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    Clinical Trial Results:
    A Phase III Open-Label Clinical Trial to Study the Efficacy and Safety of the Combination Regimen Grazoprevir (GZR) and Elbasvir (EBR) in Treatment-Naïve Subjects with Chronic HCV GT1, GT4, and GT6 Infection who are Co-Infected with HIV

    Summary
    EudraCT number
    2014-000342-30
    Trial protocol
    DK   ES  
    Global end of trial date
    22 May 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    26 Feb 2016
    First version publication date
    26 Feb 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    5172-061
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02105662
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    MK-5172-061: Merck Registration
    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
    22 May 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 May 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to assess the efficacy and safety of grazoprevir (MK-5172) 100 mg in combination with elbasvir (MK-8742) 50 mg in the treatment of chronic hepatitis C virus (HCV) in participants who are co-infected with human immunodeficiency virus (HIV). The primary hypothesis is that the percentage of participants who receive grazoprevir + elbasvir and achieve Sustained Virologic Response after 12 weeks of therapy (SVR12) will be greater than 70%.
    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
    03 Jun 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy
    Long term follow-up duration
    3 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 13
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Denmark: 18
    Country: Number of subjects enrolled
    France: 26
    Country: Number of subjects enrolled
    Germany: 16
    Country: Number of subjects enrolled
    Israel: 6
    Country: Number of subjects enrolled
    Spain: 28
    Country: Number of subjects enrolled
    United Kingdom: 19
    Country: Number of subjects enrolled
    United States: 83
    Worldwide total number of subjects
    218
    EEA total number of subjects
    107
    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)
    212
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    218 participants were enrolled and treated on study, 212 participants completed 24 weeks of follow-up.

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

    Arms
    Arm title
    Grazoprevir+Elbasvir
    Arm description
    Participants received a fixed-dose combination (FDC) of grazoprevir 100 mg plus elbasvir 50 mg once daily for 12 weeks and were followed-up for 24 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Grazoprevir 100 mg/Elbasvir 50 mg fixed-dose combination (FDC) tablet
    Investigational medicinal product code
    Other name
    MK-5172A
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MK5172A FDC tablet: MK5172 (100 mg)/MK8742 (50 mg)

    Number of subjects in period 1
    Grazoprevir+Elbasvir
    Started
    218
    Completed
    212
    Not completed
    6
         Consent withdrawn by subject
    1
         Lost to follow-up
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Grazoprevir+Elbasvir
    Reporting group description
    Participants received a fixed-dose combination (FDC) of grazoprevir 100 mg plus elbasvir 50 mg once daily for 12 weeks and were followed-up for 24 weeks.

    Reporting group values
    Grazoprevir+Elbasvir Total
    Number of subjects
    218
    Age categorical
    Units: Subjects
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    48.7 ± 8.9 -
    Gender, Male/Female
    Units: participants
        Female
    35 35
        Male
    183 183

    End points

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    End points reporting groups
    Reporting group title
    Grazoprevir+Elbasvir
    Reporting group description
    Participants received a fixed-dose combination (FDC) of grazoprevir 100 mg plus elbasvir 50 mg once daily for 12 weeks and were followed-up for 24 weeks.

    Primary: Percentage of participants achieving Sustained Virologic Response 12 weeks after the end of all study therapy (SVR12)

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    End point title
    Percentage of participants achieving Sustained Virologic Response 12 weeks after the end of all study therapy (SVR12) [1]
    End point description
    Blood was drawn from each participant to assess Hepatitis C Virus ribonucleic acid (HCV RNA) plasma levels using the Roche COBAS™ Taqman™ HCV Test, v2.0 (High Pure System). The Roche COBAS Taqman HCV Test, v2.0 assay (High Pure System) had a lower limit of quantification of 15 IU/mL and a limit of detection of 9.3 IU/mL (in plasma). SVR12 was defined as HCV RNA less than the Lower Limit of Quantitation (<LLOQ) at 12 weeks after the end of all study therapy.
    End point type
    Primary
    End point timeframe
    12 weeks after end of all therapy (Study 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: "There was no statistical analysis performed on the updated SVR12 data."
    End point values
    Grazoprevir+Elbasvir
    Number of subjects analysed
    218 [2]
    Units: percentage of participants
        number (confidence interval 95%)
    96.3 (92.9 to 98.4)
    Notes
    [2] - Full Analysis Set (FAS); all allocated participants who received ≥1 dose of study treatment.
    No statistical analyses for this end point

    Primary: Percentage of participants experiencing adverse events (AEs) during the treatment period and first 14 follow-up days

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    End point title
    Percentage of participants experiencing adverse events (AEs) during the treatment period and first 14 follow-up days [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. An AE can 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 (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor’s product, is also an AE.
    End point type
    Primary
    End point timeframe
    Treatment Period plus first 14 follow-up days (up to 14 weeks)
    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: No formal hypothesis testing was planned for this safety endpoint, and there were no between-group statistical comparisons performed in this single-arm study.
    End point values
    Grazoprevir+Elbasvir
    Number of subjects analysed
    218 [4]
    Units: percentage of participants
        number (confidence interval 95%)
    73.9 (67.5 to 79.6)
    Notes
    [4] - All Subjects as Treated (ASaT) Population; participants who received ≥1 dose of study treatment.
    No statistical analyses for this end point

    Primary: Percentage of participants discontinuing study therapy due to AEs during the treatment period

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    End point title
    Percentage of participants discontinuing study therapy due to AEs during the treatment period [5]
    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. An AE can 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 (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition that is temporally associated with the use of the Sponsor’s product, is also an AE.
    End point type
    Primary
    End point timeframe
    Treatment Period (up to 12 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 formal hypothesis testing was planned for this safety endpoint, and there were no between-group statistical comparisons performed in this single-arm study.
    End point values
    Grazoprevir+Elbasvir
    Number of subjects analysed
    218 [6]
    Units: percentage of participants
        number (confidence interval 95%)
    0 (0 to 1.7)
    Notes
    [6] - ASaT Population; all participants who received ≥1 dose of study treatment.
    No statistical analyses for this end point

    Secondary: Percentage of participants achieving Sustained Virologic Response 24 weeks after the end of all study therapy (SVR24)

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    End point title
    Percentage of participants achieving Sustained Virologic Response 24 weeks after the end of all study therapy (SVR24)
    End point description
    Blood was drawn from each participant to assess HCV RNA plasma levels using the Roche COBAS™ Taqman™ HCV Test, v2.0 (High Pure System). The Roche COBAS Taqman HCV Test, v2.0 assay (High Pure System) had a lower limit of quantification of 15 IU/mL and a limit of detection of 9.3 IU/mL (in plasma). 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
    Number of subjects analysed
    218 [7]
    Units: percentage of participants
        number (confidence interval 95%)
    93.1 (88.9 to 96.1)
    Notes
    [7] - FAS; all allocated participants who received ≥1 dose of study treatment.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12 week treatment period plus 24 week follow-up period (up to 36 weeks)
    Adverse event reporting additional description
    ASaT Population; all participants who received at least one dose of study treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Grazoprevir + Elbasvir
    Reporting group description
    Participants received a FDC of grazoprevir 100 mg plus elbasvir 50 mg once daily for 12 weeks and were followed-up for 24 weeks.

    Serious adverse events
    Grazoprevir + Elbasvir
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 218 (3.67%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Ulna fracture
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Squamous cell carcinoma of the tongue
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Acute psychosis
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 218 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Grazoprevir + Elbasvir
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    106 / 218 (48.62%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    27 / 218 (12.39%)
         occurrences all number
    33
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    29 / 218 (13.30%)
         occurrences all number
    31
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    16 / 218 (7.34%)
         occurrences all number
    16
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    11 / 218 (5.05%)
         occurrences all number
    11
    Diarrhoea
         subjects affected / exposed
    18 / 218 (8.26%)
         occurrences all number
    19
    Nausea
         subjects affected / exposed
    20 / 218 (9.17%)
         occurrences all number
    20
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    14 / 218 (6.42%)
         occurrences all number
    14
    Upper respiratory tract infection
         subjects affected / exposed
    17 / 218 (7.80%)
         occurrences all number
    18

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jun 2014
    Protocol amendment 1 (AM1) added urinalysis to specified study visits and revised some eligibility criteria for HIV-co-infected participants.
    08 Sep 2014
    AM2 indicated that participants infected with HCV GT5 were no longer eligible for enrollment.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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