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    Clinical Trial Results:
    An Open-Label, Multicenter Study to Evaluate the Pharmacokinetics, Safety, and Efficacy of Glecaprevir/Pibrentasvir in Pediatric Subjects with Genotypes 1 – 6 Chronic Hepatitis C Virus (HCV) Infection (DORA)

    Summary
    EudraCT number
    		 2016-004102-34
    Trial protocol
    		 ES   BE   DE   GB  
    Global end of trial date
    12 Sep 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Mar 2023
    First version publication date
    11 Mar 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    M16-123
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03067129
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AbbVie
    Sponsor organisation address
    1 North Waukegan Road, North Chicago, IL, United States, 60064
    Public contact
    Global Medical Services, AbbVie, 001 800-633-9110, abbvieclinicaltrials@abbvie.com
    Scientific contact
    Global Medical Services, AbbVie, 001 800-633-9110, abbvieclinicaltrials@abbvie.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001832-PIP01-15
    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
    12 Sep 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Sep 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this study were to: ● Assess the steady state area under the concentration-time curve (AUC), and to assess the pharmacokinetics (PK) of glecaprevir/pibrentasvir (GLE/PIB) in paediatric subjects following multiple dosing by age group; ● Evaluate the safety and tolerability of GLE/PIB by age group, cirrhosis status, and across all subjects; ● Evaluate the percentage of subjects with sustained virologic response for 12 weeks post-treatment (SVR12) in HCV Genotype 1 – 6 infected paediatric subjects (US FDA only, otherwise secondary).
    Protection of trial subjects
    Subject and/or legal guardian read and understood the information provided about the study and gave written permission.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Mar 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 33 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 9
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Japan: 13
    Country: Number of subjects enrolled
    Puerto Rico: 6
    Country: Number of subjects enrolled
    Russian Federation: 6
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    United Kingdom: 11
    Country: Number of subjects enrolled
    United States: 58
    Worldwide total number of subjects
    129
    EEA total number of subjects
    26
    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)
    81
    Adolescents (12-17 years)
    48
    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
    		 Participants were enrolled at 38 sites in North America, Europe, and Japan. Cohort 1 enrolled adolescent subjects aged 12 to < 18 years old. Subsequently, children aged 9 to < 12 (Cohort 2), 6 to < 9 (Cohort 3), and 3 to < 6 (Cohort 4) years old were enrolled in parallel.

    Pre-assignment
    Screening details
    		 In each cohort, subjects were first enrolled into an intense pharmacokinetics (IPK) portion to characterize the PK and safety in each age group, followed by a non-IPK safety/efficacy part. PK samples from the first 6 subjects in the IPK part were analyzed to determine the final dose used for the remaining IPK participants and in the non-IPK group.

    Pre-assignment period milestones
    Number of subjects started
    		 129
    Number of subjects completed
    		 127

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Enrolled but not dosed: 2
    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
    		 Cohort 1: 12 to < 18 years old
    Arm description
    		 Adolescents aged 12 to < 18 years old received the adult formulation of glecaprevir (GLE)/pibrentasvir (PIB) 100 mg/40 mg co-formulated film-coated tablets for a once daily (QD) total dose of 300 mg/120 mg by mouth for 8, 12, or 16 weeks depending on hepatitis C virus (HCV) genotype, cirrhosis status, and prior treatment experience.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Glecaprevir (GLE)/Pibrentasvir (PIB)
    Investigational medicinal product code
    ABT-493/ABT-530
    Other name
    MAVYRET®, MAVIRET®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    GLE/PIB was provided as 100 mg/40 mg film-coated tablets taken orally at GLE 300 mg/PIB 120 mg (three × GLE 100 mg/PIB 40 mg tablets) QD and with food.

    Arm title
    		 Cohort 2: 9 to < 12 years old
    Arm description
    		 Children aged 9 to < 12 years old received a paediatric formulation of GLE + PIB as small film-coated granules taken with a small amount of food once daily for 8, 12, or 16 weeks depending on HCV genotype, cirrhosis status, and prior treatment experience. The final dose for children weighing 30 to < 45 kg was GLE 250 mg + PIB 100 mg.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Glecaprevir + Pibrentasvir Paediatric Formulation
    Investigational medicinal product code
    ABT-493 + ABT-530
    Other name
    Pharmaceutical forms
    Film-coated granules
    Routes of administration
    Oral use
    Dosage and administration details
    The initial proposed dose for paediatric participants 9 to < 12 years old (30 to < 45 kg) was GLE 200 mg + PIB 75 mg. After PK analysis from the first 6 enrolled participants the dose was adjusted to GLE 250 mg + PIB 100 mg. The paediatric formulation was to be administered by mixing the granules with a small amount (1-2 teaspoons) of a soft food vehicle, such as hazelnut spread, Greek yogurt, or peanut butter.

    Arm title
    		 Cohort 3: 6 to < 9 years old
    Arm description
    		 Children aged 6 to < 9 years old received a paediatric formulation of GLE + PIB as small film-coated granules taken with a small amount of food once daily for 8, 12, or 16 weeks depending on HCV genotype, cirrhosis status, and prior treatment experience. The final dose for children weighing ≥ 20 to < 30 kg was GLE 200 mg + PIB 80 mg; one participant received GLE 250 mg + PIB 100 mg based on weight at screening.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Glecaprevir + Pibrentasvir Paediatric Formulation
    Investigational medicinal product code
    ABT-493 + ABT-530
    Other name
    Pharmaceutical forms
    Film-coated granules
    Routes of administration
    Oral use
    Dosage and administration details
    The initial proposed dose for paediatric participants 6 to < 9 years old (20 to < 30 kg) was GLE 160 mg + PIB 60 mg. After PK analysis from the first 6 enrolled participants the dose was adjusted to GLE 200 mg + PIB 80 mg. The paediatric formulation was to be administered by mixing the granules with a small amount (1-2 teaspoons) of a soft food vehicle, such as hazelnut spread, Greek yogurt, or peanut butter.

    Arm title
    		 Cohort 4: 3 to < 6 years old
    Arm description
    		 Children aged 3 to < 6 years old received a paediatric formulation of GLE + PIB as small film-coated granules taken with a small amount of food once daily for 8, 12, or 16 weeks depending on HCV genotype, cirrhosis status, and prior treatment experience. The final dose for children weighing 12 to < 20 kg was GLE 150 mg + PIB 60 mg; one participant received GLE 200 mg + PIB 80 mg based on weight at screening.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Glecaprevir + Pibrentasvir Paediatric Formulation
    Investigational medicinal product code
    ABT-493 + ABT-530
    Other name
    Pharmaceutical forms
    Film-coated granules
    Routes of administration
    Oral use
    Dosage and administration details
    The initial proposed dose for paediatric participants 3 to < 6 years old (12 to < 20 kg) was GLE 120 mg + PIB 45 mg. After PK analysis from the first 5 enrolled participants the dose was adjusted to GLE 150 mg + PIB 60 mg. The paediatric formulation was to be administered by mixing the granules with a small amount (1-2 teaspoons) of a soft food vehicle, such as hazelnut spread, Greek yogurt, or peanut butter.

    Number of subjects in period 1 [1]
    		Cohort 1: 12 to < 18 years old Cohort 2: 9 to < 12 years old Cohort 3: 6 to < 9 years old Cohort 4: 3 to < 6 years old
    Started
    47
    29
    27
    24
    Completed
    42
    24
    22
    18
    Not completed
    5
    5
    5
    6
         Consent withdrawn by subject
    -
    -
    1
    2
         Partially dosed; refused to swallow entire dose
    -
    -
    -
    1
         Lost to follow-up
    5
    5
    4
    3
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Two participants enrolled but did not receive study drug and are therefore not included in the baseline period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: 12 to < 18 years old
    Reporting group description
    		 Adolescents aged 12 to < 18 years old received the adult formulation of glecaprevir (GLE)/pibrentasvir (PIB) 100 mg/40 mg co-formulated film-coated tablets for a once daily (QD) total dose of 300 mg/120 mg by mouth for 8, 12, or 16 weeks depending on hepatitis C virus (HCV) genotype, cirrhosis status, and prior treatment experience.

    Reporting group title
    Cohort 2: 9 to < 12 years old
    Reporting group description
    		 Children aged 9 to < 12 years old received a paediatric formulation of GLE + PIB as small film-coated granules taken with a small amount of food once daily for 8, 12, or 16 weeks depending on HCV genotype, cirrhosis status, and prior treatment experience. The final dose for children weighing 30 to < 45 kg was GLE 250 mg + PIB 100 mg.

    Reporting group title
    Cohort 3: 6 to < 9 years old
    Reporting group description
    		 Children aged 6 to < 9 years old received a paediatric formulation of GLE + PIB as small film-coated granules taken with a small amount of food once daily for 8, 12, or 16 weeks depending on HCV genotype, cirrhosis status, and prior treatment experience. The final dose for children weighing ≥ 20 to < 30 kg was GLE 200 mg + PIB 80 mg; one participant received GLE 250 mg + PIB 100 mg based on weight at screening.

    Reporting group title
    Cohort 4: 3 to < 6 years old
    Reporting group description
    		 Children aged 3 to < 6 years old received a paediatric formulation of GLE + PIB as small film-coated granules taken with a small amount of food once daily for 8, 12, or 16 weeks depending on HCV genotype, cirrhosis status, and prior treatment experience. The final dose for children weighing 12 to < 20 kg was GLE 150 mg + PIB 60 mg; one participant received GLE 200 mg + PIB 80 mg based on weight at screening.

    Reporting group values
    		 Cohort 1: 12 to < 18 years old Cohort 2: 9 to < 12 years old Cohort 3: 6 to < 9 years old Cohort 4: 3 to < 6 years old Total
    Number of subjects
    		 47 29 27 24 127
    Age categorical
    Age at Baseline is reported; Cohorts were defined in the interactive response technology (IRT) system as age group at Screening which may differ from Baseline age.
    Units: Subjects
        12 to < 18 years
    		 47 0 0 0 47
        9 to < 12 years
    		 0 29 1 0 30
        6 to < 9 years
    		 0 0 26 0 26
        3 to < 6 years
    		 0 0 0 24 24
    Age continuous
    Units: years
        median (full range (min-max))
    		 14 (12 to 17) 10 (9 to 11) 7 (6 to 9) 4 (3 to 5) -
    Gender categorical
    Units: Subjects
        Female
    		 26 15 17 12 70
        Male
    		 21 14 10 12 57
    Race
    Units: Subjects
        White
    		 35 21 18 16 90
        Black or African American
    		 4 1 1 1 7
        Asian
    		 6 5 5 4 20
        American Indian or Alaska Native
    		 0 1 0 1 2
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 1 1
        Multiple
    		 2 1 3 1 7
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 5 5 4 4 18
        Not Hispanic or Latino
    		 42 24 23 20 109
    Weight
    Units: Subjects
        12 to < 20 kg
    		 0 0 1 23 24
        20 to < 30 kg
    		 0 2 25 1 28
        30 to < 45 kg
    		 3 27 1 0 31
        ≥ 45 kg
    		 44 0 0 0 44
    Hepatitis C Virus Genotype
    Units: Subjects
        Genotype 1
    		 37 19 22 17 95
        Genotype 2
    		 3 2 0 0 5
        Genotype 3
    		 4 8 3 7 22
        Genotype 4
    		 3 0 2 0 5
        Genotype 5
    		 0 0 0 0 0
        Genotype 6
    		 0 0 0 0 0
    Prior HCV Treatment History
    Units: Subjects
        Naive
    		 36 27 27 24 114
        Experienced
    		 11 2 0 0 13
    Baseline Fibrosis Stage
    Fibrosis stage was determined by biopsy score, FibroScan score (if biopsy not available), or FibroTest score (if biopsy and FibroScan not available) and is equivalent to the liver biopsy Metavir score: F0: no fibrosis; F1: portal fibrosis without septa; F2: portal fibrosis with few septa; F3: numerous septa without cirrhosis; F4: cirrhosis.
    Units: Subjects
        F0-F1
    		 45 28 26 24 123
        F2
    		 1 1 1 0 3
        F3
    		 1 0 0 0 1
        F4
    		 0 0 0 0 0
    Co-infection with Human Immunodeficiency Virus (HIV)
    Units: Subjects
        Yes
    		 2 0 1 0 3
        No
    		 45 29 26 24 124
    HCV Ribonucleic Acid (RNA) Level
    HCV RNA quantified by Roche COBAS Ampliprep/COBAS TaqMan HCV Quantitative Test, version 2.0.
    Units: Log₁₀ IU/mL
        median (full range (min-max))
    		 6.20 (4.63 to 7.18) 6.20 (4.79 to 7.19) 5.89 (4.53 to 7.15) 5.83 (3.43 to 6.90) -

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: 12 to < 18 years old
    Reporting group description
    		 Adolescents aged 12 to < 18 years old received the adult formulation of glecaprevir (GLE)/pibrentasvir (PIB) 100 mg/40 mg co-formulated film-coated tablets for a once daily (QD) total dose of 300 mg/120 mg by mouth for 8, 12, or 16 weeks depending on hepatitis C virus (HCV) genotype, cirrhosis status, and prior treatment experience.

    Reporting group title
    Cohort 2: 9 to < 12 years old
    Reporting group description
    		 Children aged 9 to < 12 years old received a paediatric formulation of GLE + PIB as small film-coated granules taken with a small amount of food once daily for 8, 12, or 16 weeks depending on HCV genotype, cirrhosis status, and prior treatment experience. The final dose for children weighing 30 to < 45 kg was GLE 250 mg + PIB 100 mg.

    Reporting group title
    Cohort 3: 6 to < 9 years old
    Reporting group description
    		 Children aged 6 to < 9 years old received a paediatric formulation of GLE + PIB as small film-coated granules taken with a small amount of food once daily for 8, 12, or 16 weeks depending on HCV genotype, cirrhosis status, and prior treatment experience. The final dose for children weighing ≥ 20 to < 30 kg was GLE 200 mg + PIB 80 mg; one participant received GLE 250 mg + PIB 100 mg based on weight at screening.

    Reporting group title
    Cohort 4: 3 to < 6 years old
    Reporting group description
    		 Children aged 3 to < 6 years old received a paediatric formulation of GLE + PIB as small film-coated granules taken with a small amount of food once daily for 8, 12, or 16 weeks depending on HCV genotype, cirrhosis status, and prior treatment experience. The final dose for children weighing 12 to < 20 kg was GLE 150 mg + PIB 60 mg; one participant received GLE 200 mg + PIB 80 mg based on weight at screening.

    Subject analysis set title
    Cohorts 2-4: 3 to < 12 years old
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Children aged 3 to < 12 years old received a paediatric formulation of GLE + PIB at a final dose of GLE 250 mg + PIB 100 mg (children 9 to < 12 years of age), GLE 200 mg + PIB 80 mg (children 6 to < 9 years of age), or GLE 150 mg + PIB 60 mg (children 3 to < 6 years of age) as small film-coated granules taken with a small amount of food once daily for 8, 12, or 16 weeks depending on HCV genotype, cirrhosis status, and prior treatment experience.

    Subject analysis set title
    Total
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants in Cohorts 1-4.

    Primary: Steady-state Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours Postdose (AUC0-24) of Glecaprevir

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    End point title
    		 Steady-state Area Under the Plasma Concentration-time Curve From Time Zero to 24 Hours Postdose (AUC0-24) of Glecaprevir [1]
    End point description
    The area under the plasma concentration-time curve (AUC) is a method of measurement of the total exposure of a drug in blood plasma. The steady-state exposure of GLE was measured up to 24 hours after dosing at Week 2 and estimated using non-compartmental analysis. PK analyses were assessed in participants with intense pharmacokinetic samples who received the final dose regimen of GLE + PIB. One participant in Cohort 4 who received GLE 200 mg + PIB 80 mg based on weight (> 20 kg) and was summarized in Cohort 3 for PK analyses based on the actual dose received.
    End point type
    Primary
    End point timeframe
    Week 2 from predose to 24 hours post-dose
    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 hypotheses were tested in this open-label study.
    End point values
    		 Cohort 1: 12 to < 18 years old Cohort 2: 9 to < 12 years old Cohort 3: 6 to < 9 years old Cohort 4: 3 to < 6 years old
    Number of subjects analysed
    14 [2]
    13 [3]
    13 [4]
    12 [5]
    Units: ng*h/mL
        geometric mean (confidence interval 95%)
    4790 (3520 to 6500)
    7870 (4140 to 14900)
    6860 (4080 to 11500)
    7520 (3870 to 14600)
    Notes
    [2] - Participants with IPK samples
    [3] - Participants with IPK samples who received the final dose regimen of GLE + PIB
    [4] - Participants with IPK samples who received the final dose regimen of GLE + PIB
    [5] - Participants with IPK samples who received the final dose regimen of GLE + PIB
    No statistical analyses for this end point

    Primary: Steady-state AUC0-24 of Pibrentasvir

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    End point title
    		 Steady-state AUC0-24 of Pibrentasvir [6]
    End point description
    The area under the plasma concentration-time curve (AUC) is a method of measurement of the total exposure of a drug in blood plasma. The steady-state exposure of PIB was measured up to 24 hours after dosing at Week 2 and estimated using non-compartmental analysis. PK analyses were assessed in participants with intense pharmacokinetic samples who received the final dose regimen of GLE + PIB. One participant in Cohort 4 who received GLE 200 mg + PIB 80 mg based on weight (> 20 kg) and was summarized in Cohort 3 for PK analyses based on the actual dose received.
    End point type
    Primary
    End point timeframe
    Week 2 from predose to 24 hours post-dose
    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: No hypotheses were tested in this open-label study.
    End point values
    		 Cohort 1: 12 to < 18 years old Cohort 2: 9 to < 12 years old Cohort 3: 6 to < 9 years old Cohort 4: 3 to < 6 years old
    Number of subjects analysed
    14 [7]
    13 [8]
    13 [9]
    12 [10]
    Units: ng*hour/mL
        geometric mean (confidence interval 95%)
    1380 (1150 to 1660)
    2200 (1460 to 3310)
    1640 (1230 to 2190)
    1790 (1350 to 2370)
    Notes
    [7] - Participants with IPK suamples
    [8] - Participants with IPK samples who received the final dose regimen of GLE + PIB
    [9] - Participants with IPK samples who received the final dose regimen of GLE + PIB
    [10] - Participants with IPK samples who received the final dose regimen of GLE + PIB
    No statistical analyses for this end point

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

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    End point title
    		 Percentage of Participants With Sustained Virologic Response 12 Weeks Post Treatment (SVR12)
    End point description
    SVR12 is defined as hepatitis C virus ribonucleic acid (HCV RNA) less than the lower limit of quantification (LLOQ; 15 IU/mL) 12 weeks after the last actual dose of study drug. Plasma HCV RNA levels were collected using the COBAS AmpliPrep/COBAS TaqMan HCV Quantitative Test v2.0. SVR12 was considered a primary efficacy endpoint by the US regulatory agency and was considered secondary outside of the US. The intention-to-treat (ITT) population includes all participants who received at least 1 dose of study drug. Backward imputation, where applicable, was used to impute missing data. Participants with missing data after backwards imputation were counted as nonresponders.
    End point type
    Secondary
    End point timeframe
    12 weeks after last dose of study drug (Week 20, 24, or 28 depending on treatment duration)
    End point values
    		 Cohort 1: 12 to < 18 years old Cohort 2: 9 to < 12 years old Cohort 3: 6 to < 9 years old Cohort 4: 3 to < 6 years old Cohorts 2-4: 3 to < 12 years old Total
    Number of subjects analysed
    47 [11]
    29 [12]
    27 [13]
    24 [14]
    80 [15]
    127 [16]
    Units: percentage of participants
        number (confidence interval 95%)
    100 (92.4 to 100.0)
    93.1 (78.0 to 98.1)
    100 (87.5 to 100.0)
    95.8 (79.8 to 99.3)
    96.3 (89.5 to 98.7)
    97.6 (93.3 to 99.2)
    Notes
    [11] - Intention-to-treat population
    [12] - Intention-to-treat population
    [13] - Intention-to-treat population
    [14] - Intention-to-treat population
    [15] - Intention-to-treat population
    [16] - Intention-to-treat population
    No statistical analyses for this end point

    Secondary: Maximum Plasma Concentration (Cmax) of Glecaprevir

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    End point title
    		 Maximum Plasma Concentration (Cmax) of Glecaprevir
    End point description
    PK analyses were assessed in participants with intense pharmacokinetic samples who received the final dose regimen of GLE + PIB. One participant in Cohort 4 who received GLE 200 mg + PIB 80 mg based on weight (> 20 kg) and was summarized in Cohort 3 for PK analyses based on the actual dose received.
    End point type
    Secondary
    End point timeframe
    Week 2 from predose to 24 hours post-dose.
    End point values
    		 Cohort 1: 12 to < 18 years old Cohort 2: 9 to < 12 years old Cohort 3: 6 to < 9 years old Cohort 4: 3 to < 6 years old
    Number of subjects analysed
    14 [17]
    13 [18]
    13 [19]
    12 [20]
    Units: ng/mL
        geometric mean (confidence interval 95%)
    1040 (733 to 1480)
    1370 (773 to 2440)
    1600 (926 to 2770)
    1530 (711 to 3290)
    Notes
    [17] - Participants with IPK samples
    [18] - Participants with IPK samples who received the final dose regimen of GLE + PIB
    [19] - Participants with IPK samples who received the final dose regimen of GLE + PIB
    [20] - Participants with IPK samples who received the final dose regimen of GLE + PIB
    No statistical analyses for this end point

    Secondary: Apparent Clearance (CL/F) of Glecaprevir From Plasma

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    End point title
    		 Apparent Clearance (CL/F) of Glecaprevir From Plasma
    End point description
    PK analyses were assessed in participants with intense pharmacokinetic samples who received the final dose regimen of GLE + PIB. One participant in Cohort 4 who received GLE 200 mg + PIB 80 mg based on weight (> 20 kg) and was summarized in Cohort 3 for PK analyses based on the actual dose received.
    End point type
    Secondary
    End point timeframe
    Week 2 from predose to 24 hours pose-dose
    End point values
    		 Cohort 1: 12 to < 18 years old Cohort 2: 9 to < 12 years old Cohort 3: 6 to < 9 years old Cohort 4: 3 to < 6 years old
    Number of subjects analysed
    14 [21]
    13 [22]
    13 [23]
    12 [24]
    Units: litres/hour
        geometric mean (confidence interval 95%)
    62.6 (46.1 to 85.1)
    31.8 (16.7 to 60.3)
    29.1 (17.3 to 49.0)
    19.9 (10.2 to 38.7)
    Notes
    [21] - Participants with IPK samples
    [22] - Participants with IPK samples who received the final dose regimen of GLE + PIB
    [23] - Participants with IPK samples who received the final dose regimen of GLE + PIB
    [24] - Participants with IPK samples who received the final dose regimen of GLE + PIB
    No statistical analyses for this end point

    Secondary: Maximum Plasma Concentration of Pibrentasvir

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    End point title
    		 Maximum Plasma Concentration of Pibrentasvir
    End point description
    PK analyses were assessed in participants with intense pharmacokinetic samples who received the final dose regimen of GLE + PIB. One participant in Cohort 4 who received GLE 200 mg + PIB 80 mg based on weight (> 20 kg) and was summarized in Cohort 3 for PK analyses based on the actual dose received.
    End point type
    Secondary
    End point timeframe
    Week 2 from predose to 24 hours post-dose
    End point values
    		 Cohort 1: 12 to < 18 years old Cohort 2: 9 to < 12 years old Cohort 3: 6 to < 9 years old Cohort 4: 3 to < 6 years old
    Number of subjects analysed
    14 [25]
    13 [26]
    13 [27]
    12 [28]
    Units: ng/mL
        geometric mean (confidence interval 95%)
    174 (148 to 205)
    225 (164 to 310)
    197 (154 to 251)
    233 (184 to 296)
    Notes
    [25] - Participants with IPK samples
    [26] - Participants with IPK samples who received the final dose regimen of GLE + PIB
    [27] - Participants with IPK samples who received the final dose regimen of GLE + PIB
    [28] - Participants with IPK samples who received the final dose regimen of GLE + PIB
    No statistical analyses for this end point

    Secondary: Apparent Clearance of Pibrentasvir

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    End point title
    		 Apparent Clearance of Pibrentasvir
    End point description
    PK analyses were assessed in participants with intense pharmacokinetic samples who received the final dose regimen of GLE + PIB. One participant in Cohort 4 who received GLE 200 mg + PIB 80 mg based on weight (> 20 kg) and was summarized in Cohort 3 for PK analyses based on the actual dose received.
    End point type
    Secondary
    End point timeframe
    Week 2 from predose to 24 hours post-dose
    End point values
    		 Cohort 1: 12 to < 18 years old Cohort 2: 9 to < 12 years old Cohort 3: 6 to < 9 years old Cohort 4: 3 to < 6 years old
    Number of subjects analysed
    14 [29]
    13 [30]
    13 [31]
    12 [32]
    Units: litres/hour
        geometric mean (confidence interval 95%)
    86.9 (72.4 to 104)
    45.4 (30.1 to 68.5)
    48.7 (36.6 to 64.8)
    33.6 (25.4 to 44.5)
    Notes
    [29] - Participants with IPK samples
    [30] - Participants with IPK samples who received the final dose regimen of GLE + PIB
    [31] - Participants with IPK samples who received the final dose regimen of GLE + PIB
    [32] - Participants with IPK samples who received the final dose regimen of GLE + PIB
    No statistical analyses for this end point

    Secondary: Percentage of Participants Who Experienced On-treatment Virologic Failure

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    End point title
    		 Percentage of Participants Who Experienced On-treatment Virologic Failure
    End point description
    On-treatment virologic failure is defined as meeting one of the following: - A confirmed (defined as two consecutive HCV RNA measurements) increase of > 1 log₁₀ IU/mL above nadir during treatment; - Confirmed HCV RNA ≥ 100 IU/mL after HCV RNA < 15 IU/mL during treatment; - HCV RNA ≥ 15 IU/mL at the end of treatment with at least 6 weeks of treatment.
    End point type
    Secondary
    End point timeframe
    Up to Week 8, 12, or 16 (depending on treatment duration)
    End point values
    		 Cohort 1: 12 to < 18 years old Cohort 2: 9 to < 12 years old Cohort 3: 6 to < 9 years old Cohort 4: 3 to < 6 years old Cohorts 2-4: 3 to < 12 years old Total
    Number of subjects analysed
    47 [33]
    29 [34]
    27 [35]
    24 [36]
    80 [37]
    127 [38]
    Units: percentage of participants
        number (confidence interval 95%)
    0.0 (0.0 to 7.6)
    0.0 (0.0 to 11.7)
    0.0 (0.0 to 12.5)
    0.0 (0.0 to 13.8)
    0.0 (0.0 to 4.6)
    0.0 (0.0 to 2.9)
    Notes
    [33] - Intention-to-treat population
    [34] - Intention-to-treat population
    [35] - Intention-to-treat population
    [36] - Intention-to-treat population
    [37] - Intention-to-treat population
    [38] - Intention-to-treat population
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Post-treatment Relapse up to 12 Weeks Post Treatment

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    End point title
    		 Percentage of Participants With Post-treatment Relapse up to 12 Weeks Post Treatment
    End point description
    Post-treatment relapse is defined as confirmed HCV RNA ≥ 15 IU/mL between the end of treatment and 12 weeks after the last dose of study drug among participants who completed treatment as planned with HCV RNA < 15 IU/mL at the end of treatment; excluding participants who had been shown to be re-infected.
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks after the last dose of study drug (Week 20, 24, or 28 depending on treatment duration)
    End point values
    		 Cohort 1: 12 to < 18 years old Cohort 2: 9 to < 12 years old Cohort 3: 6 to < 9 years old Cohort 4: 3 to < 6 years old Cohorts 2-4: 3 to < 12 years old Total
    Number of subjects analysed
    47 [39]
    28 [40]
    27 [41]
    23 [42]
    78 [43]
    125 [44]
    Units: percentage of participants
        number (confidence interval 95%)
    0.0 (0.0 to 7.6)
    3.6 (0.6 to 17.7)
    0.0 (0.0 to 12.5)
    0.0 (0.0 to 14.3)
    1.3 (0.2 to 6.9)
    0.8 (0.1 to 4.4)
    Notes
    [39] - Participants who completed treatment as planned with HCV RNA < 15 IU/mL at the end of treatment
    [40] - Participants who completed treatment as planned with HCV RNA < 15 IU/mL at the end of treatment
    [41] - Participants who completed treatment as planned with HCV RNA < 15 IU/mL at the end of treatment
    [42] - Participants who completed treatment as planned with HCV RNA < 15 IU/mL at the end of treatment
    [43] - Participants who completed treatment as planned with HCV RNA < 15 IU/mL at the end of treatment
    [44] - Participants who completed treatment as planned with HCV RNA < 15 IU/mL at the end of treatment
    No statistical analyses for this end point

    Secondary: Percentage of Participants with New HCV Infection (Reinfection)

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    End point title
    		 Percentage of Participants with New HCV Infection (Reinfection)
    End point description
    Reinfection is defined as confirmed HCV RNA ≥ 15 IU/mL in the post-treatment period in a participant who had HCV RNA < 15 IU/mL at the Final Treatment Visit, along with post-treatment detection of a different HCV genotype, subtype, or clade compared with Baseline, as determined by phylogenetic analysis of the nonstructural viral protein 3 (NS3) or NS5A, and/or NS5B gene sequences.
    End point type
    Secondary
    End point timeframe
    From the end of treatment up to post-treatment Week 144
    End point values
    		 Cohort 1: 12 to < 18 years old Cohort 2: 9 to < 12 years old Cohort 3: 6 to < 9 years old Cohort 4: 3 to < 6 years old Cohorts 2-4: 3 to < 12 years old Total
    Number of subjects analysed
    47 [45]
    29 [46]
    27 [47]
    24 [48]
    80 [49]
    127 [50]
    Units: percentage of participants
        number (confidence interval 95%)
    0.0 (0.0 to 7.6)
    0.0 (0.0 to 11.7)
    0.0 (0.0 to 12.5)
    0.0 (0.0 to 13.8)
    0.0 (0.0 to 4.6)
    0.0 (0.0 to 2.9)
    Notes
    [45] - Intention-to-treat population
    [46] - Intention-to-treat population
    [47] - Intention-to-treat population
    [48] - Intention-to-treat population
    [49] - Intention-to-treat population
    [50] - Intention-to-treat population
    No statistical analyses for this end point

    Secondary: Palatability Questionnaire Question 1: How Convenient or Inconvenient Was it to Prepare the Dose?

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    End point title
    		 Palatability Questionnaire Question 1: How Convenient or Inconvenient Was it to Prepare the Dose? [51]
    End point description
    For each participant who received the paediatric formulation (Cohorts 2 - 4), the parent(s)/guardian(s) completed a Palatability Questionnaire to provide feedback on the perception of the dosage form. The Palatability Questionnaire included 6 questions related to the administration and ingestion of the paediatric GLE + PIB formulation. Question 1 "How Convenient or Inconvenient Was it to Prepare the Dose?" was answered as "very convenient", "convenient", "borderline", "inconvenient", or "very inconvenient".
    End point type
    Secondary
    End point timeframe
    Final treatment visit (up to Week 8, 12, or 16, depending on treatment duration)
    Notes
    [51] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Assessment of palatability/acceptability of the paediatric formulation was not conducted in adolescents (Cohort 1).
    End point values
    		 Cohort 2: 9 to < 12 years old Cohort 3: 6 to < 9 years old Cohort 4: 3 to < 6 years old Cohorts 2-4: 3 to < 12 years old
    Number of subjects analysed
    28 [52]
    27 [53]
    23 [54]
    78 [55]
    Units: participants
        Very convenient
    7
    9
    9
    25
        Convenient
    13
    10
    8
    31
        Borderline
    2
    7
    4
    13
        Inconvenient
    6
    1
    1
    8
        Very inconvenient
    0
    0
    1
    1
    Notes
    [52] - Intention-to-treat population who completed the Palatability Questionnaire at final treatment visit
    [53] - Intention-to-treat population who completed the Palatability Questionnaire at final treatment visit
    [54] - Intention-to-treat population who completed the Palatability Questionnaire at final treatment visit
    [55] - Intention-to-treat population who completed the Palatability Questionnaire at final treatment visit
    No statistical analyses for this end point

    Secondary: Palatability Questionnaire Question 2: How Long Did it Typically Take for the Child to Take the Dose?

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    End point title
    		 Palatability Questionnaire Question 2: How Long Did it Typically Take for the Child to Take the Dose? [56]
    End point description
    For each participant who received the paediatric formulation (Cohorts 2 - 4), the parent(s)/guardian(s) completed a Palatability Questionnaire to provide feedback on the perception of the dosage form. The Palatability Questionnaire included 6 questions related to the administration and ingestion of the paediatric GLE + PIB formulation. Question 2 "How Long Did it Typically Take for the Child to Take the Dose?" was answered as "5 minutes or less", "5 to 15 minutes", "15 to 30 minutes", or "more than 30 minutes".
    End point type
    Secondary
    End point timeframe
    Final treatment visit (up to Week 8, 12, or 16, depending on duration of treatment)
    Notes
    [56] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Assessment of palatability/acceptability of the paediatric formulation was not conducted in adolescents (Cohort 1).
    End point values
    		 Cohort 2: 9 to < 12 years old Cohort 3: 6 to < 9 years old Cohort 4: 3 to < 6 years old Cohorts 2-4: 3 to < 12 years old
    Number of subjects analysed
    28 [57]
    27 [58]
    23 [59]
    78 [60]
    Units: participants
        5 minutes or less
    22
    23
    21
    66
        5 to 15 minutes
    5
    4
    2
    11
        15 to 30 minutes
    1
    0
    0
    1
        More than 30 minutes
    0
    0
    0
    0
    Notes
    [57] - Intention-to-treat population who completed the Palatability Questionnaire at final treatment visit
    [58] - Intention-to-treat population who completed the Palatability Questionnaire at final treatment visit
    [59] - Intention-to-treat population who completed the Palatability Questionnaire at final treatment visit
    [60] - Intention-to-treat population who completed the Palatability Questionnaire at final treatment visit
    No statistical analyses for this end point

    Secondary: Palatability Questionnaire Question 3: Were You Able to Successfully Administer the Whole Dose to the Child With 1 to 2 Teaspoons (5 to 10 mL) of Soft Food?

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    End point title
    		 Palatability Questionnaire Question 3: Were You Able to Successfully Administer the Whole Dose to the Child With 1 to 2 Teaspoons (5 to 10 mL) of Soft Food? [61]
    End point description
    For each participant who received the paediatric formulation (Cohorts 2 - 4), the parent(s)/guardian(s) completed a Palatability Questionnaire to provide feedback on the perception of the dosage form. The Palatability Questionnaire included 6 questions related to the administration and ingestion of the paediatric GLE + PIB formulation. Question 3 "Were You Able to Successfully Administer the Whole Dose to the Child With 1 to 2 Teaspoons (5 to 10 mL) of Soft Food?" was answered as "Yes" or "No".
    End point type
    Secondary
    End point timeframe
    Final treatment visit (up to Week 8, 12, or 16, depending on treatment duration)
    Notes
    [61] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Assessment of palatability/acceptability of the paediatric formulation was not conducted in adolescents (Cohort 1).
    End point values
    		 Cohort 2: 9 to < 12 years old Cohort 3: 6 to < 9 years old Cohort 4: 3 to < 6 years old Cohorts 2-4: 3 to < 12 years old
    Number of subjects analysed
    28 [62]
    27 [63]
    23 [64]
    78 [65]
    Units: participants
        Yes
    20
    19
    19
    58
        No
    8
    8
    3
    19
        Missing
    0
    0
    1
    1
    Notes
    [62] - Intention-to-treat population who completed the Palatability Questionnaire at final treatment visit
    [63] - Intention-to-treat population who completed the Palatability Questionnaire at final treatment visit
    [64] - Intention-to-treat population who completed the Palatability Questionnaire at final treatment visit
    [65] - Intention-to-treat population who completed the Palatability Questionnaire at final treatment visit
    No statistical analyses for this end point

    Secondary: Palatability Questionnaire Question 4: Did You Experience Any Resistance When Feeding the Child the Medicine?

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    End point title
    		 Palatability Questionnaire Question 4: Did You Experience Any Resistance When Feeding the Child the Medicine? [66]
    End point description
    For each participant who received the paediatric formulation (Cohorts 2 - 4), the parent(s)/guardian(s) completed a Palatability Questionnaire to provide feedback on the perception of the dosage form. The Palatability Questionnaire included 6 questions related to the administration and ingestion of the paediatric GLE + PIB formulation. Question 4 "Did You Experience Any Resistance When Feeding the Child the Medicine?" was answered as "Yes" or "No".
    End point type
    Secondary
    End point timeframe
    Final treatment visit (up to Week 8, 12, or 16 depending on treatment duration)
    Notes
    [66] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Assessment of palatability/acceptability of the paediatric formulation was not conducted in adolescents (Cohort 1).
    End point values
    		 Cohort 2: 9 to < 12 years old Cohort 3: 6 to < 9 years old Cohort 4: 3 to < 6 years old Cohorts 2-4: 3 to < 12 years old
    Number of subjects analysed
    28 [67]
    27 [68]
    23 [69]
    78 [70]
    Units: participants
        Yes
    6
    4
    7
    17
        No
    22
    23
    15
    60
        Missing
    0
    0
    1
    1
    Notes
    [67] - Intention-to-treat population who completed the Palatability Questionnaire at final treatment visit
    [68] - Intention-to-treat population who completed the Palatability Questionnaire at final treatment visit
    [69] - Intention-to-treat population who completed the Palatability Questionnaire at final treatment visit
    [70] - Intention-to-treat population who completed the Palatability Questionnaire at final treatment visit
    No statistical analyses for this end point

    Secondary: Palatability Questionnaire Question 4a: Type of Feeding Resistance

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    End point title
    		 Palatability Questionnaire Question 4a: Type of Feeding Resistance [71]
    End point description
    For each participant who received the paediatric formulation (Cohorts 2 - 4), the parent(s)/guardian(s) completed a Palatability Questionnaire to provide feedback on the perception of the dosage form. The Palatability Questionnaire included 6 questions related to the administration and ingestion of the paediatric GLE + PIB formulation. Question 4a "Type of feeding resistance?" tracks feeding resistance experienced at any time during treatment, and was answered as "Did not like taste of medicine", "Did not like texture of medicine", "Did not like the soft food used", "Did not like to swallow the amount of medicine", or "Unrelated to the medicine".
    End point type
    Secondary
    End point timeframe
    Up to final treatment visit (up to Week 8, 12, or 16 depending on treatment duration)
    Notes
    [71] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Assessment of palatability/acceptability of the paediatric formulation was not conducted in adolescents (Cohort 1).
    End point values
    		 Cohort 2: 9 to < 12 years old Cohort 3: 6 to < 9 years old Cohort 4: 3 to < 6 years old Cohorts 2-4: 3 to < 12 years old
    Number of subjects analysed
    28 [72]
    27 [73]
    23 [74]
    78 [75]
    Units: participants
        Did not like taste of medicine
    3
    5
    7
    15
        Did not like texture of medicine
    2
    2
    5
    9
        Did not like the soft food used
    3
    2
    0
    5
        Did not like to swallow the amount of medicine
    3
    2
    3
    8
        Unrelated to the medicine
    0
    0
    1
    1
        Missing
    0
    0
    1
    1
    Notes
    [72] - Intention-to-treat population who completed the Palatability Questionnaire at final treatment visit
    [73] - Intention-to-treat population who completed the Palatability Questionnaire at final treatment visit
    [74] - Intention-to-treat population who completed the Palatability Questionnaire at final treatment visit
    [75] - Intention-to-treat population who completed the Palatability Questionnaire at final treatment visit
    No statistical analyses for this end point

    Secondary: Palatability Questionnaire Question 5: How Easy or Difficult Was it for the Child to Swallow the Medicine?

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    End point title
    		 Palatability Questionnaire Question 5: How Easy or Difficult Was it for the Child to Swallow the Medicine? [76]
    End point description
    For each participant who received the paediatric formulation (Cohorts 2 - 4), the parent(s)/guardian(s) completed a Palatability Questionnaire to provide feedback on the perception of the dosage form. The Palatability Questionnaire included 6 questions related to the administration and ingestion of the paediatric GLE/PIB formulation. Question 5 "How Easy or Difficult Was it for the Child to Swallow the Medicine?" was answered as "very easy", "easy", "borderline", "difficult", or "very difficult."
    End point type
    Secondary
    End point timeframe
    Final treatment visit (up to Week 8, 12, or 16, depending on treatment duration)
    Notes
    [76] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Assessment of palatability/acceptability of the paediatric formulation was not conducted in adolescents (Cohort 1).
    End point values
    		 Cohort 2: 9 to < 12 years old Cohort 3: 6 to < 9 years old Cohort 4: 3 to < 6 years old Cohorts 2-4: 3 to < 12 years old
    Number of subjects analysed
    28 [77]
    27 [78]
    23 [79]
    78 [80]
    Units: participants
        Very easy
    10
    8
    11
    29
        Easy
    13
    16
    10
    39
        Borderline
    4
    3
    1
    8
        Difficult
    1
    0
    0
    1
        Very difficult
    0
    0
    0
    0
        Missing
    0
    0
    1
    1
    Notes
    [77] - Intention-to-treat population who completed the Palatability Questionnaire at final treatment visit
    [78] - Intention-to-treat population who completed the Palatability Questionnaire at final treatment visit
    [79] - Intention-to-treat population who completed the Palatability Questionnaire at final treatment visit
    [80] - Intention-to-treat population who completed the Palatability Questionnaire at final treatment visit
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are reported from first dose of study drug up to 30 days after last dose (up to 20 weeks depending on the duration of treatment). Deaths are reported through Post Treatment Week 144.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Cohort 1: 12 to < 18 years old
    Reporting group description
    		 Adolescents aged 12 to < 18 years old received the adult formulation of GLE/PIB 100 mg/40 mg co-formulated film-coated tablets for a once daily total dose of 300 mg/120 mg by mouth for 8, 12, or 16 weeks depending on HCV genotype, cirrhosis status, and prior treatment experience.

    Reporting group title
    Cohort 2: 9 to < 12 years old
    Reporting group description
    		 Children aged 9 to < 12 years old received a paediatric formulation of GLE + PIB as small film-coated granules taken with a small amount of food once daily for 8, 12, or 16 weeks depending on HCV genotype, cirrhosis status, and prior treatment experience. The final dose for children weighing 30 to < 45 kg was GLE 250 mg + PIB 100 mg.

    Reporting group title
    Cohort 3: 6 to < 9 years old
    Reporting group description
    		 Children aged 6 to < 9 years old received a paediatric formulation of GLE + PIB as small film-coated granules taken with a small amount of food once daily for 8, 12, or 16 weeks depending on HCV genotype, cirrhosis status, and prior treatment experience. The final dose for children weighing ≥ 20 to < 30 kg was GLE 200 mg + PIB 80 mg; one participant received GLE 250 mg + PIB 100 mg based on weight at screening.

    Reporting group title
    Cohort 4: 3 to < 6 years old
    Reporting group description
    		 Children aged 3 to < 6 years old received a paediatric formulation of GLE + PIB as small film-coated granules taken with a small amount of food once daily for 8, 12, or 16 weeks depending on HCV genotype, cirrhosis status, and prior treatment experience. The final dose for children weighing 12 to < 20 kg was GLE 150 mg + PIB 60 mg; one participant received GLE 200 mg + PIB 80 mg based on weight at screening.

    Reporting group title
    Cohorts 2-4: 3 to < 12 years old
    Reporting group description
    		 Children aged 3 to < 12 years old received a paediatric formulation of GLE + PIB at a final dose of GLE 250 mg + PIB 100 mg (children 9 to < 12 years of age), GLE 200 mg + PIB 80 mg (children 6 to < 9 years of age), or GLE 150 mg + PIB 60 mg (children 3 to < 6 years of age) as small film-coated granules taken with a small amount of food once daily for 8, 12, or 16 weeks depending on HCV genotype, cirrhosis status, and prior treatment experience.

    Reporting group title
    All Subjects
    Reporting group description
    		 Participants in Cohorts 1-4 received glecaprevir and pibrentasvir based on age and weight once daily for 8, 12, or 16 weeks depending on HCV genotype, cirrhosis status, and prior treatment experience.

    Serious adverse events
    		 Cohort 1: 12 to < 18 years old Cohort 2: 9 to < 12 years old Cohort 3: 6 to < 9 years old Cohort 4: 3 to < 6 years old Cohorts 2-4: 3 to < 12 years old All Subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 80 (0.00%)
    0 / 127 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1: 12 to < 18 years old Cohort 2: 9 to < 12 years old Cohort 3: 6 to < 9 years old Cohort 4: 3 to < 6 years old Cohorts 2-4: 3 to < 12 years old All Subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    31 / 47 (65.96%)
    15 / 29 (51.72%)
    16 / 27 (59.26%)
    17 / 24 (70.83%)
    48 / 80 (60.00%)
    79 / 127 (62.20%)
    Cardiac disorders
    PALPITATIONS
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 29 (0.00%)
    2 / 27 (7.41%)
    0 / 24 (0.00%)
    2 / 80 (2.50%)
    2 / 127 (1.57%)
         occurrences all number
    0
    0
    2
    0
    2
    2
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    8 / 47 (17.02%)
    3 / 29 (10.34%)
    6 / 27 (22.22%)
    3 / 24 (12.50%)
    12 / 80 (15.00%)
    20 / 127 (15.75%)
         occurrences all number
    12
    3
    6
    3
    12
    24
    General disorders and administration site conditions
    FATIGUE
         subjects affected / exposed
    5 / 47 (10.64%)
    1 / 29 (3.45%)
    3 / 27 (11.11%)
    3 / 24 (12.50%)
    7 / 80 (8.75%)
    12 / 127 (9.45%)
         occurrences all number
    5
    1
    3
    3
    7
    12
    PYREXIA
         subjects affected / exposed
    5 / 47 (10.64%)
    1 / 29 (3.45%)
    2 / 27 (7.41%)
    2 / 24 (8.33%)
    5 / 80 (6.25%)
    10 / 127 (7.87%)
         occurrences all number
    6
    1
    3
    2
    6
    12
    Ear and labyrinth disorders
    MOTION SICKNESS
         subjects affected / exposed
    0 / 47 (0.00%)
    2 / 29 (6.90%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    2 / 80 (2.50%)
    2 / 127 (1.57%)
         occurrences all number
    0
    2
    0
    0
    2
    2
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    2 / 47 (4.26%)
    2 / 29 (6.90%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    3 / 80 (3.75%)
    5 / 127 (3.94%)
         occurrences all number
    2
    2
    1
    0
    3
    5
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 29 (6.90%)
    1 / 27 (3.70%)
    2 / 24 (8.33%)
    5 / 80 (6.25%)
    6 / 127 (4.72%)
         occurrences all number
    1
    2
    1
    3
    6
    7
    DIARRHOEA
         subjects affected / exposed
    3 / 47 (6.38%)
    2 / 29 (6.90%)
    4 / 27 (14.81%)
    2 / 24 (8.33%)
    8 / 80 (10.00%)
    11 / 127 (8.66%)
         occurrences all number
    3
    2
    4
    2
    8
    11
    NAUSEA
         subjects affected / exposed
    4 / 47 (8.51%)
    2 / 29 (6.90%)
    2 / 27 (7.41%)
    1 / 24 (4.17%)
    5 / 80 (6.25%)
    9 / 127 (7.09%)
         occurrences all number
    4
    2
    2
    1
    5
    9
    VOMITING
         subjects affected / exposed
    5 / 47 (10.64%)
    1 / 29 (3.45%)
    6 / 27 (22.22%)
    4 / 24 (16.67%)
    11 / 80 (13.75%)
    16 / 127 (12.60%)
         occurrences all number
    5
    1
    6
    4
    11
    16
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    2 / 47 (4.26%)
    1 / 29 (3.45%)
    1 / 27 (3.70%)
    5 / 24 (20.83%)
    7 / 80 (8.75%)
    9 / 127 (7.09%)
         occurrences all number
    2
    1
    1
    6
    8
    10
    DYSPNOEA
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    3 / 24 (12.50%)
    3 / 80 (3.75%)
    3 / 127 (2.36%)
         occurrences all number
    0
    0
    0
    3
    3
    3
    NASAL CONGESTION
         subjects affected / exposed
    4 / 47 (8.51%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    0 / 80 (0.00%)
    4 / 127 (3.15%)
         occurrences all number
    4
    0
    0
    0
    0
    4
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    5 / 47 (10.64%)
    1 / 29 (3.45%)
    0 / 27 (0.00%)
    0 / 24 (0.00%)
    1 / 80 (1.25%)
    6 / 127 (4.72%)
         occurrences all number
    5
    1
    0
    0
    1
    6
    RHINORRHOEA
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    2 / 24 (8.33%)
    2 / 80 (2.50%)
    2 / 127 (1.57%)
         occurrences all number
    0
    0
    0
    2
    2
    2
    Skin and subcutaneous tissue disorders
    PRURITUS
         subjects affected / exposed
    0 / 47 (0.00%)
    2 / 29 (6.90%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    3 / 80 (3.75%)
    3 / 127 (2.36%)
         occurrences all number
    0
    2
    1
    0
    3
    3
    RASH
         subjects affected / exposed
    1 / 47 (2.13%)
    2 / 29 (6.90%)
    1 / 27 (3.70%)
    0 / 24 (0.00%)
    3 / 80 (3.75%)
    4 / 127 (3.15%)
         occurrences all number
    1
    3
    1
    0
    4
    5
    Infections and infestations
    LICE INFESTATION
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    2 / 24 (8.33%)
    2 / 80 (2.50%)
    2 / 127 (1.57%)
         occurrences all number
    0
    0
    0
    2
    2
    2
    NASOPHARYNGITIS
         subjects affected / exposed
    11 / 47 (23.40%)
    4 / 29 (13.79%)
    1 / 27 (3.70%)
    1 / 24 (4.17%)
    6 / 80 (7.50%)
    17 / 127 (13.39%)
         occurrences all number
    12
    5
    1
    1
    7
    19
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    9 / 47 (19.15%)
    1 / 29 (3.45%)
    3 / 27 (11.11%)
    2 / 24 (8.33%)
    6 / 80 (7.50%)
    15 / 127 (11.81%)
         occurrences all number
    11
    1
    6
    2
    9
    20
    VIRAL INFECTION
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 29 (0.00%)
    2 / 27 (7.41%)
    2 / 24 (8.33%)
    4 / 80 (5.00%)
    4 / 127 (3.15%)
         occurrences all number
    0
    0
    2
    2
    4
    4
    Metabolism and nutrition disorders
    INCREASED APPETITE
         subjects affected / exposed
    0 / 47 (0.00%)
    0 / 29 (0.00%)
    0 / 27 (0.00%)
    2 / 24 (8.33%)
    2 / 80 (2.50%)
    2 / 127 (1.57%)
         occurrences all number
    0
    0
    0
    2
    2
    2

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Jul 2017
    Key changes included: - Included specific changes for subjects in Japan to account for the participation of subjects in Japan. - Updated language regarding the SVR12 efficacy analysis to clarify the criteria that will establish when the Wilson's score method will be used as opposed to the normal approximation to the binomial distribution in determination of the confidence interval as per FDA Biometric comment.
    09 Mar 2018
    Key changes included: - Provided dosing details about the GLE/PIB pediatric formulation to be used in Part 2 for subjects 3 to 11 years old. - Updated the proposed doses for 3 to 11 year old subjects (proposed dosing for each age group and weight range were added based on the current knowledge of the GLE and PIB exposures). - Included retreatment study information clarifying subjects in Part 1 who met the virologic failure criteria in the PT period have the option to enroll into Study M15-942 for retreatment of their virologic failure. - Included information on Study M17-142 results for pediatric formulation to support the proposed pediatric formulation dosing. - Updated the recommendations for use of pravastatin or rosuvastatin dose to clarify the timing of statin management. - Updated the statistical analysis section to clarify the number of planned analyses and to align the description of endpoints with the approved PIP.
    22 Mar 2019
    Key changes included: - Updated the proposed doses for ≥ 3 to < 12 year old subjects based on current PK and safety knowledge of the pediatric doses for GLE and PIB. - Updated total number of subjects to be enrolled from 110 to 125 subjects, due to change in dosing and need for additional subject enrollment. - Details on the waived pediatric requirement for children < 3 years were added. - Update to the product identity with proposed doses and storage requirements, including a reference to the interchangeable nomenclature of pellets and granules. - The Suspected Unexpected Serious Adverse Reaction reporting process was added per company guidance. - Clarification on the use of the eCRF questionnaire added that would require completion in the event of active Hepatitis B. - Clarification provided on the lab draw procedures for the coagulation panel and addition of collection of HCV resistance samples.

    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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