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    Clinical Trial Results:
    A Phase III Double Blind Clinical Trial to Study the Efficacy and Safety of the Combination Regimen of MK-5172 and MK-8742 in Subjects With Chronic HCV GT1, GT4 and GT6 Infection With Inherited Blood Disorders With and Without HIV Co-Infection

    Summary
    EudraCT number
    		 2014-002356-27
    Trial protocol
    		 DE   IT   GB   GR  
    Global end of trial date
    14 Jun 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Jun 2017
    First version publication date
    15 Jun 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    5172-065
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02252016
    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
    14 Jun 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a randomized, multi-site, placebo-controlled trial of a fixed dose combination (FDC) of grazoprevir (MK-5172) 100 mg + elbasvir (MK-8742) 50 mg in participants with chronic Hepatitis C Virus (HCV) genotype (GT) 1, GT4 or GT6 with inherited blood disorders. The primary hypothesis is that the proportion of participants treated with grazoprevir+elbasvir achieving Sustained Virologic Response (SVR) 12 weeks after the end of all study therapy (SVR12) will be greater than the reference rate of 40%.
    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
    22 Oct 2014
    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
    Australia: 13
    Country: Number of subjects enrolled
    Canada: 2
    Country: Number of subjects enrolled
    France: 23
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    Greece: 10
    Country: Number of subjects enrolled
    Israel: 15
    Country: Number of subjects enrolled
    Italy: 34
    Country: Number of subjects enrolled
    Thailand: 4
    Country: Number of subjects enrolled
    United Kingdom: 13
    Country: Number of subjects enrolled
    United States: 35
    Worldwide total number of subjects
    159
    EEA total number of subjects
    90
    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)
    154
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Adult participants with hepatitis C virus (HCV) genotypes (GT)1, GT4, and GT6 with inherited blood disorders and with or without human immunodeficiency virus (HIV) co-infection were recruited at study centers around the world.

    Pre-assignment
    Screening details
    		 The screening period lasted up to 45 days.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Immediate Treatment
    Arm description
    		 Participants took grazoprevir 100 mg + elbasvir 50 mg once daily (q.d.) during the initial 12-week treatment period, followed by a 24-week safety monitoring period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Grazoprevir 100 mg + Elbasvir 50 mg
    Investigational medicinal product code
    MK-5172A; MK-5172 + MK-8742
    Other name
    ZEPATIER
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A single FDC tablet containing grazoprevir 100 mg + Elbasvir 50 mg taken once daily by mouth.

    Arm title
    		 Deferred Treatment
    Arm description
    		 Participants took placebo tablets q.d. during the initial 12-week treatment period, and then underwent a 4-week safety monitoring follow-up period. Next, participants took open-label grazoprevir 100 mg + elbasvir 50 mg q.d. for 12 weeks, followed by a 24-week safety monitoring period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Grazoprevir 100 mg + Elbasvir 50 mg
    Investigational medicinal product code
    MK-5172A; MK-5172 + MK-8742
    Other name
    ZEPATIER
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A single FDC tablet containing grazoprevir 100 mg + Elbasvir 50 mg taken once daily by mouth.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablet matched to MK-5172A taken once daily by mouth.

    Number of subjects in period 1
    		Immediate Treatment Deferred Treatment
    Started
    107
    52
    Completed
    104
    49
    Not completed
    3
    3
         Physician decision
    1
    -
         Consent withdrawn by subject
    -
    2
         Lost to follow-up
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Immediate Treatment
    Reporting group description
    		 Participants took grazoprevir 100 mg + elbasvir 50 mg once daily (q.d.) during the initial 12-week treatment period, followed by a 24-week safety monitoring period.

    Reporting group title
    Deferred Treatment
    Reporting group description
    		 Participants took placebo tablets q.d. during the initial 12-week treatment period, and then underwent a 4-week safety monitoring follow-up period. Next, participants took open-label grazoprevir 100 mg + elbasvir 50 mg q.d. for 12 weeks, followed by a 24-week safety monitoring period.

    Reporting group values
    		 Immediate Treatment Deferred Treatment Total
    Number of subjects
    		 107 52 159
    Age categorical
    Units: Subjects
        Adults (18 to 64 years of age)
    		 102 52 154
        From 65 to 84 years of age
    		 5 0 5
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 44.2 ( 11.2 ) 42.5 ( 9.8 ) -
    Gender, Male/Female
    Units: Subjects
        Female
    		 27 13 40
        Male
    		 80 39 119

    End points

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    End points reporting groups
    Reporting group title
    Immediate Treatment
    Reporting group description
    		 Participants took grazoprevir 100 mg + elbasvir 50 mg once daily (q.d.) during the initial 12-week treatment period, followed by a 24-week safety monitoring period.

    Reporting group title
    Deferred Treatment
    Reporting group description
    		 Participants took placebo tablets q.d. during the initial 12-week treatment period, and then underwent a 4-week safety monitoring follow-up period. Next, participants took open-label grazoprevir 100 mg + elbasvir 50 mg q.d. for 12 weeks, followed by a 24-week safety monitoring period.

    Primary: Percentage of participants achieving sustained virologic response 12 weeks after completing study therapy (SVR12)

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    End point title
    		 Percentage of participants achieving sustained virologic response 12 weeks after completing study therapy (SVR12) [1]
    End point description
    The percentage of participants in the both arms achieving SVR12 (i.e., HCV riboncleic acid [RNA] level below the lower limit of quantification [LLoQ] 12 weeks after completing study therapy) was determined. HCV RNA levels were measured using the Roche COBAS™ Taqman™ HCV Test v2.0 (High Pure System), which has a LLoQ of <15 IU/mL. All randomized participants who received at least one dose of study treatment and had available data were analyzed. Data for the Deferred Treatment Arm was reported after participants received open-label active treatment.
    End point type
    Primary
    End point timeframe
    12 weeks after completing study therapy (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: No statistical comparisons between experimental arms were performed for this endpoint.
    End point values
    		 Immediate Treatment Deferred Treatment
    Number of subjects analysed
    107
    49
    Units: Percentage of participants
        number (confidence interval 95%)
    93.5 (87 to 97.3)
    91.8 (80.4 to 97.7)
    No statistical analyses for this end point

    Primary: Percentage of participants experiencing an adverse event (AE)

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    End point title
    		 Percentage of participants experiencing an adverse event (AE)
    End point description
    An AE is any untoward medical occurrence which does not necessarily have to have a causal relationship with this treatment. All participants receiving ≥1 dose(s) of study drug were analyzed. For the Deferred Treatment arm, data indicate results obtained during the initial 12-week placebo treatment period.
    End point type
    Primary
    End point timeframe
    Up to Week 14
    End point values
    		 Immediate Treatment Deferred Treatment
    Number of subjects analysed
    107
    52
    Units: Percentage of Participants
        number (not applicable)
    72.9
    65.4
    Statistical analysis title
    		 Difference in Percentage
    Statistical analysis description
    The estimated difference (95% confidence interval [CI]) in percentage of participants experiencing an AE in the Immediate versus Deferred arms was determined.
    Comparison groups
    Immediate Treatment v Deferred Treatment
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    7.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.3
         upper limit
    		 23.3

    Primary: Percentage of participants discontinuing from study treatment due to an AE(s)

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    End point title
    		 Percentage of participants discontinuing from study treatment due to an AE(s)
    End point description
    An AE is any untoward medical occurrence which does not necessarily have to have a causal relationship with this treatment. All participants receiving ≥1 dose(s) of study drug were analyzed. For the Deferred Treatment arm, data indicate results obtained during the initial 12-week placebo treatment period.
    End point type
    Primary
    End point timeframe
    Up to Week 12
    End point values
    		 Immediate Treatment Deferred Treatment
    Number of subjects analysed
    107
    52
    Units: Percentage of Participants
        number (not applicable)
    0
    1.9
    Statistical analysis title
    		 Difference in Percentage
    Statistical analysis description
    The estimated difference (95% confidence interval [CI]) in percentage of participants discontinuing due to an AE(s) in the Immediate versus Deferred arms was determined.
    Comparison groups
    Immediate Treatment v Deferred Treatment
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.155
    Method
    		 Miettinen & Nurminen method
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.2
         upper limit
    		 1.6

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

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    End point title
    		 Percentage of participants achieving sustained virologic response 24 weeks after completing study therapy (SVR24)
    End point description
    The percentage of participants in both arms achieving SVR24 (i.e., HCV RNA level below the LLoQ 24 weeks after completing study therapy) was determined. HCV RNA levels were measured using the Roche COBAS™ Taqman™ HCV Test v2.0 (High Pure System), which has a LLoQ of <15 IU/mL. All randomized participants who received at least one dose of study treatment and had available data were analyzed. Data for the Deferred Treatment Arm was reported after participants received open-label active treatment.
    End point type
    Secondary
    End point timeframe
    24 weeks after completing study therapy (Week 36)
    End point values
    		 Immediate Treatment Deferred Treatment
    Number of subjects analysed
    107
    49
    Units: Percentage of participants
        number (confidence interval 95%)
    90.7 (83.5 to 95.4)
    91.8 (80.4 to 97.7)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 52 weeks.
    Adverse event reporting additional description
    An AE is any untoward medical occurrence which does not necessarily have to have a causal relationship with this treatment. AEs were reported for all participants receiving ≥1 dose of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Deferred Treatment Group
    Reporting group description
    		 Participants took placebo tablets q.d. during the initial 12-week treatment period, and then underwent a 4-week safety monitoring follow-up period. Next, participants took open-label grazoprevir 100 mg + elbasvir 50 mg q.d. for 12 weeks, followed by a 24-week safety monitoring period.

    Reporting group title
    Immediate Treatment Group
    Reporting group description
    		 Participants took grazoprevir 100 mg + elbasvir 50 mg once daily (q.d.) during the initial 12-week treatment period, followed by a 24-week safety monitoring period.

    Serious adverse events
    		 Deferred Treatment Group Immediate Treatment Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 52 (11.54%)
    6 / 107 (5.61%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Chronic myeloid leukaemia
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 107 (0.93%)
         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
    1 / 52 (1.92%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sickle cell anaemia with crisis
         subjects affected / exposed
    2 / 52 (3.85%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastritis erosive
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatitis acute
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteonecrosis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 107 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periarthritis
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypophosphataemia
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 107 (0.93%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Deferred Treatment Group Immediate Treatment Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 52 (40.38%)
    53 / 107 (49.53%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    6 / 52 (11.54%)
    23 / 107 (21.50%)
         occurrences all number
    7
    33
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 52 (3.85%)
    8 / 107 (7.48%)
         occurrences all number
    2
    11
    Fatigue
         subjects affected / exposed
    4 / 52 (7.69%)
    18 / 107 (16.82%)
         occurrences all number
    4
    18
    Pyrexia
         subjects affected / exposed
    0 / 52 (0.00%)
    6 / 107 (5.61%)
         occurrences all number
    0
    6
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    3 / 52 (5.77%)
    2 / 107 (1.87%)
         occurrences all number
    4
    2
    Abdominal pain
         subjects affected / exposed
    2 / 52 (3.85%)
    8 / 107 (7.48%)
         occurrences all number
    2
    8
    Diarrhoea
         subjects affected / exposed
    3 / 52 (5.77%)
    4 / 107 (3.74%)
         occurrences all number
    3
    5
    Nausea
         subjects affected / exposed
    8 / 52 (15.38%)
    9 / 107 (8.41%)
         occurrences all number
    9
    9
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    1 / 52 (1.92%)
    6 / 107 (5.61%)
         occurrences all number
    1
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 52 (5.77%)
    7 / 107 (6.54%)
         occurrences all number
    4
    8
    Haemarthrosis
         subjects affected / exposed
    4 / 52 (7.69%)
    4 / 107 (3.74%)
         occurrences all number
    8
    13
    Pain in extremity
         subjects affected / exposed
    4 / 52 (7.69%)
    1 / 107 (0.93%)
         occurrences all number
    4
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 52 (3.85%)
    7 / 107 (6.54%)
         occurrences all number
    2
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Feb 2015
    AM2: The primary purposes of AM2 were to reduce target enrollment of participants with sickle cell anaemia and thalassemia, and to increase the pretreatment period to 12 weeks to more accurately collect safety events.
    09 Nov 2015
    AM3: The primary purposes of AM3 were to change the statistical methodology for efficacy analyses and to change the efficacy population of interest.
    14 Mar 2016
    AM4: The primary purpose of AM4 was to change the efficacy analysis population.

    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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