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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-controlled, Multicenter Study to Evaluate the Efficacy and Safety of ABT-493/ABT-530 in Adults with Chronic Hepatitis C Virus Genotype 2 Infection (ENDURANCE-2)

    Summary
    EudraCT number
    		 2015-002348-14
    Trial protocol
    		 BE   PT   LT   IT  
    Global end of trial date
    23 Feb 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Feb 2018
    First version publication date
    02 Feb 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    M15-464
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02640482
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AbbVie Deutschland GmbH & Co. KG
    Sponsor organisation address
    AbbVie House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6-4UB
    Public contact
    Global Medical Services, AbbVie, 001 800-633-9110,
    Scientific contact
    Neddie Zadeikis, AbbVie, neddie.zadeikis@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
    23 Feb 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Feb 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to evaluate the safety and efficacy of ABT-493/ABT-530 in adults with genotype 2 chronic hepatitis C virus (HCV) infection.
    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
    27 Nov 2015
    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
    Italy: 54
    Country: Number of subjects enrolled
    Korea, Republic of: 65
    Country: Number of subjects enrolled
    Taiwan: 41
    Country: Number of subjects enrolled
    United States: 53
    Country: Number of subjects enrolled
    Portugal: 7
    Country: Number of subjects enrolled
    Belgium: 21
    Country: Number of subjects enrolled
    France: 45
    Country: Number of subjects enrolled
    Lithuania: 18
    Worldwide total number of subjects
    304
    EEA total number of subjects
    145
    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)
    203
    From 65 to 84 years
    101
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Safety population: All participants who received at least one dose of study drug.

    Pre-assignment
    Screening details
    		 A total of 304 subjects were enrolled of which 302 received at least 1 dose of study drug and were included in the intent-to-treat (ITT) population (N=302; 202 in Arm A and 100 in Arm B). Most efficacy analyses were performed on Arm A only (N=202) and excluded prior sofosbuvir (SOF) + ribavirin (RBV) ± pegylated-interferon (pegIFN) failures (N=6).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A DB Active Drug
    Arm description
    		 ABT-493/ABT-530 (300 mg/120 mg) coformulated once daily (QD) for 12 weeks (double-blind [DB] treatment period)
    Arm type
    		 Experimental

    Investigational medicinal product name
    ABT-493/ABT-530
    Investigational medicinal product code
    Other name
    ABT-493 also known as glecaprevir, ABT-530 also known as pibrentasvir, MAVIRET
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet; ABT-493 coformulated with ABT-530 administered orally

    Arm title
    		 Arm B DB Placebo Then OL Active
    Arm description
    		 Placebo for ABT-493/ABT-530 QD for 12 weeks (DB treatment period) followed by ABT-493/ABT-530 (300 mg/120 mg) coformulated once daily (QD) for 12 weeks (open-label [OL] treatment period)
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablet administered orally

    Investigational medicinal product name
    ABT-493/ABT-530
    Investigational medicinal product code
    Other name
    ABT-493 also known as glecaprevir, ABT-530 also known as pibrentasvir, MAVIRET
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablet; ABT-493 coformulated with ABT-530 administered orally.

    Number of subjects in period 1 [1]
    		Arm A DB Active Drug Arm B DB Placebo Then OL Active
    Started
    202
    100
    Completed
    199
    100
    Not completed
    3
    0
         Lost to follow-up
    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: A total of 304 subjects were enrolled of which 302 received at least 1 dose of study drug and were included in the intent-to-treat (ITT) population (N = 302; 202 subjects in Arm A and 100 subjects in Arm B). Most efficacy analyses were performed on Arm A only (N = 202) and excluded prior SOF + RBV ± pegIFN failures (N = 6).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A DB Active Drug
    Reporting group description
    		 ABT-493/ABT-530 (300 mg/120 mg) coformulated once daily (QD) for 12 weeks (double-blind [DB] treatment period)

    Reporting group title
    Arm B DB Placebo Then OL Active
    Reporting group description
    		 Placebo for ABT-493/ABT-530 QD for 12 weeks (DB treatment period) followed by ABT-493/ABT-530 (300 mg/120 mg) coformulated once daily (QD) for 12 weeks (open-label [OL] treatment period)

    Reporting group values
    		 Arm A DB Active Drug Arm B DB Placebo Then OL Active Total
    Number of subjects
    		 202 100 302
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.77 ( 12.79 ) 57.60 ( 12.04 ) -
    Gender categorical
    Units: Subjects
        Female
    		 104 55 159
        Male
    		 98 45 143

    End points

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    End points reporting groups
    Reporting group title
    Arm A DB Active Drug
    Reporting group description
    		 ABT-493/ABT-530 (300 mg/120 mg) coformulated once daily (QD) for 12 weeks (double-blind [DB] treatment period)

    Reporting group title
    Arm B DB Placebo Then OL Active
    Reporting group description
    		 Placebo for ABT-493/ABT-530 QD for 12 weeks (DB treatment period) followed by ABT-493/ABT-530 (300 mg/120 mg) coformulated once daily (QD) for 12 weeks (open-label [OL] treatment period)

    Primary: Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment (SVR12) in Arm A DB Active Drug Excluding Prior SOF + Ribavirin (RBV) ± pegIFN Failures: Noninferiority Analysis

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    End point title
    		 Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment (SVR12) in Arm A DB Active Drug Excluding Prior SOF + Ribavirin (RBV) ± pegIFN Failures: Noninferiority Analysis [1] [2]
    End point description
    SVR12 was defined as plasma HCV RNA level <LLOQ 12 weeks after the last dose of study drug. The primary efficacy endpoint was the noninferiority of the percentage of participants who achieved SVR12 in Arm A Double Blind (DB) Active Drug excluding prior SOF + RBV ± pegIFN failures compared with the historical control rate for patients treated with the current standard of care (SOC) (SOF + RBV for 12 weeks). The lower confidence bound of the 2-sided 95% confidence interval (95% CI) for the percentage of participants with SVR12 must exceed 89% to achieve noninferiority.
    End point type
    Primary
    End point timeframe
    12 weeks after the last actual dose of active 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 noninferiority of the rate of sustained virologic response at 12 weeks after treatment for Arm A as compared with the historical rate for patients treated with the current standard of care (SOF + RBV for 12 weeks) was analyzed; the lower confidence bound of the 2-sided 95% CI for the percentage of participants with sustained virologic response at 12 weeks after treatment must exceed 89% to achieve noninferiority.
    [2] - 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: The primary endpoint included Arm A.
    End point values
    		 Arm A DB Active Drug
    Number of subjects analysed
    196 [3]
    Units: Percentage of participants
        number (confidence interval 95%)
    99.5 (98.5 to 100)
    Notes
    [3] - ITT participants in Arm A excluding participants with prior SOF + RBV ± pegIFN failures.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With SVR12 in Arm A DB Active Drug Excluding Prior SOF + RBV ± pegIFN Failures: Superiority Analysis

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    End point title
    		 Percentage of Participants With SVR12 in Arm A DB Active Drug Excluding Prior SOF + RBV ± pegIFN Failures: Superiority Analysis [4]
    End point description
    SVR12 was defined as plasma HCV RNA level <LLOQ 12 weeks after the last dose of study drug. The secondary efficacy endpoint was the superiority of the percentage of participants who achieved SVR12 in Arm A Double Blind (DB) Active Drug excluding prior SOF + RBV ± pegIFN failures compared with the historical control rate for patients treated with the current standard of care (SOC) (SOF + RBV for 12 weeks). The lower confidence bound of the 2-sided 95% CI for the percentage of participants with SVR12 must exceed 95% to achieve superiority.
    End point type
    Secondary
    End point timeframe
    12 weeks after the last actual dose of active study drug
    Notes
    [4] - 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: The secondary endpoint included Arm A.
    End point values
    		 Arm A DB Active Drug
    Number of subjects analysed
    196 [5]
    Units: Percentage of participants
        number (confidence interval 95%)
    99.5 (98.5 to 100)
    Notes
    [5] - ITT participants in Arm A excluding participants with prior SOF + RBV ± pegIFN failures.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With On-treatment Virologic Failure in Arm A DB Active Drug Excluding Prior SOF + RBV ± pegIFN Failures

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    End point title
    		 Percentage of Participants With On-treatment Virologic Failure in Arm A DB Active Drug Excluding Prior SOF + RBV ± pegIFN Failures [6]
    End point description
    On-treatment virologic failure was defined as confirmed increase of > 1 log(subscript)10(subscript) IU/mL above the lowest value of post-baseline HCV RNA during treatment; confirmed HCV RNA ≥ 100 IU/mL after HCV RNA < LLOQ during treatment, or HCV RNA ≥ LLOQ at end of treatment with at least 6 weeks of treatment.
    End point type
    Secondary
    End point timeframe
    Up to Week 12 post baseline
    Notes
    [6] - 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: The secondary endpoint included Arm A.
    End point values
    		 Arm A DB Active Drug
    Number of subjects analysed
    196 [7]
    Units: percentage of participants
        number (confidence interval 95%)
    0 (0 to 1.9)
    Notes
    [7] - ITT participants in Arm A excluding participants with prior SOF + RBV ± pegIFN failures.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Post-treatment Relapse in Arm A DB Active Drug Excluding Prior SOF + RBV ± pegIFN Failures

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    End point title
    		 Percentage of Participants With Post-treatment Relapse in Arm A DB Active Drug Excluding Prior SOF + RBV ± pegIFN Failures [8]
    End point description
    Post-treatment relapse was defined as confirmed HCV RNA ≥ LLOQ between the end of DB treatment and 12 weeks after the last dose of active study drug among participants who completed treatment with HCV RNA levels < LLOQ at the end of treatment, excluding reinfection.
    End point type
    Secondary
    End point timeframe
    Between End of Treatment (Week 12) and 12 weeks after the last dose of Arm A DB active drug (up to Week 24)
    Notes
    [8] - 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: The secondary endpoint included Arm A.
    End point values
    		 Arm A DB Active Drug
    Number of subjects analysed
    195 [9]
    Units: Percentage of participants
        number (confidence interval 95%)
    0 (0 to 1.9)
    Notes
    [9] - ITT: Arm A, HCV RNA <LLOQ at final treatment, completed DB, excluding prior SOF+RBV±pegIFN failures
    No statistical analyses for this end point

    Secondary: Percentage of Participants With SVR12 in Arm A DB Active Drug With Prior SOF + RBV ± pegIFN Failure

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    End point title
    		 Percentage of Participants With SVR12 in Arm A DB Active Drug With Prior SOF + RBV ± pegIFN Failure [10]
    End point description
    SVR12 was defined as HCV RNA level <LLOQ 12 weeks after the last dose of active study drug.
    End point type
    Secondary
    End point timeframe
    12 weeks after the last actual dose of active study drug
    Notes
    [10] - 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: The secondary endpoint included Arm A.
    End point values
    		 Arm A DB Active Drug
    Number of subjects analysed
    6 [11]
    Units: Percentage of participants
        number (not applicable)
    100
    Notes
    [11] - ITT participants in Arm A DB with prior SOF + RBV ± pegIFN failures.
    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) and serious adverse events (TESAEs) were collected from initial study drug administration until 30 days after the last dose of study drug (up to 16 weeks) in both the double-blind (DB) open-label (OL) periods.
    Adverse event reporting additional description
    TEAEs and TESAEs are defined as any AE or SAE with an onset date after the first dose of study drug until 30 days after the last dose of study drug (or until prior to the first dose of open-label active drug for subjects who received DB placebo then OL active study drug) and collected whether elicited or spontaneously reported by the participant.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Arm A DB Active Drug
    Reporting group description
    		 ABT-493/ABT-530 (300 mg/120 mg) coformulated once daily (QD) for 12 weeks (double-blind [DB] treatment period)

    Reporting group title
    Arm B DB Placebo
    Reporting group description
    		 Placebo for ABT-493/ABT-530 QD for 12 weeks (DB treatment period)

    Reporting group title
    Arm B OL Active Drug
    Reporting group description
    		 ABT-493/ABT-530 (300 mg/120 mg) coformulated once daily (QD) for 12 weeks (open-label [OL] treatment period)

    Serious adverse events
    		 Arm A DB Active Drug Arm B DB Placebo Arm B OL Active Drug
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 202 (1.49%)
    1 / 100 (1.00%)
    1 / 100 (1.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 100 (0.00%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 100 (0.00%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Haemorrhoids
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 100 (0.00%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 202 (0.50%)
    0 / 100 (0.00%)
    0 / 100 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rhuematoid arthritis
         subjects affected / exposed
    0 / 202 (0.00%)
    1 / 100 (1.00%)
    1 / 100 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A DB Active Drug Arm B DB Placebo Arm B OL Active Drug
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    75 / 202 (37.13%)
    38 / 100 (38.00%)
    31 / 100 (31.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 202 (0.99%)
    5 / 100 (5.00%)
    2 / 100 (2.00%)
         occurrences all number
    2
    5
    2
    Nervous system disorders
    Dizzness
         subjects affected / exposed
    6 / 202 (2.97%)
    5 / 100 (5.00%)
    1 / 100 (1.00%)
         occurrences all number
    6
    6
    1
    Headache
         subjects affected / exposed
    24 / 202 (11.88%)
    12 / 100 (12.00%)
    8 / 100 (8.00%)
         occurrences all number
    32
    12
    8
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    19 / 202 (9.41%)
    8 / 100 (8.00%)
    5 / 100 (5.00%)
         occurrences all number
    21
    8
    5
    Fatigue
         subjects affected / exposed
    23 / 202 (11.39%)
    10 / 100 (10.00%)
    5 / 100 (5.00%)
         occurrences all number
    24
    10
    5
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    20 / 202 (9.90%)
    3 / 100 (3.00%)
    5 / 100 (5.00%)
         occurrences all number
    20
    3
    5
    Nausea
         subjects affected / exposed
    15 / 202 (7.43%)
    4 / 100 (4.00%)
    8 / 100 (8.00%)
         occurrences all number
    16
    4
    8
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    4 / 202 (1.98%)
    5 / 100 (5.00%)
    1 / 100 (1.00%)
         occurrences all number
    4
    6
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    12 / 202 (5.94%)
    6 / 100 (6.00%)
    5 / 100 (5.00%)
         occurrences all number
    12
    6
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Aug 2015
    The purpose of this amendment was to revise the inclusion criteria, to add a list of potential birth control options, and to expand the categories of treatment-experienced subjects allowed (allowed sofosbuvir [SOF] + ribavirin [RBV] ± pegIFN treatment failures in the study). In addition, this amendment specified a reflex assay used for determination of Chronic Hepatitis C Virus (HCV) genotype/subtype and updated the historical control rate of the Sustained Virologic Response 12 Weeks Post-treatment (SVR12) for primary and secondary efficacy endpoints and the determination of sample size to accommodate the expanded study population
    14 Oct 2015
    The purpose of this amendment was to update the inclusion criteria to require only 1 effective method of contraception and added text detailing allowable methods of contraceptives. In addition, this amendment included an update to the definitions of prior treatment experience, removed prior SOF + RBV ± pegIFN failures from the analysis of the primary endpoint and made it a separate secondary endpoint, and allowed an increase of the total sample size for the study to up to 321 subjects, particularly to increase the sample size of subjects who failed a previous SOF-containing regimen.

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

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

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