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    Clinical Trial Results:
    A Phase II Randomized, Dose Ranging, Clinical Trial to Evaluate the Safety, Tolerability, and Efficacy of Different Doses of MK-5172 When Administered Concomitantly with Peginterferon alfa-2b and Ribavirin in Treatment Naïve Subjects with Chronic Hepatitis C Virus Infection

    Summary
    EudraCT number
    		 2012-003333-42
    Trial protocol
    		 SE   GB  
    Global end of trial date
    29 Jan 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Mar 2016
    First version publication date
    25 Feb 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    5172-038
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01710501
    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
    29 Jan 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jan 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a study designed to compare the safety and efficacy of 3 different doses of grazoprevir (MK-5172) combined with pegylated interferon alfa-2b (Peg-IFN) and ribavirin (RBV) in treatment-naïve participants with genotype 1 chronic hepatitis. Participants will receive 12 weeks of treatment with grazoprevir combined with Peg-IFN and RBV, and depending on response at Week 4 may go on to receive an additional 12 weeks of treatment with Peg-IFN and RBV.
    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. The following additional measure defined for this individual study was in place for the protection of trial subjects: Boceprevir in combination with Peg-IFN and RBV as rescue therapy was offered (i.e. not mandatory) to any participant who met the virologic failure criterion of relapse. Participants were encouraged to start on rescue as soon as possible or within 4 months from the time of completing therapy for participants who did not achieve SVR12 or within 4 months from SVR12 for participants who did achieve SVR12.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Dec 2012
    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
    Sweden: 10
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    New Zealand: 4
    Country: Number of subjects enrolled
    United States: 56
    Worldwide total number of subjects
    87
    EEA total number of subjects
    18
    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)
    84
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Of 136 screened participants, 87 were randomized to treatment at 19 sites worldwide.

    Period 1
    Period 1 title
    Treatment Period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Grazoprevir 25 mg + PEG-IFN + RBV
    Arm description
    		 After a maximum of a 45 day screening window, randomized participants received 25 mg grazoprevir in combination with PEG-IFN and RBV for 12 weeks followed by 24 weeks of follow-up.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Grazoprevir
    Investigational medicinal product code
    Other name
    MK-5172
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg once daily (QD), 50 mg QD, or 100 mg QD depending on randomization, administered orally without regard to food.

    Investigational medicinal product name
    PEG-IFN
    Investigational medicinal product code
    Other name
    PegIntron
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1.5 μg/kg/week administered as weekly subcutaneous (SC) injection.

    Investigational medicinal product name
    RBV
    Investigational medicinal product code
    Other name
    Rebetol™
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Administered as twice-daily oral doses, at a total daily dose of 800 to 1400 mg based on the participant's weight on Day 1. Per product label, RBV was to be taken with food.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to match grazoprevir tablets to maintain dose blinding

    Arm title
    		 Grazoprevir 50 mg + PEG-IFN + RBV
    Arm description
    		 After a maximum of a 45 day screening window, randomized participants received 50 mg grazoprevir in combination with PEG-IFN and RBV for 12 weeks followed by 24 weeks of follow-up.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Grazoprevir
    Investigational medicinal product code
    Other name
    MK-5172
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg once daily (QD), 50 mg QD, or 100 mg QD depending on randomization, administered orally without regard to food.

    Investigational medicinal product name
    PEG-IFN
    Investigational medicinal product code
    Other name
    PegIntron
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1.5 μg/kg/week administered as weekly subcutaneous (SC) injection.

    Investigational medicinal product name
    RBV
    Investigational medicinal product code
    Other name
    Rebetol™
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Administered as twice-daily oral doses, at a total daily dose of 800 to 1400 mg based on the participant's weight on Day 1. Per product label, RBV was to be taken with food.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to match grazoprevir tablets to maintain dose blinding

    Arm title
    		 Grazoprevir 100 mg + PEG-IFN + RBV
    Arm description
    		 After a maximum of a 45 day screening window, randomized participants received 100 mg grazoprevir in combination with PEG-IFN and RBV for 12 weeks followed by 24 weeks of follow-up.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Grazoprevir
    Investigational medicinal product code
    Other name
    MK-5172
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg once daily (QD), 50 mg QD, or 100 mg QD depending on randomization, administered orally without regard to food.

    Investigational medicinal product name
    PEG-IFN
    Investigational medicinal product code
    Other name
    PegIntron
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    1.5 μg/kg/week administered as weekly subcutaneous (SC) injection.

    Investigational medicinal product name
    RBV
    Investigational medicinal product code
    Other name
    Rebetol™
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Administered as twice-daily oral doses, at a total daily dose of 800 to 1400 mg based on the participant's weight on Day 1. Per product label, RBV was to be taken with food.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to match grazoprevir tablets to maintain dose blinding

    Number of subjects in period 1
    		Grazoprevir 25 mg + PEG-IFN + RBV Grazoprevir 50 mg + PEG-IFN + RBV Grazoprevir 100 mg + PEG-IFN + RBV
    Started
    29
    28
    30
    Completed
    27
    28
    30
    Not completed
    2
    0
    0
         Lost to follow-up
    2
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Grazoprevir 25 mg + PEG-IFN + RBV
    Reporting group description
    		 After a maximum of a 45 day screening window, randomized participants received 25 mg grazoprevir in combination with PEG-IFN and RBV for 12 weeks followed by 24 weeks of follow-up.

    Reporting group title
    Grazoprevir 50 mg + PEG-IFN + RBV
    Reporting group description
    		 After a maximum of a 45 day screening window, randomized participants received 50 mg grazoprevir in combination with PEG-IFN and RBV for 12 weeks followed by 24 weeks of follow-up.

    Reporting group title
    Grazoprevir 100 mg + PEG-IFN + RBV
    Reporting group description
    		 After a maximum of a 45 day screening window, randomized participants received 100 mg grazoprevir in combination with PEG-IFN and RBV for 12 weeks followed by 24 weeks of follow-up.

    Reporting group values
    		 Grazoprevir 25 mg + PEG-IFN + RBV Grazoprevir 50 mg + PEG-IFN + RBV Grazoprevir 100 mg + PEG-IFN + RBV Total
    Number of subjects
    		 29 28 30 87
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52 ( 7.9 ) 48.5 ( 12.5 ) 46.4 ( 13.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 8 18 15 41
        Male
    		 21 10 15 46

    End points

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    End points reporting groups
    Reporting group title
    Grazoprevir 25 mg + PEG-IFN + RBV
    Reporting group description
    		 After a maximum of a 45 day screening window, randomized participants received 25 mg grazoprevir in combination with PEG-IFN and RBV for 12 weeks followed by 24 weeks of follow-up.

    Reporting group title
    Grazoprevir 50 mg + PEG-IFN + RBV
    Reporting group description
    		 After a maximum of a 45 day screening window, randomized participants received 50 mg grazoprevir in combination with PEG-IFN and RBV for 12 weeks followed by 24 weeks of follow-up.

    Reporting group title
    Grazoprevir 100 mg + PEG-IFN + RBV
    Reporting group description
    		 After a maximum of a 45 day screening window, randomized participants received 100 mg grazoprevir in combination with PEG-IFN and RBV for 12 weeks followed by 24 weeks of follow-up.

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

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    End point title
    		 Percentage of participants achieving Sustained Virologic Response (SVR) at 12 weeks (SVR12) after the end of treatment [1]
    End point description
    HCV RNA was measured using the Roche COBAS™ Taqman™ HCV Test, v2.0® assay, which has a lower limit of quantification of 25 IU/mL and a limit of detection of 9.3 IU/mL. SVR12 was defined as Hepatitis C Virus (HCV) ribonucleic acid (RNA) <25 IU/mL 12 weeks after the end of all study therapy.
    End point type
    Primary
    End point timeframe
    12 weeks after end of treatment (up to 36 weeks total)
    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 formal efficacy hypothesis testing conducted in this study.
    End point values
    		 Grazoprevir 25 mg + PEG-IFN + RBV Grazoprevir 50 mg + PEG-IFN + RBV Grazoprevir 100 mg + PEG-IFN + RBV
    Number of subjects analysed
    24 [2]
    25 [3]
    26 [4]
    Units: percentage of participants
        number (confidence interval 95%)
    54.2 (32.8 to 74.4)
    84 (63.9 to 95.5)
    88.5 (69.8 to 97.6)
    Notes
    [2] - All randomized participants receiving ≥1 dose of study treatment and no important protocol deviation
    [3] - All randomized participants receiving ≥1 dose of study treatment and no important protocol deviation
    [4] - All randomized participants receiving ≥1 dose of study treatment and no important protocol deviation
    No statistical analyses for this end point

    Primary: Number of participants experiencing at least one adverse event (AE)

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    End point title
    		 Number of participants experiencing at least one adverse event (AE) [5]
    End point description
    An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event 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 adverse event.
    End point type
    Primary
    End point timeframe
    Fourteen days following last dose of study drug (up to 26 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: There was no formal efficacy hypothesis testing conducted in this study.
    End point values
    		 Grazoprevir 25 mg + PEG-IFN + RBV Grazoprevir 50 mg + PEG-IFN + RBV Grazoprevir 100 mg + PEG-IFN + RBV
    Number of subjects analysed
    29 [6]
    28 [7]
    30 [8]
    Units: participants
    28
    28
    28
    Notes
    [6] - All randomized participants who received at least one dose of study treatment.
    [7] - All randomized participants who received at least one dose of study treatment.
    [8] - All randomized participants who received at least one dose of study treatment.
    No statistical analyses for this end point

    Primary: Number of participants discontinued from study treatment due to AEs

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    End point title
    		 Number of participants discontinued from study treatment due to AEs [9]
    End point description
    An adverse event is defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. An adverse event 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 adverse event.
    End point type
    Primary
    End point timeframe
    up to 24 weeks
    Notes
    [9] - 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 formal efficacy hypothesis testing conducted in this study.
    End point values
    		 Grazoprevir 25 mg + PEG-IFN + RBV Grazoprevir 50 mg + PEG-IFN + RBV Grazoprevir 100 mg + PEG-IFN + RBV
    Number of subjects analysed
    29 [10]
    28 [11]
    30 [12]
    Units: participant
    1
    1
    1
    Notes
    [10] - All randomized participants who received at least one dose of study treatment.
    [11] - All randomized participants who received at least one dose of study treatment.
    [12] - All randomized participants who received at least one dose of study treatment.
    No statistical analyses for this end point

    Secondary: Percentage of participants achieving undetectable HCV RNA by time point

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    End point title
    		 Percentage of participants achieving undetectable HCV RNA by time point
    End point description
    HCV RNA levels in plasma were measured using the Roche COBAS™ Taqman™ HCV Test, v2.0® assay on blood samples drawn from each participant at Week 2, Week 4, Week 12, and at end of treatment. The assay has a lower limit of quantification of 25 IU/mL and a limit of detection of 9.3 IU/mL. Undetectable HCV RNA was defined as below the limit of detection of 9.3 IU/mL.
    End point type
    Secondary
    End point timeframe
    From Week 2 through end of treatment (up to 24 weeks)
    End point values
    		 Grazoprevir 25 mg + PEG-IFN + RBV Grazoprevir 50 mg + PEG-IFN + RBV Grazoprevir 100 mg + PEG-IFN + RBV
    Number of subjects analysed
    29 [13]
    26 [14]
    29 [15]
    Units: percentage of participants
    number (confidence interval 95%)
        Week 2 (n=29, 25, 29)
    34.5 (17.9 to 54.3)
    32 (14.9 to 53.5)
    55.2 (35.7 to 73.6)
        Week 4 (n=28, 26, 29)
    82.1 (63.1 to 93.9)
    76.9 (56.4 to 91)
    89.7 (72.6 to 97.8)
        Week 12 (n=28, 26, 28)
    96.4 (81.7 to 99.9)
    92.3 (74.9 to 99.1)
    100 (87.7 to 100)
        End of All Therapy (n=26, 25, 26)
    92.3 (74.9 to 99.1)
    92 (74 to 99)
    100 (86.8 to 100)
    Notes
    [13] - All randomized participants receiving ≥1 dose of study treatment and no important protocol deviation
    [14] - All randomized participants receiving ≥1 dose of study treatment and no important protocol deviation
    [15] - All randomized participants receiving ≥1 dose of study treatment and no important protocol deviation
    No statistical analyses for this end point

    Secondary: Percentage of participants achieving HCV RNA <25 IU/mL by time point

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    End point title
    		 Percentage of participants achieving HCV RNA <25 IU/mL by time point
    End point description
    HCV RNA levels in plasma were measured using the Roche COBAS™ Taqman™ HCV Test, v2.0® assay on blood samples drawn from each participant at Week 2, Week 4, Week 12, and at end of treatment. The assay has a lower limit of quantification of 25 IU/mL and a limit of detection of 9.3 IU/mL.
    End point type
    Secondary
    End point timeframe
    From Week 2 through end of treatment (up to 24 weeks)
    End point values
    		 Grazoprevir 25 mg + PEG-IFN + RBV Grazoprevir 50 mg + PEG-IFN + RBV Grazoprevir 100 mg + PEG-IFN + RBV
    Number of subjects analysed
    29 [16]
    26 [17]
    29 [18]
    Units: percentage of participants
    number (confidence interval 95%)
        Week 2 (n=29, 25, 29)
    86.2 (68.3 to 96.1)
    88 (68.8 to 97.5)
    96.6 (82.2 to 99.9)
        Week 4 (n=28, 26, 29)
    96.4 (81.7 to 99.9)
    100 (86.8 to 100)
    100 (88.1 to 100)
        Week 12 (n=28, 26, 28)
    96.4 (81.7 to 99.9)
    100 (86.8 to 100)
    100 (87.7 to 100)
        End of all Therapy (n=26, 25, 26)
    92.3 (74.9 to 99.1)
    100 (86.3 to 100)
    100 (86.8 to 100)
    Notes
    [16] - All randomized participants receiving ≥1 dose of study treatment and no important protocol deviation
    [17] - All randomized participants receiving ≥1 dose of study treatment and no important protocol deviation
    [18] - All randomized participants receiving ≥1 dose of study treatment and no important protocol deviation
    No statistical analyses for this end point

    Secondary: Percentage of participants achieving SVR 4 weeks after the end of all study therapy (SVR4)

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    End point title
    		 Percentage of participants achieving SVR 4 weeks after the end of all study therapy (SVR4)
    End point description
    HCV RNA was measured using the Roche COBAS™ Taqman™ HCV Test, v2.0® assay, which has a lower limit of quantification of 25 IU/mL and a limit of detection of 9.3 IU/mL. SVR4 was defined as HCV RNA <25 IU/mL 4 weeks after the end of all study therapy.
    End point type
    Secondary
    End point timeframe
    4 weeks after end of treatment (up to 28 weeks total)
    End point values
    		 Grazoprevir 25 mg + PEG-IFN + RBV Grazoprevir 50 mg + PEG-IFN + RBV Grazoprevir 100 mg + PEG-IFN + RBV
    Number of subjects analysed
    26 [19]
    25 [20]
    26 [21]
    Units: percentage of participants
        number (confidence interval 95%)
    76.9 (56.4 to 91)
    88 (68.8 to 97.5)
    92.3 (74.9 to 99.1)
    Notes
    [19] - All randomized participants receiving ≥1 dose of study treatment and no important protocol deviation
    [20] - All randomized participants receiving ≥1 dose of study treatment and no important protocol deviation
    [21] - All randomized participants receiving ≥1 dose of study treatment and no important protocol deviation
    No statistical analyses for this end point

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

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    End point title
    		 Percentage of participants achieving SVR 24 weeks after the end of all study therapy (SVR24)
    End point description
    HCV RNA was measured using the Roche COBAS™ Taqman™ HCV Test, v2.0® assay, which has a lower limit of quantification of 25 IU/mL and a limit of detection of 9.3 IU/mL. SVR24 was defined as HCV RNA <25 IU/mL 24 weeks after the end of all study therapy.
    End point type
    Secondary
    End point timeframe
    24 weeks after end of treatment (up to 48 weeks total)
    End point values
    		 Grazoprevir 25 mg + PEG-IFN + RBV Grazoprevir 50 mg + PEG-IFN + RBV Grazoprevir 100 mg + PEG-IFN + RBV
    Number of subjects analysed
    24 [22]
    25 [23]
    26 [24]
    Units: percentage of participants
        number (confidence interval 95%)
    54.2 (32.8 to 74.4)
    84 (63.9 to 95.5)
    84.6 (65.1 to 95.6)
    Notes
    [22] - All randomized participants receiving ≥1 dose of study treatment and no important protocol deviation
    [23] - All randomized participants receiving ≥1 dose of study treatment and no important protocol deviation
    [24] - All randomized participants receiving ≥1 dose of study treatment and no important protocol deviation
    No statistical analyses for this end point

    Secondary: Number of participants developing post-baseline antiviral resistance to grazoprevir among participants not achieving SVR24 Response

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    End point title
    		 Number of participants developing post-baseline antiviral resistance to grazoprevir among participants not achieving SVR24 Response
    End point description
    Post-baseline resistance associated variants (RAV) analysis was conducted by comparing the amino acid sequences at the time of virologic failure to those at baseline (BL): Day 1, pre-dose. A post-BL variant was defined as an amino acid substitution within HCV protease (NS3/4A) that was present after the first dose at virologic failure and follow-up visits but not at BL. Post-BL variant analysis was conducted for participants who did not achieve SVR24 and had sequence data available.
    End point type
    Secondary
    End point timeframe
    From Day 1 up to Follow-up Week 24 (up to 48 weeks total)
    End point values
    		 Grazoprevir 25 mg + PEG-IFN + RBV Grazoprevir 50 mg + PEG-IFN + RBV Grazoprevir 100 mg + PEG-IFN + RBV
    Number of subjects analysed
    12 [25]
    7 [26]
    4 [27]
    Units: participants
    9
    5
    3
    Notes
    [25] - Treated non-SVR24 participants with BL and post-BL samples sequenced for RAVs.
    [26] - Treated non-SVR24 participants with BL and post-BL samples sequenced for RAVs.
    [27] - Treated non-SVR24 participants with BL and post-BL samples sequenced for RAVs.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From 1st day of treatment (Day 1) through Follow-up Week 24 (up to 48 weeks)
    Adverse event reporting additional description
    All randomized participants who received at least one dose of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Grazoprevir 25 mg + PEG-IFN + RBV
    Reporting group description
    		 After a maximum of a 45 day screening window, randomized participants received 25 mg grazoprevir in combination with PEG-IFN and RBV for 12 weeks followed by 24 weeks of follow-up.

    Reporting group title
    Grazoprevir 100 mg + PEG-IFN + RB
    Reporting group description
    		 After a maximum of a 45 day screening window, randomized participants received 100 mg grazoprevir in combination with PEG-IFN and RBV for 12 weeks followed by 24 weeks of follow-up.

    Reporting group title
    Grazoprevir 50 mg + PEG-IFN + RBV
    Reporting group description
    		 After a maximum of a 45 day screening window, randomized participants received 50 mg grazoprevir in combination with PEG-IFN and RBV for 12 weeks followed by 24 weeks of follow-up.

    Serious adverse events
    		 Grazoprevir 25 mg + PEG-IFN + RBV Grazoprevir 100 mg + PEG-IFN + RB Grazoprevir 50 mg + PEG-IFN + RBV
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    2 / 28 (7.14%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Grazoprevir 25 mg + PEG-IFN + RBV Grazoprevir 100 mg + PEG-IFN + RB Grazoprevir 50 mg + PEG-IFN + RBV
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 29 (96.55%)
    27 / 30 (90.00%)
    28 / 28 (100.00%)
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    0
    Asthenia
         subjects affected / exposed
    2 / 29 (6.90%)
    3 / 30 (10.00%)
    2 / 28 (7.14%)
         occurrences all number
    2
    3
    2
    Chills
         subjects affected / exposed
    13 / 29 (44.83%)
    13 / 30 (43.33%)
    12 / 28 (42.86%)
         occurrences all number
    14
    13
    12
    Fatigue
         subjects affected / exposed
    18 / 29 (62.07%)
    18 / 30 (60.00%)
    17 / 28 (60.71%)
         occurrences all number
    18
    19
    17
    Influenza like illness
         subjects affected / exposed
    6 / 29 (20.69%)
    7 / 30 (23.33%)
    7 / 28 (25.00%)
         occurrences all number
    6
    7
    7
    Feeling cold
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    2
    Injection site erythema
         subjects affected / exposed
    9 / 29 (31.03%)
    7 / 30 (23.33%)
    8 / 28 (28.57%)
         occurrences all number
    9
    7
    8
    Irritability
         subjects affected / exposed
    8 / 29 (27.59%)
    7 / 30 (23.33%)
    2 / 28 (7.14%)
         occurrences all number
    8
    8
    2
    Malaise
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    1
    0
    2
    Pain
         subjects affected / exposed
    3 / 29 (10.34%)
    6 / 30 (20.00%)
    2 / 28 (7.14%)
         occurrences all number
    5
    6
    2
    Pyrexia
         subjects affected / exposed
    10 / 29 (34.48%)
    11 / 30 (36.67%)
    7 / 28 (25.00%)
         occurrences all number
    12
    11
    7
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 29 (13.79%)
    5 / 30 (16.67%)
    3 / 28 (10.71%)
         occurrences all number
    4
    6
    3
    Dysphonia
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 30 (3.33%)
    0 / 28 (0.00%)
         occurrences all number
    2
    1
    0
    Dyspnoea
         subjects affected / exposed
    5 / 29 (17.24%)
    5 / 30 (16.67%)
    5 / 28 (17.86%)
         occurrences all number
    5
    5
    5
    Dyspnoea exertional
         subjects affected / exposed
    3 / 29 (10.34%)
    4 / 30 (13.33%)
    3 / 28 (10.71%)
         occurrences all number
    3
    4
    3
    Oropharyngeal pain
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 30 (6.67%)
    1 / 28 (3.57%)
         occurrences all number
    2
    3
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 30 (3.33%)
    2 / 28 (7.14%)
         occurrences all number
    1
    1
    2
    Depression
         subjects affected / exposed
    3 / 29 (10.34%)
    1 / 30 (3.33%)
    3 / 28 (10.71%)
         occurrences all number
    3
    2
    3
    Insomnia
         subjects affected / exposed
    5 / 29 (17.24%)
    4 / 30 (13.33%)
    3 / 28 (10.71%)
         occurrences all number
    5
    5
    3
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 29 (3.45%)
    3 / 30 (10.00%)
    1 / 28 (3.57%)
         occurrences all number
    1
    3
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 30 (6.67%)
    1 / 28 (3.57%)
         occurrences all number
    1
    2
    3
    Blood bilirubin increased
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    2 / 28 (7.14%)
         occurrences all number
    0
    1
    4
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 29 (3.45%)
    3 / 30 (10.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    4
    0
    Red cell distribution width increased
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 30 (6.67%)
    0 / 28 (0.00%)
         occurrences all number
    1
    2
    0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    4 / 29 (13.79%)
    1 / 30 (3.33%)
    4 / 28 (14.29%)
         occurrences all number
    4
    1
    4
    Nervous system disorders
    Disturbance in attention
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 30 (3.33%)
    2 / 28 (7.14%)
         occurrences all number
    1
    1
    2
    Dizziness
         subjects affected / exposed
    6 / 29 (20.69%)
    2 / 30 (6.67%)
    5 / 28 (17.86%)
         occurrences all number
    7
    2
    6
    Dysgeusia
         subjects affected / exposed
    2 / 29 (6.90%)
    4 / 30 (13.33%)
    2 / 28 (7.14%)
         occurrences all number
    2
    4
    2
    Headache
         subjects affected / exposed
    10 / 29 (34.48%)
    13 / 30 (43.33%)
    17 / 28 (60.71%)
         occurrences all number
    13
    17
    19
    Lethargy
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 30 (6.67%)
    0 / 28 (0.00%)
         occurrences all number
    0
    2
    0
    Sinus headache
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 30 (6.67%)
    0 / 28 (0.00%)
         occurrences all number
    1
    2
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 29 (27.59%)
    11 / 30 (36.67%)
    11 / 28 (39.29%)
         occurrences all number
    11
    11
    11
    Leukopenia
         subjects affected / exposed
    3 / 29 (10.34%)
    3 / 30 (10.00%)
    0 / 28 (0.00%)
         occurrences all number
    3
    5
    0
    Monocytosis
         subjects affected / exposed
    1 / 29 (3.45%)
    3 / 30 (10.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    3
    0
    Neutropenia
         subjects affected / exposed
    9 / 29 (31.03%)
    7 / 30 (23.33%)
    4 / 28 (14.29%)
         occurrences all number
    9
    12
    5
    Thrombocytopenia
         subjects affected / exposed
    2 / 29 (6.90%)
    2 / 30 (6.67%)
    1 / 28 (3.57%)
         occurrences all number
    2
    3
    3
    Eye disorders
    Eye pain
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 30 (3.33%)
    2 / 28 (7.14%)
         occurrences all number
    1
    1
    2
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 30 (6.67%)
    0 / 28 (0.00%)
         occurrences all number
    0
    2
    0
    Abdominal pain
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 30 (3.33%)
    4 / 28 (14.29%)
         occurrences all number
    1
    1
    4
    Aphthous stomatitis
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 30 (3.33%)
    0 / 28 (0.00%)
         occurrences all number
    2
    1
    0
    Constipation
         subjects affected / exposed
    2 / 29 (6.90%)
    3 / 30 (10.00%)
    3 / 28 (10.71%)
         occurrences all number
    2
    3
    4
    Diarrhoea
         subjects affected / exposed
    2 / 29 (6.90%)
    5 / 30 (16.67%)
    7 / 28 (25.00%)
         occurrences all number
    2
    5
    8
    Dry mouth
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 30 (3.33%)
    3 / 28 (10.71%)
         occurrences all number
    0
    1
    3
    Dyspepsia
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 30 (6.67%)
    1 / 28 (3.57%)
         occurrences all number
    1
    2
    1
    Haemorrhoids
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 30 (0.00%)
    3 / 28 (10.71%)
         occurrences all number
    1
    0
    4
    Nausea
         subjects affected / exposed
    11 / 29 (37.93%)
    9 / 30 (30.00%)
    17 / 28 (60.71%)
         occurrences all number
    11
    10
    18
    Vomiting
         subjects affected / exposed
    3 / 29 (10.34%)
    6 / 30 (20.00%)
    1 / 28 (3.57%)
         occurrences all number
    3
    6
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    2 / 29 (6.90%)
    3 / 30 (10.00%)
    3 / 28 (10.71%)
         occurrences all number
    2
    3
    3
    Dry skin
         subjects affected / exposed
    2 / 29 (6.90%)
    3 / 30 (10.00%)
    5 / 28 (17.86%)
         occurrences all number
    2
    3
    6
    Pruritus
         subjects affected / exposed
    5 / 29 (17.24%)
    5 / 30 (16.67%)
    8 / 28 (28.57%)
         occurrences all number
    5
    5
    9
    Pruritus generalised
         subjects affected / exposed
    1 / 29 (3.45%)
    3 / 30 (10.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    3
    0
    Rash
         subjects affected / exposed
    5 / 29 (17.24%)
    4 / 30 (13.33%)
    5 / 28 (17.86%)
         occurrences all number
    7
    5
    6
    Rash maculo-papular
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 30 (6.67%)
    0 / 28 (0.00%)
         occurrences all number
    2
    2
    0
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 30 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 29 (17.24%)
    1 / 30 (3.33%)
    8 / 28 (28.57%)
         occurrences all number
    6
    1
    8
    Back pain
         subjects affected / exposed
    1 / 29 (3.45%)
    4 / 30 (13.33%)
    2 / 28 (7.14%)
         occurrences all number
    1
    5
    2
    Muscle spasms
         subjects affected / exposed
    0 / 29 (0.00%)
    3 / 30 (10.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    3
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 29 (0.00%)
    3 / 30 (10.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    3
    2
    Myalgia
         subjects affected / exposed
    11 / 29 (37.93%)
    9 / 30 (30.00%)
    6 / 28 (21.43%)
         occurrences all number
    12
    10
    7
    Infections and infestations
    Folliculitis
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 30 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    0
    Sinusitis
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 30 (6.67%)
    0 / 28 (0.00%)
         occurrences all number
    0
    4
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 30 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    2
    0
    6
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 30 (6.67%)
    0 / 28 (0.00%)
         occurrences all number
    0
    2
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    12 / 29 (41.38%)
    14 / 30 (46.67%)
    7 / 28 (25.00%)
         occurrences all number
    12
    14
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Feb 2013
    Several changes were made in amendment 1 including revision of text regarding dosing duration modification, revision of clinical criteria for early termination, revision of text detailing rescue medications and supportive care, clarification of eligibility and withdrawal/discontinuation criteria, redefinition of several endpoints, and definition of viral rebound.
    27 May 2013
    Amendment 2 added a prohibited drug pathway (OATP1B1 substrates) and examples of that pathway to the list of prohibited medications to reflect the results of recently completed drug interaction studies. It also clarified the drug pathway for OATP1B1 inhibitors, providing guidance on which are prohibited and which may be permitted.

    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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    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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