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    Clinical Trial Results:
    A Single Arm, Open-label Study to Evaluate the Efficacy and Safety of Glecaprevir (GLE)/Pibrentasvir (PIB) in Treatment Naïve Adults with Chronic Hepatitis C Virus (HCV) Genotype 1, 2, 4, 5 or 6 Infection and Compensated Cirrhosis

    Summary
    EudraCT number
    		 2016-004967-38
    Trial protocol
    		 GR   PL   PT   HU   CZ   BG   IE   ES   GB   RO  
    Global end of trial date
    08 Nov 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Jul 2020
    First version publication date
    30 Jul 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    M16-135
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03089944
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AbbVie
    Sponsor organisation address
    AbbVie House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6 4UB
    Public contact
    Global Medical Services, AbbVie, +001 8006339110, abbvieclinicaltrials@abbvie.com
    Scientific contact
    Global Medical Services, AbbVie, +001 8006339110, abbvieclinicaltrials@abbvie.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Nov 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    A Phase 3b, single arm, open-label, multicenter study in treatment naïve adults with chronic HCV infection and compensated cirrhosis to assess the safety of 8 weeks of treatment with glecaprevir/pibrentasvir and to demonstrate the efficacy of the sustained virologic response 12 weeks post dosing (SVR12) rates of 8 weeks of treatment with glecaprevir/pibrentasvir compared to the historical SVR12 rates of 12 weeks of treatment with glecaprevir/pibrentasvir.
    Protection of trial subjects
    Subject read and understood the information provided about the study and gave written permission.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Apr 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 12
    Country: Number of subjects enrolled
    Portugal: 7
    Country: Number of subjects enrolled
    Spain: 20
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    Bulgaria: 20
    Country: Number of subjects enrolled
    Czech Republic: 17
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Hungary: 15
    Country: Number of subjects enrolled
    Ireland: 5
    Country: Number of subjects enrolled
    Canada: 8
    Country: Number of subjects enrolled
    Israel: 16
    Country: Number of subjects enrolled
    Italy: 15
    Country: Number of subjects enrolled
    Puerto Rico: 20
    Country: Number of subjects enrolled
    Romania: 21
    Country: Number of subjects enrolled
    Russian Federation: 30
    Country: Number of subjects enrolled
    Taiwan: 15
    Country: Number of subjects enrolled
    United States: 89
    Country: Number of subjects enrolled
    Vietnam: 9
    Worldwide total number of subjects
    343
    EEA total number of subjects
    156
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    257
    From 65 to 84 years
    85
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The intent to treat (ITT) population included 343 subjects that enrolled and received ≥ 1 dose of study drug. The Per Protocol (PP) Population, a subset of ITT, excluded subjects who experienced breakthrough, or discontinued treatment prior to Week 8, or had no HCV RNA value in SVR12 visit window or later for reasons other than virologic failure.

    Period 1
    Period 1 title
    GLE/PIB for 8 weeks (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Glecaprevir (GLE)/Pibrentasvir (PIB) for 8 weeks
    Arm description
    		 Glecaprevir (GLE)/Pibrentasvir (PIB) 300 mg/120 mg administered orally once daily (QD) for 8 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Glecaprevir/Pibrentasvir tablet
    Investigational medicinal product code
    Other name
    ABT-493, ABT-530
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received glecaprevir (GLE)/pibrentasvir(PIB) 300 mg/120 mg orally (with food) once daily for 8 weeks.

    Number of subjects in period 1
    		Glecaprevir (GLE)/Pibrentasvir (PIB) for 8 weeks
    Started
    343
    Completed
    331
    Not completed
    12
         Adverse event, non-fatal
    1
         Other, not specified
    1
         Lost to follow-up
    8
         Withdrew consent
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    GLE/PIB for 8 weeks
    Reporting group description
    		 -

    Reporting group values
    		 GLE/PIB for 8 weeks Total
    Number of subjects
    		 343 343
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.61 ± 10.58 -
    Gender categorical
    Units: Subjects
        Female
    		 126 126
        Male
    		 217 217
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 43 43
        Not Hispanic or Latino
    		 300 300

    End points

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    End points reporting groups
    Reporting group title
    Glecaprevir (GLE)/Pibrentasvir (PIB) for 8 weeks
    Reporting group description
    		 Glecaprevir (GLE)/Pibrentasvir (PIB) 300 mg/120 mg administered orally once daily (QD) for 8 weeks.

    Primary: Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment (SVR12) in Hepatitis C Virus (HCV) Genotype (GT) 1,2,4,5 and 6-infected Participants in the Per Protocol (PP) Population

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    End point title
    		 Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment (SVR12) in Hepatitis C Virus (HCV) Genotype (GT) 1,2,4,5 and 6-infected Participants in the Per Protocol (PP) Population [1]
    End point description
    SVR12 was defined as plasma hepatitis C virus ribonucleic acid (HCV RNA) level less than the lower limit of quantification (<LLOQ; less than 15 IU/mL) 12 weeks after the last dose of study drug. Efficacy of the 8-week treatment duration compared to the historical 12-week treatment duration was demonstrated if the lower bound of the 2-sided 95% confidence interval (CI) for the percentage of participants with HCV GT1, GT2, GT4, GT5, or GT6 infection in the 8 week treatment duration achieving SVR12 was greater than 94% in the PP population. Efficacy analyses were performed following a fixed-sequence testing procedure to control the type I error rate. The percentage of participants achieving SVR12 was summarized with a 2-sided 95% CI, calculated using the normal approximation to the binomial distribution. If the number of participants who failed to achieve SVR12 rate was less than 5, the Wilson's score method was used to calculate the CI.
    End point type
    Primary
    End point timeframe
    12 weeks after last dose of study drug
    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: The statistical analysis are presented in the Endpoint Data Table, per protocol.
    End point values
    		 Glecaprevir (GLE)/Pibrentasvir (PIB) for 8 weeks
    Number of subjects analysed
    274 [2]
    Units: percentage of participants
    number (confidence interval 95%)
        Percentage with SVR12 (PP)
    100 (98.6 to 100.0)
    Notes
    [2] - Per Protocol (PP) Population
    No statistical analyses for this end point

    Primary: Percentage of Participants With SVR12 in HCV GT 1,2,4,5 and 6-infected Participants in the Intent-To-Treat (ITT) Population

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    End point title
    		 Percentage of Participants With SVR12 in HCV GT 1,2,4,5 and 6-infected Participants in the Intent-To-Treat (ITT) Population [3]
    End point description
    SVR12 was defined as HCV RNA level less than the LLOQ (less than 15 IU/mL) 12 weeks after the last dose of study drug. Efficacy of the 8-week treatment duration compared to the historical 12-week treatment duration was demonstrated if the lower bound of the 2-sided 95% CI for the percentage of participants with HCV GT1, GT2, GT4, GT5, or GT6 infection in the 8 week treatment duration achieving SVR12 was greater than 93% in the ITT population. Primary efficacy analyses were performed following a fixed-sequence testing procedure to control the type I error rate. The percentage of participants achieving SVR12 was summarized with a 2-sided 95% CI, calculated using the normal approximation to the binomial distribution. If the number of participants who failed to achieve SVR12 rate was less than 5, the Wilson's score method was used to calculate the CI.
    End point type
    Primary
    End point timeframe
    12 weeks after last dose of study drug
    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: The statistical analysis are presented in the Endpoint Data Table, per protocol.
    End point values
    		 Glecaprevir (GLE)/Pibrentasvir (PIB) for 8 weeks
    Number of subjects analysed
    280 [4]
    Units: percentage of participants
    number (confidence interval 95%)
        Percentage with SVR12 (ITT)
    98.2 (96.7 to 99.8)
    Notes
    [4] - Intent to treat (ITT) population: Participants who received at least one dose of study drug.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With SVR12 in HCV GT1-6-infected Participants in the PP Population

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    End point title
    		 Percentage of Participants With SVR12 in HCV GT1-6-infected Participants in the PP Population
    End point description
    SVR12 was defined as HCV RNA level less than the LLOQ (less than 15 IU/mL) 12 weeks after the last dose of study drug. Efficacy of the 8-week treatment duration compared to the historical 12-week treatment duration was demonstrated if the lower bound of the 2-sided 95% CI for the percentage of participants with HCV GT1, GT2, GT3, GT4, GT5, or GT6 infection in the 8 week treatment duration achieving SVR12 was greater than 94% in the PP population. These efficacy analyses were performed only if success was demonstrated for both primary efficacy analyses, following a fixed-sequence testing procedure.
    End point type
    Secondary
    End point timeframe
    12 weeks after last dose of study drug
    End point values
    		 Glecaprevir (GLE)/Pibrentasvir (PIB) for 8 weeks
    Number of subjects analysed
    335 [5]
    Units: percentage of participants
    number (confidence interval 95%)
        With SVR12 in HCV GT1-6-infected PP Population
    99.7 (98.3 to 99.9)
    Notes
    [5] - PP population
    No statistical analyses for this end point

    Secondary: Percentage of Participants With SVR12 in HCV GT1-6-infected Participants in the ITT Population

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    End point title
    		 Percentage of Participants With SVR12 in HCV GT1-6-infected Participants in the ITT Population
    End point description
    SVR12 was defined as HCV RNA level less than the LLOQ (less than 15 IU/mL) 12 weeks after the last dose of study drug. Efficacy of the 8-week treatment duration compared to the historical 12-week treatment duration was demonstrated if the lower bound of the 2-sided 95% CI for the percentage of participants with HCV GT1, GT2, GT3, GT4, GT5, or GT6 infection in the 8 week treatment duration achieving SVR12 was greater than 93% in the ITT population. These efficacy analyses were performed only if success was demonstrated for both primary efficacy analyses, following a fixed-sequence testing procedure.
    End point type
    Secondary
    End point timeframe
    12 weeks after the last dose of study drug
    End point values
    		 Glecaprevir (GLE)/Pibrentasvir (PIB) for 8 weeks
    Number of subjects analysed
    343 [6]
    Units: Percentage of participants
    number (confidence interval 95%)
        With SVR12 in HCV GT-1-6-infected in ITT
    97.7 (96.1 to 99.3)
    Notes
    [6] - ITT population
    No statistical analyses for this end point

    Secondary: Percentage of Participants With On-treatment Virologic Failure in the ITT Population

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    End point title
    		 Percentage of Participants With On-treatment Virologic Failure in the ITT Population
    End point description
    On-treatment virologic failure was defined as confirmed HCV RNA ≥ 100 IU/mL after HCV RNA < LLOQ during treatment; confirmed increase of > 1 log(subscript)10(subscript) IU/mL above the lowest value post-baseline in HCV RNA during treatment; or HCV RNA ≥ LLOQ at end of treatment with at least 6 weeks of treatment.
    End point type
    Secondary
    End point timeframe
    8 weeks on treatment
    End point values
    		 Glecaprevir (GLE)/Pibrentasvir (PIB) for 8 weeks
    Number of subjects analysed
    343 [7]
    Units: Percentage of participants
    number (confidence interval 95%)
        With On-treatment Virologic Failure in ITT
    0 (0.0 to 1.1)
    Notes
    [7] - ITT population
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Post-treatment Relapse

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    End point title
    		 Percentage of Participants With Post-treatment Relapse
    End point description
    Post-treatment relapse was defined as confirmed HCV RNA ≥ LLOQ between the end of treatment and 12 weeks after the last dose of study drug among participants who completed treatment as planned (defined as study drug duration ≥ 52 days for participants assigned to 8 weeks of treatment) and with HCV RNA levels < LLOQ at the end of treatment excluding participants who had been reinfected.
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks after the last dose of study drug
    End point values
    		 Glecaprevir (GLE)/Pibrentasvir (PIB) for 8 weeks
    Number of subjects analysed
    336 [8]
    Units: Percentage of Participants
    number (confidence interval 95%)
        Participants with Post treatment Relapse
    0.3 (0.1 to 1.7)
    Notes
    [8] - ITT population
    No statistical analyses for this end point

    Secondary: Percentage of HCV GT3-infected Participants Who Achieved SVR12 in the PP Population

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    End point title
    		 Percentage of HCV GT3-infected Participants Who Achieved SVR12 in the PP Population
    End point description
    SVR12 was defined as HCV RNA level less than the LLOQ (less than 15 IU/mL) 12 weeks after the last dose of study drug.
    End point type
    Secondary
    End point timeframe
    12 weeks after the last dose of study drug
    End point values
    		 Glecaprevir (GLE)/Pibrentasvir (PIB) for 8 weeks
    Number of subjects analysed
    61 [9]
    Units: Percentage of participants
    number (confidence interval 95%)
        HCV GT3-infected Who Achieved SVR12 in PP
    98.4 (91.3 to 99.7)
    Notes
    [9] - PP population
    No statistical analyses for this end point

    Secondary: Percentage of HCV GT3-infected Participants Who Achieved SVR12 in the ITT Population

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    End point title
    		 Percentage of HCV GT3-infected Participants Who Achieved SVR12 in the ITT Population
    End point description
    SVR12 was defined as HCV RNA level less than the LLOQ (less than 15 IU/mL) 12 weeks after the last dose of study drug.
    End point type
    Secondary
    End point timeframe
    12 weeks after the last dose of study drug
    End point values
    		 Glecaprevir (GLE)/Pibrentasvir (PIB) for 8 weeks
    Number of subjects analysed
    63 [10]
    Units: Percentage of Participants
    number (confidence interval 95%)
        HCV GT3-infected Who Achieved SVR12 in ITT
    95.2 (86.9 to 98.4)
    Notes
    [10] - ITT population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment emergent adverse events (TEAEs) were defined as any adverse event with an onset date that was on or after the first dose of study drug and no more than 30 days after the last dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Glecaprevir (GLE)/Pibrentasvir (PIB) for 8 weeks
    Reporting group description
    		 Glecaprevir (GLE)/Pibrentasvir (PIB) 300 mg/120 mg administered orally once daily (QD) for 8 weeks.

    Serious adverse events
    		 Glecaprevir (GLE)/Pibrentasvir (PIB) for 8 weeks
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 343 (1.75%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma gastric
         subjects affected / exposed
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 343 (0.29%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Glecaprevir (GLE)/Pibrentasvir (PIB) for 8 weeks
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    82 / 343 (23.91%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    28 / 343 (8.16%)
         occurrences all number
    31
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    30 / 343 (8.75%)
         occurrences all number
    31
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    19 / 343 (5.54%)
         occurrences all number
    19
    Skin and subcutaneous tissue disorders
    Pruritis
         subjects affected / exposed
    29 / 343 (8.45%)
         occurrences all number
    31

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Apr 2017
    This amendment clarified the protocol deviation process, specified that participants experiencing virologic failure will be offered retreatment and excluded participants with a medical history of solid organ transplantation.
    06 Sep 2017
    This amendment included an update to Primary Efficacy Endpoints, based on regulatory authority feedback, the analysis of SVR12 based on the ITT population has been elevated from a secondary to a primary efficacy endpoint , references to non-inferiority have been removed, and the Wilson score method will be used to calculate the confidence intervals for the primary efficacy endpoints if the number of SVR12 non-responders is less than 5, clarification of pregnancy test requirements during the study,include additional language on empiric use of lactulose and rifaximin and to clarify the list of approved and investigational anti-HCV compounds and that historical presence of HCC within the previous 5 years is exclusionary,clarify that specific statins must be discontinued at least 14 days or 10 half-lives (whichever is longer) prior to the first dose of study drug, clarify when study procedures to be performed, and clarify that the Physical Exam and labs are to be drawn for FibroTest and Child-Pugh scores.
    11 Jun 2018
    Allow for the enrollment of participants infected with HCV Genotype 3 to evaluate the efficacy and safety of an 8-week treatment regimen in a treatment-naïve cirrhotic patient population inclusive of patients with HCV GT3 infection. Update prohibited therapy based on the marketing approval of GLE/PIB.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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