-F4 stage fibrosis, and treatment-experienced participants with F0-F4 stage fibrosis received EBR/GZR FDC (50 mg/100 mg) for 12 weeks, followed by 24 weeks of follow-up.

    Primary: Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After End of Treatment (SVR12)

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    End point title
    		 Percentage of Participants Achieving Sustained Virologic Response 12 Weeks After End of Treatment (SVR12) [1]
    End point description
    The percentage of participants to achieve SVR12 was determined for each arm (SVR12 was defined as HCV ribonucleic acid [RNA] < lower limit of quantification [LLOQ] at 12 weeks after the end of all study therapy). Plasma HCV RNA was measured using the COBAS™ AmpliPrep/COBAS™ TaqMan HCV Test, v2.0®, which has a LLOQ of 15 IU/mL. All randomized participants who received ≥1 dose of study treatment are included.
    End point type
    Primary
    End point timeframe
    12 weeks after completing study treatment (Arm 1: Week 20 / Arm 2: Week 24)
    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: Per protocol, only descriptive statistics are presented.
    End point values
    		 Arm 1: EBR/GZR for 8 Weeks Arm 2: EBR/GZR for 12 Weeks
    Number of subjects analysed
    53
    64
    Units: Percentage of Participants
        number (confidence interval 95%)
    94.3 (84.3 to 98.8)
    95.3 (86.9 to 99.0)
    No statistical analyses for this end point

    Primary: Number of Participants With ≥ 1 Adverse Events (AEs)

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    End point title
    		 Number of Participants With ≥ 1 Adverse Events (AEs) [2]
    End point description
    An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. All randomized participants who received ≥1 dose of study treatment are included, classified according to treatment duration actually received.
    End point type
    Primary
    End point timeframe
    Up to Week 14 (up to 14 days after completing treatment)
    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: Per protocol, only descriptive statistics are presented.
    End point values
    		 Arm 1: EBR/GZR for 8 Weeks Arm 2: EBR/GZR for 12 Weeks
    Number of subjects analysed
    53
    64
    Units: Number of Participants
    33
    46
    No statistical analyses for this end point

    Primary: Number of Participants Who Discontinued from Study Treatment Due to an AE

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    End point title
    		 Number of Participants Who Discontinued from Study Treatment Due to an AE [3]
    End point description
    An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. All randomized participants who received ≥1 dose of study treatment are included, classified according to treatment duration actually received.
    End point type
    Primary
    End point timeframe
    Up to Week 12
    Notes
    [3] - 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: Per protocol, only descriptive statistics are presented.
    End point values
    		 Arm 1: EBR/GZR for 8 Weeks Arm 2: EBR/GZR for 12 Weeks
    Number of subjects analysed
    53
    64
    Units: Number of Participants
    0
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After End of Treatment (SVR24)

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    End point title
    		 Percentage of Participants Achieving Sustained Virologic Response 24 Weeks After End of Treatment (SVR24)
    End point description
    The percentage of participants to achieve SVR24 was determined for each arm (SVR24 was defined as HCV RNA < LLOQ at 24 weeks after the end of all study therapy). Plasma HCV RNA was measured using the COBAS™ AmpliPrep/COBAS™ TaqMan HCV Test, v2.0®, which has a LLOQ of 15 IU/mL. All randomized participants who received ≥1 dose of study treatment are included.
    End point type
    Secondary
    End point timeframe
    24 weeks after completing study treatment (Arm 1: Week 32 / Arm 2: Week 36)
    End point values
    		 Arm 1: EBR/GZR for 8 Weeks Arm 2: EBR/GZR for 12 Weeks
    Number of subjects analysed
    53
    64
    Units: Percentage of Participants
        number (confidence interval 95%)
    94.3 (84.3 to 98.8)
    93.8 (84.8 to 98.3)
    No statistical analyses for this end point

    Secondary: Prevalence of Baseline NS3 Resistance-Associated Substitutions (RASs) to EBR or GZR

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    End point title
    		 Prevalence of Baseline NS3 Resistance-Associated Substitutions (RASs) to EBR or GZR
    End point description
    Blood samples for viral resistance assays were collected at Baseline (Day 1) and analyzed for substitutions in the NS3 gene region. Results are pooled for all participants with baseline sequencing data available, and the number of participants with RASs is reported according HCV genotype. Resistance-associated substitutions are defined as amino acid substitutions that confer reduced susceptibility to a direct-acting antiviral (DAA) and may contribute to virologic failure. The prevalence of baseline substitutions in participants infected with HCV GT4 subtypes was assessed by evaluating amino acid substitutions in NS3. All randomized participants with baseline sequencing data for NS3 are included.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Arm 1: EBR/GZR for 8 Weeks Arm 2: EBR/GZR for 12 Weeks
    Number of subjects analysed
    51
    59
    Units: Number of Participants
        GT4
    5
    6
        GT4d
    3
    3
        GT4-Other
    6
    9
    No statistical analyses for this end point

    Secondary: Prevalence of Baseline NS5A RASs to EBR or GZR

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    End point title
    		 Prevalence of Baseline NS5A RASs to EBR or GZR
    End point description
    Blood samples for viral resistance assays were collected at Baseline (Day 1) and analyzed for substitutions in the NS5A gene region. Results are pooled for all participants with baseline sequencing data available, and the number of participants with RASs is reported according HCV genotype. Resistance-associated substitutions are defined as amino acid substitutions that confer reduced susceptibility to a DAA and may contribute to virologic failure. The prevalence of baseline substitutions in participants infected with HCV GT4 subtypes was assessed by evaluating amino acid substitutions in NS5A. All randomized participants with baseline sequencing data for NS5A are included.
    End point type
    Secondary
    End point timeframe
    Day 1
    End point values
    		 Arm 1: EBR/GZR for 8 Weeks Arm 2: EBR/GZR for 12 Weeks
    Number of subjects analysed
    53
    63
    Units: Number of Participants
        GT4
    3
    2
        GT4d
    10
    16
        GT4-Other
    13
    21
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 36 weeks (up to 24 weeks after completing study treatment)
    Adverse event reporting additional description
    All participants who received ≥1 dose of study medication are included.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Arm 1: EBR/GZR for 8 Weeks
    Reporting group description
    		 Treatment-naïve HCV GT4 participants with stage 0-2 fibrosis (F0-F2) received EBR/GZR fixed dose combination (FDC) [50 mg/100 mg] for 8 weeks, followed by 24 weeks of follow-up.

    Reporting group title
    Arm 2: EBR/GZR for 12 Weeks
    Reporting group description
    		 Treatment-naïve HCV GT4 participants with F0-F2 stage fibrosis, treatment-naïve participants with F3-F4 stage fibrosis, and treatment-experienced participants with F0-F4 stage fibrosis received EBR/GZR FDC (50 mg/100 mg) for 12 weeks, followed by 24 weeks of follow-up.

    Serious adverse events
    		 Arm 1: EBR/GZR for 8 Weeks Arm 2: EBR/GZR for 12 Weeks
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 53 (3.77%)
    2 / 64 (3.13%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Nervous system disorders
    Cerebellar stroke
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Post procedural infection
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 64 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 64 (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
    		 Arm 1: EBR/GZR for 8 Weeks Arm 2: EBR/GZR for 12 Weeks
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 53 (50.94%)
    38 / 64 (59.38%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 64 (1.56%)
         occurrences all number
    4
    1
    Headache
         subjects affected / exposed
    9 / 53 (16.98%)
    16 / 64 (25.00%)
         occurrences all number
    10
    16
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    12 / 53 (22.64%)
    14 / 64 (21.88%)
         occurrences all number
    12
    14
    Fatigue
         subjects affected / exposed
    1 / 53 (1.89%)
    4 / 64 (6.25%)
         occurrences all number
    1
    4
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 53 (0.00%)
    4 / 64 (6.25%)
         occurrences all number
    0
    4
    Diarrhoea
         subjects affected / exposed
    3 / 53 (5.66%)
    3 / 64 (4.69%)
         occurrences all number
    4
    4
    Nausea
         subjects affected / exposed
    4 / 53 (7.55%)
    4 / 64 (6.25%)
         occurrences all number
    4
    5
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    2 / 53 (3.77%)
    4 / 64 (6.25%)
         occurrences all number
    2
    5
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 53 (3.77%)
    5 / 64 (7.81%)
         occurrences all number
    2
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 64 (1.56%)
         occurrences all number
    3
    1
    Back pain
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 64 (1.56%)
         occurrences all number
    3
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 53 (5.66%)
    1 / 64 (1.56%)
         occurrences all number
    3
    1
    Influenza
         subjects affected / exposed
    2 / 53 (3.77%)
    4 / 64 (6.25%)
         occurrences all number
    2
    4
    Nasopharyngitis
         subjects affected / exposed
    1 / 53 (1.89%)
    5 / 64 (7.81%)
         occurrences all number
    1
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Dec 2016
    AM01: The primary purpose of the amendment was to change the drug supply from 16-count bottles to 14-count blister cards.
    12 Dec 2016
    AM02: The primary purpose of this amendment was to correct typographical errors.
    26 Jan 2018
    AM03: The primary purpose of the amendment was to increase the target for enrollment of treatment-naïve participants.

    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
    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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