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    Clinical Trial Results:
    A Phase IIb Clinical Study to Assess the Pharmacokinetics, Safety, and Efficacy of the Combination Regimen of Elbasvir (EBR)/Grazoprevir (GZR) in Participants Aged 3 to less than 18 Years with Chronic Hepatitis C Infection

    Summary
    EudraCT number
    		 2015-003006-16
    Trial protocol
    		 DE   SE   PL   Outside EU/EEA  
    Global end of trial date
    23 Jul 2020

    Results information
    Results version number
    		 v2(current)
    This version publication date
    18 Aug 2021
    First version publication date
    24 Oct 2020
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    5172-079
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03379506
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NC, 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)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001604-PIP01-13
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Jul 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Oct 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jul 2020
    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 pharmacokinetics (PK), safety, and efficacy of oral MK-5172 (a fixed dose combination [FDC] tablet containing elbasvir [EBR] 50 mg and grazoprevir [GZR] 100 mg) and EBR/GZR (varying doses) pediatric granules in pediatric hepatitis C virus (HCV)-infected participants who are 3 to <18 years of age. Within each age cohort (Cohort 1: 12 to <18 years of age; Cohort 2: 7 to <12 years of age; and Cohort 3: 3 to <7 years of age), a Mini Cohort of 7 participants will be enrolled first. For the oldest cohort (Cohort 1), the Mini Cohort will assess ability to swallow a placebo tablet prior to administering active FDC tablets. Participants in Cohorts 2 and 3 will take pediatric granules instead of a tablet.
    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
    25 Jan 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 15
    Country: Number of subjects enrolled
    Poland: 19
    Country: Number of subjects enrolled
    United States: 23
    Worldwide total number of subjects
    57
    EEA total number of subjects
    34
    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)
    35
    Adolescents (12-17 years)
    22
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Male and female participants 3 to <18 years of age with chronic hepatitis C virus (HCV) genotype 1 (GT1) or GT4 were enrolled at 14 global study sites.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Age Cohort 1: 12 to <18 Years: Mini and Expanded
    Arm description
    		 Pediatric participants 12 to <18 years of age received elbasvir (EBR) 50 mg / grazoprevir (GZR) 100 mg fixed dose combination (FDC) tablets once daily for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo Tablet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants who are 12 to <18 years of age will receive oral placebo tablet matched to EBR/GZR FDC tablet.

    Investigational medicinal product name
    EBR/GZR FDC Tablet
    Investigational medicinal product code
    Other name
    MK-5172A; ZEPATIER®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants who are 12 to <18 years of age will receive oral FDC tablets with EBR 50 mg/GZR 100 mg once daily by mouth.

    Arm title
    		 Age Cohort 2: 7 to <12 Years: Mini and Expanded
    Arm description
    		 Participants who are 7 to <12 years of age received EBR/GZR 30 mg/60 mg pediatric granules once daily for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Grazoprevir Oral Granules
    Investigational medicinal product code
    Other name
    MK-5172
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Participants 7 to <12 years of age take grazoprevir oral granules 1 mg by mouth in a soft food vehicle at a dose not to exceed 100 mg.

    Investigational medicinal product name
    Elbasvir Oral Granules
    Investigational medicinal product code
    Other name
    MK-8742
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Participants 7 to <12 years of age take elbasvir oral granules 0.5 mg by mouth in a soft food vehicle at a dose not to exceed 50 mg.

    Arm title
    		 Age Cohort 3: 3 to <7 Years: Mini
    Arm description
    		 Participants who are 3 to <7 years of age received a pediatric formulation of EBR/GZR (weight-based dosing) once daily for 12 weeks. The Mini cohort consists of the first 7 participants enrolled into Age Cohort 3. Participants <20 kg received EBR/GZR 15 mg/30 mg, and participants ≥20 kg received EBR/GZR 15 mg/50 mg.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Elbasvir Oral Granules
    Investigational medicinal product code
    Other name
    MK-8742
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Participants 3 to <7 years of age take elbasvir oral granules 0.5 mg by mouth in a soft food vehicle at a dose not to exceed 50 mg.

    Investigational medicinal product name
    Grazoprevir Oral Granules
    Investigational medicinal product code
    Other name
    MK-5172
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Participants 3 to <7 years of age take grazoprevir oral granules 1 mg by mouth in a soft food vehicle at a dose not to exceed 100 mg.

    Arm title
    		 Age Cohort 3: 3 to <7 Years: Expanded
    Arm description
    		 Participants who are 3 to <7 years of age received a pediatric formulation of EBR/GZR 25 mg/50 mg once daily for 12 weeks. The Expanded cohort consists of 11 participants enrolled after the Mini Cohort of 7 participants.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Elbasvir Oral Granules
    Investigational medicinal product code
    Other name
    MK-8742
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Participants 3 to <7 years of age take elbasvir oral granules 0.5 mg by mouth in a soft food vehicle at a dose not to exceed 50 mg.

    Investigational medicinal product name
    Grazoprevir Oral Granules
    Investigational medicinal product code
    Other name
    MK-5172
    Pharmaceutical forms
    Granules
    Routes of administration
    Oral use
    Dosage and administration details
    Participants 3 to <7 years of age take grazoprevir oral granules 1 mg by mouth in a soft food vehicle at a dose not to exceed 100 mg.

    Number of subjects in period 1
    		Age Cohort 1: 12 to <18 Years: Mini and Expanded Age Cohort 2: 7 to <12 Years: Mini and Expanded Age Cohort 3: 3 to <7 Years: Mini Age Cohort 3: 3 to <7 Years: Expanded
    Started
    22
    17
    7
    11
    Completed
    22
    17
    7
    11

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Age Cohort 1: 12 to <18 Years: Mini and Expanded
    Reporting group description
    		 Pediatric participants 12 to <18 years of age received elbasvir (EBR) 50 mg / grazoprevir (GZR) 100 mg fixed dose combination (FDC) tablets once daily for 12 weeks.

    Reporting group title
    Age Cohort 2: 7 to <12 Years: Mini and Expanded
    Reporting group description
    		 Participants who are 7 to <12 years of age received EBR/GZR 30 mg/60 mg pediatric granules once daily for 12 weeks.

    Reporting group title
    Age Cohort 3: 3 to <7 Years: Mini
    Reporting group description
    		 Participants who are 3 to <7 years of age received a pediatric formulation of EBR/GZR (weight-based dosing) once daily for 12 weeks. The Mini cohort consists of the first 7 participants enrolled into Age Cohort 3. Participants <20 kg received EBR/GZR 15 mg/30 mg, and participants ≥20 kg received EBR/GZR 15 mg/50 mg.

    Reporting group title
    Age Cohort 3: 3 to <7 Years: Expanded
    Reporting group description
    		 Participants who are 3 to <7 years of age received a pediatric formulation of EBR/GZR 25 mg/50 mg once daily for 12 weeks. The Expanded cohort consists of 11 participants enrolled after the Mini Cohort of 7 participants.

    Reporting group values
    		 Age Cohort 1: 12 to <18 Years: Mini and Expanded Age Cohort 2: 7 to <12 Years: Mini and Expanded Age Cohort 3: 3 to <7 Years: Mini Age Cohort 3: 3 to <7 Years: Expanded Total
    Number of subjects
    		 22 17 7 11 57
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 17 7 11 35
        Adolescents (12-17 years)
    		 22 0 0 0 22
        Adults (18-64 years)
    		 0 0 0 0 0
        From 65-84 years
    		 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 14.1 ( 1.9 ) 8.7 ( 1.2 ) 3.7 ( 0.8 ) 4.8 ( 1.3 ) -
    Sex: Female, Male
    Units: Participants
        Female
    		 11 7 3 8 29
        Male
    		 11 10 4 3 28
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0
        Asian
    		 0 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0
        Black or African American
    		 0 0 0 0 0
        White
    		 21 17 7 11 56
        More than one race
    		 1 0 0 0 1
        Unknown or Not Reported
    		 0 0 0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 3 2 1 0 6
        Not Hispanic or Latino
    		 19 14 6 11 50
        Unknown or Not Reported
    		 0 1 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    Age Cohort 1: 12 to <18 Years: Mini and Expanded
    Reporting group description
    		 Pediatric participants 12 to <18 years of age received elbasvir (EBR) 50 mg / grazoprevir (GZR) 100 mg fixed dose combination (FDC) tablets once daily for 12 weeks.

    Reporting group title
    Age Cohort 2: 7 to <12 Years: Mini and Expanded
    Reporting group description
    		 Participants who are 7 to <12 years of age received EBR/GZR 30 mg/60 mg pediatric granules once daily for 12 weeks.

    Reporting group title
    Age Cohort 3: 3 to <7 Years: Mini
    Reporting group description
    		 Participants who are 3 to <7 years of age received a pediatric formulation of EBR/GZR (weight-based dosing) once daily for 12 weeks. The Mini cohort consists of the first 7 participants enrolled into Age Cohort 3. Participants <20 kg received EBR/GZR 15 mg/30 mg, and participants ≥20 kg received EBR/GZR 15 mg/50 mg.

    Reporting group title
    Age Cohort 3: 3 to <7 Years: Expanded
    Reporting group description
    		 Participants who are 3 to <7 years of age received a pediatric formulation of EBR/GZR 25 mg/50 mg once daily for 12 weeks. The Expanded cohort consists of 11 participants enrolled after the Mini Cohort of 7 participants.

    Primary: Area Under the Plasma Concentration-Time Curve from Dosing to 24 Hours Postdose (AUC0-24hr) of EBR at Steady State

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    End point title
    		 Area Under the Plasma Concentration-Time Curve from Dosing to 24 Hours Postdose (AUC0-24hr) of EBR at Steady State [1]
    End point description
    The AUC0-24hr of EBR at steady state (Week 4) was determined in each cohort. All randomized and treated participants who complied with the protocol sufficiently to ensure that their pharmacokinetic (PK) data was likely to exhibit the effects of treatment, according to the underlying scientific model, are included.
    End point type
    Primary
    End point timeframe
    Week 4: Predose and 0.5, 1, 2, 3, 4, 6, 8, 10, and 24 hours postdose
    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
    		 Age Cohort 1: 12 to <18 Years: Mini and Expanded Age Cohort 2: 7 to <12 Years: Mini and Expanded Age Cohort 3: 3 to <7 Years: Mini Age Cohort 3: 3 to <7 Years: Expanded
    Number of subjects analysed
    22
    17
    7
    11
    Units: µM*hr
        geometric mean (confidence interval 95%)
    2.41 (1.97 to 2.94)
    2.79 (2.31 to 3.37)
    1.71 (1.36 to 2.15)
    3.15 (2.52 to 3.96)
    No statistical analyses for this end point

    Primary: Maximum Plasma Concentration (Cmax) of EBR

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    End point title
    		 Maximum Plasma Concentration (Cmax) of EBR [2]
    End point description
    The Cmax of EBR at steady state (Week 4) was determined in each cohort. All randomized and treated participants who complied with the protocol sufficiently to ensure that their PK data was likely to exhibit the effects of treatment, according to the underlying scientific model, are included.
    End point type
    Primary
    End point timeframe
    Week 4: Predose and 0.5, 1, 2, 3, 4, 6, 8, 10, and 24 hours postdose
    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
    		 Age Cohort 1: 12 to <18 Years: Mini and Expanded Age Cohort 2: 7 to <12 Years: Mini and Expanded Age Cohort 3: 3 to <7 Years: Mini Age Cohort 3: 3 to <7 Years: Expanded
    Number of subjects analysed
    22
    17
    7
    11
    Units: µM
        geometric mean (confidence interval 95%)
    0.19 (0.15 to 0.23)
    0.21 (0.17 to 0.25)
    0.14 (0.11 to 0.19)
    0.28 (0.22 to 0.36)
    No statistical analyses for this end point

    Primary: Steady State Predose Drug Concentration (Ctrough) of EBR

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    End point title
    		 Steady State Predose Drug Concentration (Ctrough) of EBR [3]
    End point description
    The Ctrough of EBR at steady state (Week 4) was determined at steady state prior to dosing in each cohort. All randomized and treated participants who complied with the protocol sufficiently to ensure that their PK data was likely to exhibit the effects of treatment, according to the underlying scientific model, are included. One participant in Age Cohort 2: 7 to <12 Years: Mini and Expanded had missing Ctrough data.
    End point type
    Primary
    End point timeframe
    Week 4: Predose
    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
    		 Age Cohort 1: 12 to <18 Years: Mini and Expanded Age Cohort 2: 7 to <12 Years: Mini and Expanded Age Cohort 3: 3 to <7 Years: Mini Age Cohort 3: 3 to <7 Years: Expanded
    Number of subjects analysed
    22
    16
    7
    11
    Units: nM
        geometric mean (confidence interval 95%)
    59.76 (47.20 to 75.67)
    59.43 (48.67 to 72.58)
    34.61 (28.00 to 42.77)
    68.92 (54.32 to 87.44)
    No statistical analyses for this end point

    Primary: Apparent Clearance (CL/F) of EBR at Steady State

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    End point title
    		 Apparent Clearance (CL/F) of EBR at Steady State [4]
    End point description
    The CL/F of EBR at steady state (Week 4) was determined in each cohort. All randomized and treated participants who complied with the protocol sufficiently to ensure that their PK data was likely to exhibit the effects of treatment, according to the underlying scientific model, are included.
    End point type
    Primary
    End point timeframe
    Week 4: Predose and 0.5, 1, 2, 3, 4, 6, 8, 10, and 24 hours postdose
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, only descriptive statistics are presented.
    End point values
    		 Age Cohort 1: 12 to <18 Years: Mini and Expanded Age Cohort 2: 7 to <12 Years: Mini and Expanded Age Cohort 3: 3 to <7 Years: Mini Age Cohort 3: 3 to <7 Years: Expanded
    Number of subjects analysed
    22
    17
    7
    11
    Units: L/hr
        geometric mean (confidence interval 95%)
    23.53 (19.25 to 28.75)
    12.21 (10.10 to 14.75)
    9.94 (7.89 to 12.53)
    8.98 (7.16 to 11.27)
    No statistical analyses for this end point

    Primary: AUC0-24hr of GZR at Steady State

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    End point title
    		 AUC0-24hr of GZR at Steady State [5]
    End point description
    The AUC0-24hr of GZR at steady state (Week 4) was determined in each cohort. All randomized and treated participants who complied with the protocol sufficiently to ensure that their PK data was likely to exhibit the effects of treatment, according to the underlying scientific model, are included.
    End point type
    Primary
    End point timeframe
    Week 4: Predose and 0.5, 1, 2, 3, 4, 6, 8, 10, and 24 hours postdose
    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: Per protocol, only descriptive statistics are presented.
    End point values
    		 Age Cohort 1: 12 to <18 Years: Mini and Expanded Age Cohort 2: 7 to <12 Years: Mini and Expanded Age Cohort 3: 3 to <7 Years: Mini Age Cohort 3: 3 to <7 Years: Expanded
    Number of subjects analysed
    22
    17
    7
    11
    Units: µM*hr
        geometric mean (confidence interval 95%)
    1.45 (1.08 to 1.94)
    1.42 (1.00 to 2.02)
    0.77 (0.48 to 1.23)
    1.66 (1.16 to 2.39)
    No statistical analyses for this end point

    Primary: Cmax of GZR

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    End point title
    		 Cmax of GZR [6]
    End point description
    The Cmax of GZR at steady state (Week 4) was determined in each cohort. All randomized and treated participants who complied with the protocol sufficiently to ensure that their PK data was likely to exhibit the effects of treatment, according to the underlying scientific model, are included.
    End point type
    Primary
    End point timeframe
    Week 4: Predose and 0.5, 1, 2, 3, 4, 6, 8, 10, and 24 hours postdose
    Notes
    [6] - 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
    		 Age Cohort 1: 12 to <18 Years: Mini and Expanded Age Cohort 2: 7 to <12 Years: Mini and Expanded Age Cohort 3: 3 to <7 Years: Mini Age Cohort 3: 3 to <7 Years: Expanded
    Number of subjects analysed
    22
    17
    7
    11
    Units: µM
        geometric mean (confidence interval 95%)
    0.25 (0.17 to 0.35)
    0.19 (0.12 to 0.31)
    0.09 (0.05 to 0.18)
    0.29 (0.18 to 0.47)
    No statistical analyses for this end point

    Primary: Ctrough of GZR

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    End point title
    		 Ctrough of GZR [7]
    End point description
    The Ctrough of GZR at steady state (Week 4) was determined at steady state prior to dosing in each cohort. All randomized and treated participants who complied with the protocol sufficiently to ensure that their PK data was likely to exhibit the effects of treatment, according to the underlying scientific model, are included. One participant in Age Cohort 2: 7 to <12 Years: Mini and Expanded had missing Ctrough data.
    End point type
    Primary
    End point timeframe
    Week 4: Predose
    Notes
    [7] - 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
    		 Age Cohort 1: 12 to <18 Years: Mini and Expanded Age Cohort 2: 7 to <12 Years: Mini and Expanded Age Cohort 3: 3 to <7 Years: Mini Age Cohort 3: 3 to <7 Years: Expanded
    Number of subjects analysed
    22
    16
    7
    11
    Units: nM
        geometric mean (confidence interval 95%)
    16.20 (12.27 to 21.38)
    16.27 (11.97 to 22.10)
    13.79 (9.55 to 19.90)
    16.17 (12.78 to 20.45)
    No statistical analyses for this end point

    Primary: CL/F of GZR at Steady State

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    End point title
    		 CL/F of GZR at Steady State [8]
    End point description
    The CL/F of GZR at steady state (Week 4) was determined in each cohort. No participants are included in the analysis as the CL/F of GZR was not calculable due to nonlinear PK.
    End point type
    Primary
    End point timeframe
    Week 4: Predose and 0.5, 1, 2, 3, 4, 6, 8, 10, and 24 hours postdose
    Notes
    [8] - 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
    		 Age Cohort 1: 12 to <18 Years: Mini and Expanded Age Cohort 2: 7 to <12 Years: Mini and Expanded Age Cohort 3: 3 to <7 Years: Mini Age Cohort 3: 3 to <7 Years: Expanded
    Number of subjects analysed
    0 [9]
    0 [10]
    0 [11]
    0 [12]
    Units: L/hr
        geometric mean (geometric coefficient of variation)
    ( )
    ( )
    ( )
    ( )
    Notes
    [9] - CL/F of GZR was not calculable due to nonlinear PK.
    [10] - CL/F of GZR was not calculable due to nonlinear PK.
    [11] - CL/F of GZR was not calculable due to nonlinear PK.
    [12] - CL/F of GZR was not calculable due to nonlinear PK.
    No statistical analyses for this end point

    Secondary: Percentage of Participants with ≥1 Adverse Event (AE)

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    End point title
    		 Percentage of Participants with ≥1 Adverse Event (AE)
    End point description
    The percentage of participants with ≥1 AE is reported in each cohort. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. All randomized participants who received ≥1 dose of study drug are included.
    End point type
    Secondary
    End point timeframe
    Up to 36 weeks
    End point values
    		 Age Cohort 1: 12 to <18 Years: Mini and Expanded Age Cohort 2: 7 to <12 Years: Mini and Expanded Age Cohort 3: 3 to <7 Years: Mini Age Cohort 3: 3 to <7 Years: Expanded
    Number of subjects analysed
    22
    17
    7
    11
    Units: Percentage of Participants
        number (not applicable)
    81.8
    76.5
    85.7
    81.8
    No statistical analyses for this end point

    Secondary: Percentage of Participants Discontinuing Study Treatment due to an AE

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    End point title
    		 Percentage of Participants Discontinuing Study Treatment due to an AE
    End point description
    The percentage of participants discontinuing study therapy due to an AE is reported in each cohort. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. All randomized participants who received ≥1 dose of study drug are included.
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    		 Age Cohort 1: 12 to <18 Years: Mini and Expanded Age Cohort 2: 7 to <12 Years: Mini and Expanded Age Cohort 3: 3 to <7 Years: Mini Age Cohort 3: 3 to <7 Years: Expanded
    Number of subjects analysed
    22
    17
    7
    11
    Units: Percentage of Participants
        number (not applicable)
    0.0
    0.0
    0.0
    0.0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Sustained Virologic Response 12 Weeks After Completing Treatment (SVR12)

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    End point title
    		 Percentage of Participants With Sustained Virologic Response 12 Weeks After Completing Treatment (SVR12)
    End point description
    The percentage of participants achieving SVR12, defined as hepatitis C virus (HCV) ribonucleic acid (RNA) < lower limit of quantification (LLOQ) 12 weeks after completing study therapy, was determined in each cohort. All randomized participants who received ≥1 dose of study treatment are included.
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Age Cohort 1: 12 to <18 Years: Mini and Expanded Age Cohort 2: 7 to <12 Years: Mini and Expanded Age Cohort 3: 3 to <7 Years: Mini Age Cohort 3: 3 to <7 Years: Expanded
    Number of subjects analysed
    22
    17
    7
    11
    Units: Percentage of Participants
        number (confidence interval 95%)
    100.0 (84.6 to 100.0)
    100.0 (80.5 to 100.0)
    100.0 (59.0 to 100.0)
    100.0 (71.5 to 100.0)
    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 for nonserious AEs (NSAEs) and serious AEs (SAEs), and up to approximately 49 weeks for all-cause mortality.
    Adverse event reporting additional description
    All participants who received ≥1 dose of study drug are included. All-cause mortality is based on all randomized participants.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1/23.0
    Reporting groups
    Reporting group title
    Age Cohort 1: 12 to <18 years
    Reporting group description
    		 Pediatric participants 12 to <18 years of age received elbasvir (EBR) 50 mg / grazoprevir (GZR) 100 mg fixed dose combination (FDC) tablets once daily for 12 weeks.

    Reporting group title
    Age Cohort 2: 7 to <12 years
    Reporting group description
    		 Participants who are 7 to <12 years of age received EBR/GZR 30 mg/60 mg pediatric granules once daily for 12 weeks.

    Reporting group title
    Age Cohort 3 Mini: 3 to <7 years
    Reporting group description
    		 Participants who are 3 to <7 years of age received a pediatric formulation of EBR/GZR (weight-based dosing) once daily for 12 weeks. The Mini cohort consists of the first 7 participants enrolled into Age Cohort 3. Participants <20 kg received EBR/GZR 15 mg/30 mg, and participants ≥20 kg received EBR/GZR 15 mg/50 mg.

    Reporting group title
    Age Cohort 3 Expanded: 3 to <7 years
    Reporting group description
    		 Participants who are 3 to <7 years of age received a pediatric formulation of EBR/GZR 25 mg/50 mg once daily for 12 weeks. The Expanded cohort consists of 11 participants enrolled after the Mini Cohort of 7 participants.

    Serious adverse events
    		 Age Cohort 1: 12 to <18 years Age Cohort 2: 7 to <12 years Age Cohort 3 Mini: 3 to <7 years Age Cohort 3 Expanded: 3 to <7 years
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Hand fracture
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Age Cohort 1: 12 to <18 years Age Cohort 2: 7 to <12 years Age Cohort 3 Mini: 3 to <7 years Age Cohort 3 Expanded: 3 to <7 years
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    17 / 22 (77.27%)
    13 / 17 (76.47%)
    6 / 7 (85.71%)
    9 / 11 (81.82%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Blood calcium decreased
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Body temperature increased
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Animal bite
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Contusion
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Intentional overdose
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    3
    Post procedural discomfort
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin laceration
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Upper limb fracture
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 22 (13.64%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Headache
         subjects affected / exposed
    8 / 22 (36.36%)
    2 / 17 (11.76%)
    0 / 7 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    14
    4
    0
    3
    General disorders and administration site conditions
    Energy increased
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Fatigue
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 17 (11.76%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    2
    2
    1
    0
    Pyrexia
         subjects affected / exposed
    3 / 22 (13.64%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 17 (5.88%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    3 / 22 (13.64%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    5
    1
    0
    0
    Constipation
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    2 / 11 (18.18%)
         occurrences all number
    1
    0
    1
    2
    Diarrhoea
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 17 (5.88%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Gastritis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    2
    Nausea
         subjects affected / exposed
    4 / 22 (18.18%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    5
    0
    0
    0
    Vomiting
         subjects affected / exposed
    3 / 22 (13.64%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    3 / 11 (27.27%)
         occurrences all number
    3
    1
    0
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 17 (5.88%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Epistaxis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    1
    0
    1
    Rhinitis allergic
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Sneezing
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rash
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Urticaria
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Behaviour disorder
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Provisional tic disorder
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Restlessness
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    1
    2
    Ear infection
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Folliculitis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    1
    3
    Herpes zoster
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Impetigo
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    1 / 7 (14.29%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Influenza
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    4 / 22 (18.18%)
    1 / 17 (5.88%)
    1 / 7 (14.29%)
    1 / 11 (9.09%)
         occurrences all number
    7
    2
    1
    1
    Otitis media
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    0
    1
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 17 (11.76%)
    1 / 7 (14.29%)
    3 / 11 (27.27%)
         occurrences all number
    0
    4
    1
    3
    Rhinitis
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Sinusitis
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Tonsillitis
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 22 (0.00%)
    3 / 17 (17.65%)
    1 / 7 (14.29%)
    3 / 11 (27.27%)
         occurrences all number
    0
    3
    1
    3
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 17 (5.88%)
    0 / 7 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 22 (0.00%)
    0 / 17 (0.00%)
    0 / 7 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Mar 2018
    AM02: The primary purpose of the amendment was to add an additional PK endpoint and modify dosing criteria.

    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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