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    Clinical Trial Results:
    An Open-Label, Multicenter Study to Evaluate Long-Term Outcomes With ABT-450/Ritonavir/ABT-267 (ABT-450/r/ABT-267) and ABT-333 With or Without Ribavirin (RBV) in Adults With Genotype 1 Chronic Hepatitis C Virus (HCV) Infection (TOPAZ-I)

    Summary
    EudraCT number
    2014-001022-14
    Trial protocol
    PT   GB   IE   AT   ES   IT   DE   NO   SE   BE   FI   NL   BG   PL   DK   GR  
    Global end of trial date
    13 May 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    29 Mar 2022
    First version publication date
    29 Mar 2022
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    M14-423
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02219490
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Companion study M14-222: NCT02167945
    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
    13 May 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 May 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study (M14-423; TOPAZ-I), was a Phase 3b, open-label, multicenter study conducted at sites outside the United States which, together with its companion study M14-422 (TOPAZ-II, conducted in the United States), was designed with the primary objective of assessing the effect of treatment response on long-term clinical outcomes in adults with chronic HCV GT1 infection with or without compensated cirrhosis, who were either treatment-naïve or interferon/ribavirin (IFN/RBV) treatment- experienced. In both studies, participants were treated with the 3-DAA regimen with or without RBV. This study consisted of a screening period of up to 42 days, a treatment period of either 12 weeks for HCV GT1a-infected subjects without cirrhosis and for HCV GT1b-infected subjects without cirrhosis or with compensated cirrhosis or 24 weeks for GT1a-infected participants with compensated cirrhosis, and a 260-week post-treatment period.
    Protection of trial subjects
    Subjects must have been able to understand and adhere to the study visit schedule and all other protocol requirements and must have voluntarily signed and dated an informed consent form, approved by an Institutional Review Board (IRB), prior to the initiation of any screening or study specific procedures.
    Background therapy
    -
    Evidence for comparator
    Number of subjects ages 18-64: 1413 in Study M14-423 and 541 in Study M14-222 Number of subjects ages 65-84 years: 183 in Study M14-423 and 74 in Study M14-222
    Actual start date of recruitment
    30 Oct 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 21
    Country: Number of subjects enrolled
    Finland: 14
    Country: Number of subjects enrolled
    France: 120
    Country: Number of subjects enrolled
    Germany: 83
    Country: Number of subjects enrolled
    Greece: 21
    Country: Number of subjects enrolled
    United States: 615
    Country: Number of subjects enrolled
    Algeria: 25
    Country: Number of subjects enrolled
    Australia: 80
    Country: Number of subjects enrolled
    Austria: 21
    Country: Number of subjects enrolled
    Belgium: 21
    Country: Number of subjects enrolled
    Bulgaria: 35
    Country: Number of subjects enrolled
    Canada: 105
    Country: Number of subjects enrolled
    Ireland: 21
    Country: Number of subjects enrolled
    Israel: 28
    Country: Number of subjects enrolled
    Italy: 161
    Country: Number of subjects enrolled
    Mexico: 77
    Country: Number of subjects enrolled
    Netherlands: 21
    Country: Number of subjects enrolled
    Norway: 27
    Country: Number of subjects enrolled
    Poland: 42
    Country: Number of subjects enrolled
    Portugal: 130
    Country: Number of subjects enrolled
    Romania: 100
    Country: Number of subjects enrolled
    Russian Federation: 113
    Country: Number of subjects enrolled
    Saudi Arabia: 23
    Country: Number of subjects enrolled
    Spain: 105
    Country: Number of subjects enrolled
    Sweden: 21
    Country: Number of subjects enrolled
    Switzerland: 21
    Country: Number of subjects enrolled
    Turkey: 55
    Country: Number of subjects enrolled
    United Kingdom: 105
    Worldwide total number of subjects
    2211
    EEA total number of subjects
    964
    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)
    1954
    From 65 to 84 years
    257
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Safety population: All participants enrolled in this study (M14-423; TOPAZ-I) and in Study M14-222; TOPAZ-II who received at least one dose of study drug

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    M14-423: ABT-450/r/ABT-267 plus ABT-333 +/- Ribavirin (RBV)
    Arm description
    Study M14-423: Participants with HCV GT1b without cirrhosis received the 3-DAA (ABT-450/ritonavir/ABT-267 and ABT-333) regimen: two 75 mg ABT-450/50 mg ritonavir/12.5 mg ABT-267 tablets taken orally every morning (QD) and one ABT-333 250 mg tablet taken orally twice a day (BID) for 12 weeks. Participants with HCV GT1a without cirrhosis and those with HCV GT1b with cirrhosis received the 3-DAA regimen and weight-based ribavirin (RBV; 1000 to 1200 mg divided twice daily per local label) for 12 weeks. Participants with HCV GT1a with cirrhosis received the 3-DAA regimen and weight-based RBV per local label for 24 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    ABT-450/r/ABT-267
    Investigational medicinal product code
    Other name
    ABT-450 also known as paritaprevir, ABT-267 also known as ombitasvir, Paritaprevir/ritonavir/ombitasvir also known as Viekirax
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants with HCV GT1b without cirrhosis, those with HCV GT1a without cirrhosis, and those with HCV GT1b with cirrhosis received two 75 mg ABT-450/50 mg ritonavir/12.5 mg ABT-267 tablets taken orally every morning (QD) for 12 weeks. Participants with HCV GT1a with cirrhosis received this regimen for 24 weeks.

    Investigational medicinal product name
    ABT-333
    Investigational medicinal product code
    Other name
    ABT-333 also known as dasabuvir, ABT-333 also known as Exviera
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants with HCV GT1b without cirrhosis, those with HCV GT1a without cirrhosis, and those with HCV GT1b with cirrhosis received one ABT-333 250 mg tablet taken orally twice a day (BID) for 12 weeks. Participants with HCV GT1a with cirrhosis received one ABT-333 250 mg tablet taken orally twice a day (BID) mg/day for 24 weeks.

    Investigational medicinal product name
    Ribavirin (RBV)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants with HCV GT1a without cirrhosis and those with HCV GT1b with cirrhosis received weight-based ribavirin (1000 to 1200 mg divided twice daily per local label) for 12 weeks. Participants with HCV GT1a with cirrhosis received weight-based RBV per local label for 24 weeks.

    Arm title
    M14-222: ABT-450/r/ABT-267 plus ABT-333 +/- Ribavirin (RBV)
    Arm description
    Study M14-222:Participants with HCV GT1b without cirrhosis received the 3-DAA (ABT-450/ritonavir/ABT-267 and ABT-333) regimen: two 75 mg ABT-450/50 mg ritonavir/12.5 mg ABT-267 tablets taken orally every morning (QD) and one ABT-333 250 mg tablet taken orally twice a day (BID) for 12 weeks. Participants with HCV GT1a without cirrhosis and those with HCV GT1b with cirrhosis received the 3-DAA regimen and weight-based ribavirin (RBV; 1000 to 1200 mg divided twice daily per local label) for 12 weeks. Participants with HCV GT1a with cirrhosis received the 3-DAA regimen and weight-based RBV per local label for 24 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    ABT-450/r/ABT-267
    Investigational medicinal product code
    Other name
    ABT-450 also known as paritaprevir, ABT-267 also known as ombitasvir, Paritaprevir/ritonavir/ombitasvir also known as Viekirax
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants with HCV GT1b without cirrhosis, those with HCV GT1a without cirrhosis, and those with HCV GT1b with cirrhosis received two 75 mg ABT-450/50 mg ritonavir/12.5 mg ABT-267 tablets taken orally every morning (QD) for 12 weeks. Participants with HCV GT1a with cirrhosis received this regimen for 24 weeks.

    Investigational medicinal product name
    ABT-333
    Investigational medicinal product code
    Other name
    ABT-333 also known as dasabuvir, ABT-333 also known as Exviera
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants with HCV GT1b without cirrhosis, those with HCV GT1a without cirrhosis, and those with HCV GT1b with cirrhosis received one ABT-333 250 mg tablet taken orally twice a day (BID) for 12 weeks. Participants with HCV GT1a with cirrhosis received one ABT-333 250 mg tablet taken orally twice a day (BID) mg/day for 24 weeks.

    Investigational medicinal product name
    Ribavirin (RBV)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants with HCV GT1a without cirrhosis and those with HCV GT1b with cirrhosis received weight-based ribavirin (1000 to 1200 mg divided twice daily per local label) for 12 weeks. Participants with HCV GT1a with cirrhosis received weight-based RBV per local label for 24 weeks.

    Number of subjects in period 1
    M14-423: ABT-450/r/ABT-267 plus ABT-333 +/- Ribavirin (RBV) M14-222: ABT-450/r/ABT-267 plus ABT-333 +/- Ribavirin (RBV)
    Started
    1596
    615
    Completed
    1258
    366
    Not completed
    338
    249
         Adverse event, non-fatal
    24
    16
         Other, not specified
    57
    63
         COVID-19 logistical restrictions
    33
    6
         Withdrew consent
    96
    42
         Lost to follow-up
    126
    122
         COVID-19 infection
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    M14-423: ABT-450/r/ABT-267 plus ABT-333 +/- Ribavirin (RBV)
    Reporting group description
    Study M14-423: Participants with HCV GT1b without cirrhosis received the 3-DAA (ABT-450/ritonavir/ABT-267 and ABT-333) regimen: two 75 mg ABT-450/50 mg ritonavir/12.5 mg ABT-267 tablets taken orally every morning (QD) and one ABT-333 250 mg tablet taken orally twice a day (BID) for 12 weeks. Participants with HCV GT1a without cirrhosis and those with HCV GT1b with cirrhosis received the 3-DAA regimen and weight-based ribavirin (RBV; 1000 to 1200 mg divided twice daily per local label) for 12 weeks. Participants with HCV GT1a with cirrhosis received the 3-DAA regimen and weight-based RBV per local label for 24 weeks.

    Reporting group title
    M14-222: ABT-450/r/ABT-267 plus ABT-333 +/- Ribavirin (RBV)
    Reporting group description
    Study M14-222:Participants with HCV GT1b without cirrhosis received the 3-DAA (ABT-450/ritonavir/ABT-267 and ABT-333) regimen: two 75 mg ABT-450/50 mg ritonavir/12.5 mg ABT-267 tablets taken orally every morning (QD) and one ABT-333 250 mg tablet taken orally twice a day (BID) for 12 weeks. Participants with HCV GT1a without cirrhosis and those with HCV GT1b with cirrhosis received the 3-DAA regimen and weight-based ribavirin (RBV; 1000 to 1200 mg divided twice daily per local label) for 12 weeks. Participants with HCV GT1a with cirrhosis received the 3-DAA regimen and weight-based RBV per local label for 24 weeks.

    Reporting group values
    M14-423: ABT-450/r/ABT-267 plus ABT-333 +/- Ribavirin (RBV) M14-222: ABT-450/r/ABT-267 plus ABT-333 +/- Ribavirin (RBV) Total
    Number of subjects
    1596 615 2211
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    51.2 ± 11.62 54.5 ± 10.84 -
    Gender categorical
    Units: Subjects
        Female
    800 243 1043
        Male
    796 372 1168

    End points

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    End points reporting groups
    Reporting group title
    M14-423: ABT-450/r/ABT-267 plus ABT-333 +/- Ribavirin (RBV)
    Reporting group description
    Study M14-423: Participants with HCV GT1b without cirrhosis received the 3-DAA (ABT-450/ritonavir/ABT-267 and ABT-333) regimen: two 75 mg ABT-450/50 mg ritonavir/12.5 mg ABT-267 tablets taken orally every morning (QD) and one ABT-333 250 mg tablet taken orally twice a day (BID) for 12 weeks. Participants with HCV GT1a without cirrhosis and those with HCV GT1b with cirrhosis received the 3-DAA regimen and weight-based ribavirin (RBV; 1000 to 1200 mg divided twice daily per local label) for 12 weeks. Participants with HCV GT1a with cirrhosis received the 3-DAA regimen and weight-based RBV per local label for 24 weeks.

    Reporting group title
    M14-222: ABT-450/r/ABT-267 plus ABT-333 +/- Ribavirin (RBV)
    Reporting group description
    Study M14-222:Participants with HCV GT1b without cirrhosis received the 3-DAA (ABT-450/ritonavir/ABT-267 and ABT-333) regimen: two 75 mg ABT-450/50 mg ritonavir/12.5 mg ABT-267 tablets taken orally every morning (QD) and one ABT-333 250 mg tablet taken orally twice a day (BID) for 12 weeks. Participants with HCV GT1a without cirrhosis and those with HCV GT1b with cirrhosis received the 3-DAA regimen and weight-based ribavirin (RBV; 1000 to 1200 mg divided twice daily per local label) for 12 weeks. Participants with HCV GT1a with cirrhosis received the 3-DAA regimen and weight-based RBV per local label for 24 weeks.

    Subject analysis set title
    Subjects in studies M14-222 & M14-423 who didn't achieve SVR12
    Subject analysis set type
    Per protocol
    Subject analysis set description
    SVR12 was defined as hepatitis C virus ribonucleic acid (HCV RNA) less than the lower limit of quantification (LLOQ) 12 weeks after the last actual dose of study drug.

    Subject analysis set title
    Subjects in studies M14-222 & M14-423 who achieved SVR12
    Subject analysis set type
    Per protocol
    Subject analysis set description
    SVR12 was defined as hepatitis C virus ribonucleic acid (HCV RNA) less than the lower limit of quantification (LLOQ) 12 weeks after the last actual dose of study drug.

    Subject analysis set title
    Subjects in study M14-423 who did not achieve SVR12
    Subject analysis set type
    Per protocol
    Subject analysis set description
    SVR12 was defined as hepatitis C virus ribonucleic acid (HCV RNA) less than the lower limit of quantification (LLOQ) 12 weeks after the last actual dose of study drug.

    Subject analysis set title
    Subjects in study M14-423 who achieved SVR12
    Subject analysis set type
    Per protocol
    Subject analysis set description
    SVR12 was defined as hepatitis C virus ribonucleic acid (HCV RNA) less than the lower limit of quantification (LLOQ) 12 weeks after the last actual dose of study drug.

    Primary: All-Cause Death: Time to Event

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    End point title
    All-Cause Death: Time to Event
    End point description
    Time to all-cause death was defined as the number of days from the first day of study drug dosing for the participant to the date of death. All deaths were to be included, regardless of whether the death occurred while the participant was still taking study drug or had previously discontinued study drug. If the participant did not die, their data was to be censored at the date of their last available assessment of clinical outcomes. For participants with no post-baseline assessment, the participant's data was to be censored on the first day of study drug dosing. The event-free survival rates were estimated using Kaplan-Meier methodology and incidence estimates are presented with 95% confidence intervals. The pre-specified analysis of all-cause death included pooled data from TOPAZ-I (this study) and the companion study TOPAZ-II (M14-222; NCT02167945).
    End point type
    Primary
    End point timeframe
    At Post-Treatment Weeks 52, 104, 156, 208, and 260
    End point values
    Subjects in studies M14-222 & M14-423 who didn't achieve SVR12 Subjects in studies M14-222 & M14-423 who achieved SVR12
    Number of subjects analysed
    77 [1]
    2134 [2]
    Units: percentage of participants
    number (confidence interval 95%)
        Kaplan-Meier estimate at PT Week 52
    8.3 (3.1 to 21.2)
    0.1 (0.1 to 0.4)
        Kaplan-Meier estimate at PT Week 104
    8.3 (3.1 to 21.2)
    0.7 (0.4 to 1.1)
        Kaplan-Meier estimate at PT Week 156
    8.3 (3.1 to 21.2)
    1.2 (0.8 to 1.8)
        Kaplan-Meier estimate at PT Week 208
    8.3 (3.1 to 21.2)
    1.5 (1.1 to 2.2)
        Kaplan-Meier estimate at PT Week 260
    8.3 (3.1 to 21.2)
    2.0 (1.5 to 2.8)
    Notes
    [1] - ITT: enrolled subjects in this study (M14-423) and Study M14-222 who rcvd ≥ 1 dose of study drug
    [2] - ITT: enrolled subjects in this study (M14-423) and Study M14-222 who rcvd ≥ 1 dose of study drug
    Statistical analysis title
    Log-rank test
    Statistical analysis description
    Comparisons between participants in studies M14-222 and M14-423 who achieved SVR12 and those who did not were performed using a log-rank test.
    Comparison groups
    Subjects in studies M14-222 & M14-423 who didn't achieve SVR12 v Subjects in studies M14-222 & M14-423 who achieved SVR12
    Number of subjects included in analysis
    2211
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Log-rank test
    Confidence interval
    Statistical analysis title
    Cox proportional hazards model
    Statistical analysis description
    A Cox proportional hazards (PH) model was constructed. The covariates for the model included baseline age, BMI, HCV genotype 1 subtype (1b, non-1b), IL28B genotype (CC, non-CC), prior treatment history (naive, experienced), baseline HCV RNA levels, baseline fibrosis stage (F0-1, F2, F3, F4), baseline albumin, baseline creatinine clearance, baseline platelet count, history of diabetes (yes, no), APRI, race (white, other), and alcohol use status (current, former, non-drinker).
    Comparison groups
    Subjects in studies M14-222 & M14-423 who didn't achieve SVR12 v Subjects in studies M14-222 & M14-423 who achieved SVR12
    Number of subjects included in analysis
    2211
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    < 0.001
    Method
    Cox proportional hazards model
    Parameter type
    Cox Proportional Hazard Ratio
    Point estimate
    0.126
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.044
         upper limit
    0.358
    Notes
    [3] - The estimated value represents the hazard ratio for developing the event in the group of participants in studies M14-222 and M14-423 who achieved SVR12 compared to the group of participants in studies M14-222 and M14-423 who didn’t achieve SVR12.

    Primary: Liver-Related Death: Time to Event

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    End point title
    Liver-Related Death: Time to Event
    End point description
    Time to liver-related death was defined as days from the 1st day of study drug dosing for the subject to date of liver-related death. All liver-related deaths were to be included, regardless of whether the death occurred while subject was still taking study drug or had previously discontinued study drug. If the subject didn’t experience event of interest nor had died (all-cause death), their data was to be censored at date of last available assessment. For those with no post-baseline assessment, data was to be censored on 1st day of study drug dosing. All-cause death was a censoring event for liver-related death. The event-free survival rates were estimated using Kaplan-Meier methodology and incidence estimates are presented with 95% confidence intervals. The pre-specified analysis of liver-related death included pooled data from TOPAZ-I (this study) and the companion study TOPAZ-II (M14-222; NCT02167945). -999 and 999 = confidence limits not calculable due to zero events at visit
    End point type
    Primary
    End point timeframe
    At Post-Treatment Weeks 52, 104, 156, 208, and 260
    End point values
    Subjects in studies M14-222 & M14-423 who didn't achieve SVR12 Subjects in studies M14-222 & M14-423 who achieved SVR12
    Number of subjects analysed
    77 [4]
    2134 [5]
    Units: percentage of participants
    number (confidence interval 95%)
        Kaplan-Meier estimate at PT Week 52
    1.4 (0.2 to 9.6)
    0 (-999 to 999)
        Kaplan-Meier estimate at PT Week 104
    1.4 (0.2 to 9.6)
    0 (-999 to 999)
        Kaplan-Meier estimate at PT Week 156
    1.4 (0.2 to 9.6)
    0.1 (0.1 to 0.4)
        Kaplan-Meier estimate at PT Week 208
    1.4 (0.2 to 9.6)
    0.1 (0.1 to 0.4)
        Kaplan-Meier estimate at PT Week 260
    1.4 (0.2 to 9.6)
    0.1 (0.1 to 0.4)
    Notes
    [4] - ITT: enrolled subjects in this study (M14-423) and Study M14-222 who rcvd ≥ 1 dose of study drug
    [5] - ITT: enrolled subjects in this study (M14-423) and Study M14-222 who rcvd ≥ 1 dose of study drug
    Statistical analysis title
    Log-rank test
    Statistical analysis description
    Comparisons between participants in studies M14-222 and M14-423 who achieved SVR12 and those who did not were performed using a log-rank test.
    Comparison groups
    Subjects in studies M14-222 & M14-423 who didn't achieve SVR12 v Subjects in studies M14-222 & M14-423 who achieved SVR12
    Number of subjects included in analysis
    2211
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Log-rank test
    Confidence interval
    Statistical analysis title
    Cox proportional hazards model
    Statistical analysis description
    A Cox proportional hazards (PH) model was constructed. The covariates for the model included baseline age, BMI, HCV genotype 1 subtype (1b, non-1b), IL28B genotype (CC, non-CC), prior treatment history (naive, experienced), baseline HCV RNA levels, baseline fibrosis stage (F0-1, F2, F3, F4), baseline albumin, baseline creatinine clearance, baseline platelet count, history of diabetes (yes, no), APRI, race (white, other), and alcohol use status (current, former, non-drinker).
    Comparison groups
    Subjects in studies M14-222 & M14-423 who didn't achieve SVR12 v Subjects in studies M14-222 & M14-423 who achieved SVR12
    Number of subjects included in analysis
    2211
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    P-value
    = 0.007
    Method
    Cox proportional hazards model
    Parameter type
    Cox Proportional Hazard Ratio
    Point estimate
    0.031
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.003
         upper limit
    0.38
    Notes
    [6] - The estimated value represents the hazard ratio for developing the event in the group of participants in studies M14-222 and M14-423 who achieved SVR12 compared to the group of participants in studies M14-222 and M14-423 who didn’t achieve SVR12.

    Primary: Liver Decompensation: Time to Event

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    End point title
    Liver Decompensation: Time to Event
    End point description
    Time to liver decompensation was defined as number of days from the 1st day of study drug dosing for the participant to the date of liver decompensation. All liver decompensation was to be included, regardless of whether it occurred while the participant was still taking study drug or had previously discontinued study drug. If the participant didn’t experience the event of interest nor had died (all-cause death), their data was to be censored at the date of their last available assessment of clinical outcomes. For participants with no post-baseline assessment, their data was to be censored on the 1st day of study drug dosing. All-cause death was a censoring event for liver decompensation. The event-free survival rates were estimated using Kaplan-Meier methodology and incidence estimates are presented with 95% confidence intervals. The pre-specified analysis of liver decompensation included pooled data from TOPAZ-I (this study) and the companion study TOPAZ-II (M14-222; NCT02167945).
    End point type
    Primary
    End point timeframe
    At Post-Treatment Weeks 52, 104, 156, 208, and 260
    End point values
    Subjects in studies M14-222 & M14-423 who didn't achieve SVR12 Subjects in studies M14-222 & M14-423 who achieved SVR12
    Number of subjects analysed
    77 [7]
    2134 [8]
    Units: percentage of participants
    number (confidence interval 95%)
        Kaplan-Meier estimate at PT Week 52
    4.5 (1.5 to 13.4)
    0.2 (0.1 to 0.5)
        Kaplan-Meier estimate at PT Week 104
    4.5 (1.5 to 13.4)
    0.2 (0.1 to 0.5)
        Kaplan-Meier estimate at PT Week 156
    4.5 (1.5 to 13.4)
    0.3 (0.1 to 0.6)
        Kaplan-Meier estimate at PT Week 208
    4.5 (1.5 to 13.4)
    0.3 (0.2 to 0.7)
        Kaplan-Meier estimate at PT Week 260
    4.5 (1.5 to 13.4)
    0.5 (0.2 to 0.9)
    Notes
    [7] - ITT: enrolled subjects in this study (M14-423) and Study M14-222 who rcvd ≥ 1 dose of study drug
    [8] - ITT: enrolled subjects in this study (M14-423) and Study M14-222 who rcvd ≥ 1 dose of study drug
    Statistical analysis title
    Log-rank test
    Statistical analysis description
    Comparisons between participants in studies M14-222 and M14-423 who achieved SVR12 and those who did not were performed using a log-rank test.
    Comparison groups
    Subjects in studies M14-222 & M14-423 who achieved SVR12 v Subjects in studies M14-222 & M14-423 who didn't achieve SVR12
    Number of subjects included in analysis
    2211
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Log-rank test
    Confidence interval
    Statistical analysis title
    Cox proportional hazards model
    Statistical analysis description
    A Cox proportional hazards (PH) model was constructed. The covariates for the model included baseline age, BMI, HCV genotype 1 subtype (1b, non-1b), IL28B genotype (CC, non-CC), prior treatment history (naive, experienced), baseline HCV RNA levels, baseline fibrosis stage (F0-1, F2, F3, F4), baseline albumin, baseline creatinine clearance, baseline platelet count, history of diabetes (yes, no), APRI, race (white, other), and alcohol use status (current, former, non-drinker).
    Comparison groups
    Subjects in studies M14-222 & M14-423 who didn't achieve SVR12 v Subjects in studies M14-222 & M14-423 who achieved SVR12
    Number of subjects included in analysis
    2211
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    < 0.001
    Method
    Cox proportional hazards model
    Parameter type
    Cox Proportional Hazard Ratio
    Point estimate
    0.038
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.009
         upper limit
    0.156
    Notes
    [9] - The estimated value represents the hazard ratio for developing the event in the group of participants in studies M14-222 and M14-423 who achieved SVR12 compared to the group of participants in studies M14-222 and M14-423 who didn’t achieve SVR12.

    Primary: Liver Transplantation: Time to Event

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    End point title
    Liver Transplantation: Time to Event
    End point description
    Time to liver transplantation was defined as days from 1st day of study drug dosing for subject to date of liver transplantation. All liver transplantation was to be included, whether it occurred while the subject was still taking study drug or had previously discontinued study drug. If the subject didn’t experience event of interest nor had died (all-cause death), their data was to be censored at the date of their last available assessment. For those with no post-baseline assessment, data was to be censored on 1st day of study drug dosing. All-cause death was a censoring event for liver transplantation. The event-free survival rates were estimated using Kaplan-Meier methodology and incidence estimates are presented with 95% confidence intervals. The pre-specified analysis of liver transplantation included pooled data from TOPAZ-I (this study) and the companion study TOPAZ-II (M14-222; NCT02167945). -999 and 999 = confidence limits not calculable due to zero events at visit
    End point type
    Primary
    End point timeframe
    At Post-Treatment Weeks 52, 104, 156, 208, and 260
    End point values
    Subjects in studies M14-222 & M14-423 who didn't achieve SVR12 Subjects in studies M14-222 & M14-423 who achieved SVR12
    Number of subjects analysed
    77 [10]
    2134 [11]
    Units: percentage of participants
    number (confidence interval 95%)
        Kaplan-Meier estimate at PT Week 52
    0 (-999 to 999)
    0 (-999 to 999)
        Kaplan-Meier estimate at PT Week 104
    0 (-999 to 999)
    0 (-999 to 999)
        Kaplan-Meier estimate at PT Week 156
    0 (-999 to 999)
    0.1 (0.1 to 0.4)
        Kaplan-Meier estimate at PT Week 208
    0 (-999 to 999)
    0.1 (0.1 to 0.4)
        Kaplan-Meier estimate at PT Week 260
    0 (-999 to 999)
    0.2 (0.1 to 0.5)
    Notes
    [10] - ITT: enrolled subjects in this study (M14-423) and Study M14-222 who rcvd ≥ 1 dose of study drug
    [11] - ITT: enrolled subjects in this study (M14-423) and Study M14-222 who rcvd ≥ 1 dose of study drug
    Statistical analysis title
    Log-rank test
    Statistical analysis description
    Comparisons between participants in studies M14-222 and M14-423 who achieved SVR12 and those who did not were performed using a log-rank test.
    Comparison groups
    Subjects in studies M14-222 & M14-423 who didn't achieve SVR12 v Subjects in studies M14-222 & M14-423 who achieved SVR12
    Number of subjects included in analysis
    2211
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.86
    Method
    Log-rank test
    Confidence interval
    Statistical analysis title
    Cox proportional hazards model
    Statistical analysis description
    A Cox proportional hazards (PH) model was constructed. The covariates for the model included baseline age, BMI, HCV genotype 1 subtype (1b, non-1b), IL28B genotype (CC, non-CC), prior treatment history (naive, experienced), baseline HCV RNA levels, baseline fibrosis stage (F0-1, F2, F3, F4), baseline albumin, baseline creatinine clearance, baseline platelet count, history of diabetes (yes, no), APRI, race (white, other), and alcohol use status (current, former, non-drinker).
    Comparison groups
    Subjects in studies M14-222 & M14-423 who didn't achieve SVR12 v Subjects in studies M14-222 & M14-423 who achieved SVR12
    Number of subjects included in analysis
    2211
    Analysis specification
    Pre-specified
    Analysis type
    superiority [12]
    P-value
    = 0.997 [13]
    Method
    Cox proportional hazards model
    Parameter type
    Cox Proportional Hazard Ratio
    Point estimate
    999
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    999
    Notes
    [12] - The estimated value represents the hazard ratio for developing the event in the group of participants in studies M14-222 and M14-423 who achieved SVR12 compared to the group of participants in studies M14-222 and M14-423 who didn’t achieve SVR12.
    [13] - The Hazard Ratio is infinite and CI is not bounded due to zero events in one of the groups.

    Primary: Hepatocellular Carcinoma: Time to Event

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    End point title
    Hepatocellular Carcinoma: Time to Event
    End point description
    Time to hepatocellular carcinoma (HCC) was defined as number of days from 1st day of study drug dosing for subject to date of hepatocellular carcinoma. All HCC was to be included, whether it occurred while subject was still taking study drug or had previously discontinued study drug. If the subject didn’t experience the event of interest nor had died (all-cause death), their data was to be censored at the date of their last available assessment. For those with no post-baseline assessment, their data was to be censored on the 1st day of study drug dosing. All-cause death was a censoring event for HCC. The event-free survival rates were estimated using Kaplan-Meier methodology and incidence estimates are presented with 95% confidence intervals. The pre-specified analysis of hepatocellular carcinoma included pooled data from TOPAZ-I (this study) and the companion study TOPAZ-II (M14-222; NCT02167945). -999 and 999 = confidence limits not calculable due to zero events at visit
    End point type
    Primary
    End point timeframe
    At Post-Treatment Weeks 52, 104, 156, 208, and 260
    End point values
    Subjects in studies M14-222 & M14-423 who didn't achieve SVR12 Subjects in studies M14-222 & M14-423 who achieved SVR12
    Number of subjects analysed
    77 [14]
    2134 [15]
    Units: percentage of participants
    number (confidence interval 95%)
        Kaplan-Meier estimate at PT Week 52
    0 (-999 to 999)
    0.2 (0.1 to 0.5)
        Kaplan-Meier estimate at PT Week 104
    0 (-999 to 999)
    0.4 (0.2 to 0.8)
        Kaplan-Meier estimate at PT Week 156
    0 (-999 to 999)
    0.5 (0.3 to 1.0)
        Kaplan-Meier estimate at PT Week 208
    0 (-999 to 999)
    0.6 (0.4 to 1.1)
        Kaplan-Meier estimate at PT Week 260
    0 (-999 to 999)
    0.9 (0.5 to 1.4)
    Notes
    [14] - ITT: enrolled subjects in this study (M14-423) and Study M14-222 who rcvd ≥ 1 dose of study drug
    [15] - ITT: enrolled subjects in this study (M14-423) and Study M14-222 who rcvd ≥ 1 dose of study drug
    Statistical analysis title
    Log-rank test
    Statistical analysis description
    Comparisons between participants in studies M14-222 and M14-423 who achieved SVR12 and those who did not were performed using a log-rank test.
    Comparison groups
    Subjects in studies M14-222 & M14-423 who didn't achieve SVR12 v Subjects in studies M14-222 & M14-423 who achieved SVR12
    Number of subjects included in analysis
    2211
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.608
    Method
    Log-rank test
    Confidence interval
    Statistical analysis title
    Cox proportional hazards model
    Statistical analysis description
    A Cox proportional hazards (PH) model was constructed. The covariates for the model included baseline age, BMI, HCV genotype 1 subtype (1b, non-1b), IL28B genotype (CC, non-CC), prior treatment history (naive, experienced), baseline HCV RNA levels, baseline fibrosis stage (F0-1, F2, F3, F4), baseline albumin, baseline creatinine clearance, baseline platelet count, history of diabetes (yes, no), APRI, race (white, other), and alcohol use status (current, former, non-drinker).
    Comparison groups
    Subjects in studies M14-222 & M14-423 who didn't achieve SVR12 v Subjects in studies M14-222 & M14-423 who achieved SVR12
    Number of subjects included in analysis
    2211
    Analysis specification
    Pre-specified
    Analysis type
    superiority [16]
    P-value
    = 0.992 [17]
    Method
    Cox proportional hazards model
    Parameter type
    Cox Proportional Hazard Ratio
    Point estimate
    999
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    999
    Notes
    [16] - The estimated value represents the hazard ratio for developing the event in the group of participants in studies M14-222 and M14-423 who achieved SVR12 compared to the group of participants in studies M14-222 and M14-423 who didn’t achieve SVR12.
    [17] - The Hazard Ratio is infinite and CI is not bounded due to zero events in one of the groups.

    Primary: All-Cause Death, Liver-Related Death, Liver Decompensation, Liver Transplantation, Hepatocellular Carcinoma: Time to Event

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    End point title
    All-Cause Death, Liver-Related Death, Liver Decompensation, Liver Transplantation, Hepatocellular Carcinoma: Time to Event
    End point description
    Time to the composite of clinical outcomes is the time to the first occurrence of all-cause death, liver-related death, liver decompensation, liver transplantation, or hepatocellular carcinoma. All first occurrences were to be included, regardless of whether it occurred while the participant was still taking study drug or had previously discontinued study drug. If the participant did not experience any of these events, their data was to be censored at the date of their last available assessment of clinical outcomes. For participants with no post-baseline assessment, the participant's data was to be censored on the first day of study drug dosing. The event-free survival rates were estimated using Kaplan-Meier methodology and incidence estimates are presented with 95% confidence intervals. Pre-specified analysis included pooled data from this study and from TOPAZ-II; NCT02167945.
    End point type
    Primary
    End point timeframe
    At Post-Treatment Weeks 52, 104, 156, 208, and 260
    End point values
    Subjects in studies M14-222 & M14-423 who didn't achieve SVR12 Subjects in studies M14-222 & M14-423 who achieved SVR12
    Number of subjects analysed
    77 [18]
    2134 [19]
    Units: percentage of participants
    number (confidence interval 95%)
        Kaplan-Meier estimate at PT Week 52
    11.4 (5.2 to 24.2)
    0.5 (0.3 to 0.9)
        Kaplan-Meier estimate at PT Week 104
    11.4 (5.2 to 24.2)
    1.2 (0.8 to 1.8)
        Kaplan-Meier estimate at PT Week 156
    11.4 (5.2 to 24.2)
    1.9 (1.4 to 2.6)
        Kaplan-Meier estimate at PT Week 208
    11.4 (5.2 to 24.2)
    2.3 (1.7 to 3.1)
        Kaplan-Meier estimate at PT Week 260
    11.4 (5.2 to 24.2)
    3.2 (2.5 to 4.1)
    Notes
    [18] - ITT: enrolled subjects in this study (M14-423) and Study M14-222 who rcvd ≥ 1 dose of study drug
    [19] - ITT: enrolled subjects in this study (M14-423) and Study M14-222 who rcvd ≥ 1 dose of study drug
    Statistical analysis title
    Log-rank test
    Statistical analysis description
    Comparisons between participants in studies M14-222 and M14-423 who achieved SVR12 and those who did not were performed using a log-rank test.
    Comparison groups
    Subjects in studies M14-222 & M14-423 who didn't achieve SVR12 v Subjects in studies M14-222 & M14-423 who achieved SVR12
    Number of subjects included in analysis
    2211
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Log-rank test
    Confidence interval
    Statistical analysis title
    Cox proportional hazards model
    Statistical analysis description
    A Cox proportional hazards (PH) model was constructed. The covariates for the model included baseline age, BMI, HCV genotype 1 subtype (1b, non-1b), IL28B genotype (CC, non-CC), prior treatment history (naive, experienced), baseline HCV RNA levels, baseline fibrosis stage (F0-1, F2, F3, F4), baseline albumin, baseline creatinine clearance, baseline platelet count, history of diabetes (yes, no), APRI, race (white, other), and alcohol use status (current, former, non-drinker).
    Comparison groups
    Subjects in studies M14-222 & M14-423 who didn't achieve SVR12 v Subjects in studies M14-222 & M14-423 who achieved SVR12
    Number of subjects included in analysis
    2211
    Analysis specification
    Pre-specified
    Analysis type
    superiority [20]
    P-value
    < 0.001
    Method
    Cox proportional hazards model
    Parameter type
    Cox Proportional Hazard Ratio
    Point estimate
    0.133
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.057
         upper limit
    0.313
    Notes
    [20] - The estimated value represents the hazard ratio for developing the event in the group of participants in studies M14-222 and M14-423 who achieved SVR12 compared to the group of participants in studies M14-222 and M14-423 who didn’t achieve SVR12.

    Secondary: Change from Baseline in FibroScan Score by SVR12 Status

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    End point title
    Change from Baseline in FibroScan Score by SVR12 Status
    End point description
    The FibroScan test is a validated non-invasive test used to assess liver fibrosis in participants with chronic liver disease, and it was performed at study sites where it was available. For participants with Hepatitis C infection, a FibroScan score of 2-7 kPa indicates no liver scarring or mild scarring; a score of 8 or 9 is associated with moderate liver scarring; 9-14 indicates severe liver scarring; and 14 or higher is indicative of advanced liver scarring, cirrhosis. Negative changes from baseline indicate improvement in liver fibrosis.
    End point type
    Secondary
    End point timeframe
    At the final treatment visit and Post-Treatment Weeks 12, 24, 52, 104, 156, 208, and 260
    End point values
    Subjects in study M14-423 who did not achieve SVR12 Subjects in study M14-423 who achieved SVR12
    Number of subjects analysed
    22 [21]
    1187 [22]
    Units: kPa
    arithmetic mean (standard deviation)
        At the final treatment visit (n= 22, 1015)
    -2.55 ± 3.282
    -1.41 ± 4.283
        Post-Treatment Week 12 (n= 18,1171)
    -1.81 ± 2.624
    -1.76 ± 4.213
        Post-Treatment Week 24 (n= 18, 1175)
    -1.26 ± 3.211
    -1.98 ± 4.363
        Post-Treatment Week 52 (n= 13, 1187)
    -0.30 ± 1.986
    -2.46 ± 4.858
        Post-Treatment Week 104 (n= 13, 1122)
    -0.35 ± 3.306
    -2.80 ± 5.195
        Post-Treatment Week 156 (n= 12, 1073)
    -0.37 ± 3.999
    -2.92 ± 5.249
        Post-Treatment Week 208 (n= 12, 978)
    -0.88 ± 2.445
    -3.08 ± 5.560
        Post-Treatment Week 260 (n= 9, 860)
    -1.31 ± 3.706
    -3.08 ± 5.662
    Notes
    [21] - ITT-I: enrolled subjects in this study (M14-423) who rcvd ≥ 1 dose of study drug
    [22] - ITT-I: enrolled subjects in this study (M14-423) who rcvd ≥ 1 dose of study drug
    Statistical analysis title
    Final Treatment Visit
    Statistical analysis description
    The effect of sustained virologic response on change from baseline in FibroScan score was evaluated by comparing mean change from baseline between subjects who achieved SVR12 and those who did not using ANCOVA analyses. SVR12 status was included as a factor and baseline FibroScan score was included as a covariate in the ANCOVA model.
    Comparison groups
    Subjects in study M14-423 who did not achieve SVR12 v Subjects in study M14-423 who achieved SVR12
    Number of subjects included in analysis
    1209
    Analysis specification
    Pre-specified
    Analysis type
    superiority [23]
    P-value
    = 0.151
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.37
         upper limit
    2.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.7
    Notes
    [23] - Difference = with SVR12 minus without SVR12
    Statistical analysis title
    Post-Treatment Week 12
    Statistical analysis description
    The effect of sustained virologic response on change from baseline in FibroScan score was evaluated by comparing mean change from baseline between subjects who achieved SVR12 and those who did not using ANCOVA analyses. SVR12 status was included as a factor and baseline FibroScan score was included as a covariate in the ANCOVA model.
    Comparison groups
    Subjects in study M14-423 who did not achieve SVR12 v Subjects in study M14-423 who achieved SVR12
    Number of subjects included in analysis
    1209
    Analysis specification
    Pre-specified
    Analysis type
    superiority [24]
    P-value
    = 0.878
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.12
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.64
         upper limit
    1.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.78
    Notes
    [24] - Difference = with SVR12 minus without SVR12
    Statistical analysis title
    Post-Treatment Week 24
    Statistical analysis description
    The effect of sustained virologic response on change from baseline in FibroScan score was evaluated by comparing mean change from baseline between subjects who achieved SVR12 and those who did not using ANCOVA analyses. SVR12 status was included as a factor and baseline FibroScan score was included as a covariate in the ANCOVA model.
    Comparison groups
    Subjects in study M14-423 who did not achieve SVR12 v Subjects in study M14-423 who achieved SVR12
    Number of subjects included in analysis
    1209
    Analysis specification
    Pre-specified
    Analysis type
    superiority [25]
    P-value
    = 0.199
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -0.92
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.33
         upper limit
    0.48
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.72
    Notes
    [25] - Difference = with SVR12 minus without SVR12
    Statistical analysis title
    Post-Treatment Week 52
    Statistical analysis description
    The effect of sustained virologic response on change from baseline in FibroScan score was evaluated by comparing mean change from baseline between subjects who achieved SVR12 and those who did not using ANCOVA analyses. SVR12 status was included as a factor and baseline FibroScan score was included as a covariate in the ANCOVA model.
    Comparison groups
    Subjects in study M14-423 who did not achieve SVR12 v Subjects in study M14-423 who achieved SVR12
    Number of subjects included in analysis
    1209
    Analysis specification
    Pre-specified
    Analysis type
    superiority [26]
    P-value
    = 0.021
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -2.16
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4
         upper limit
    -0.33
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.93
    Notes
    [26] - Difference = with SVR12 minus without SVR12
    Statistical analysis title
    Post-Treatment Week 104
    Statistical analysis description
    The effect of sustained virologic response on change from baseline in FibroScan score was evaluated by comparing mean change from baseline between subjects who achieved SVR12 and those who did not using ANCOVA analyses. SVR12 status was included as a factor and baseline FibroScan score was included as a covariate in the ANCOVA model.
    Comparison groups
    Subjects in study M14-423 who did not achieve SVR12 v Subjects in study M14-423 who achieved SVR12
    Number of subjects included in analysis
    1209
    Analysis specification
    Pre-specified
    Analysis type
    superiority [27]
    P-value
    = 0.006
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -2.47
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.22
         upper limit
    -0.71
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.89
    Notes
    [27] - Difference = with SVR12 minus without SVR12
    Statistical analysis title
    Post-Treatment Week 156
    Statistical analysis description
    The effect of sustained virologic response on change from baseline in FibroScan score was evaluated by comparing mean change from baseline between subjects who achieved SVR12 and those who did not using ANCOVA analyses. SVR12 status was included as a factor and baseline FibroScan score was included as a covariate in the ANCOVA model.
    Comparison groups
    Subjects in study M14-423 who did not achieve SVR12 v Subjects in study M14-423 who achieved SVR12
    Number of subjects included in analysis
    1209
    Analysis specification
    Pre-specified
    Analysis type
    superiority [28]
    P-value
    = 0.005
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -2.58
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.38
         upper limit
    -0.79
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.92
    Notes
    [28] - Difference = with SVR12 minus without SVR12
    Statistical analysis title
    Post-Treatment Week 208
    Statistical analysis description
    The effect of sustained virologic response on change from baseline in FibroScan score was evaluated by comparing mean change from baseline between subjects who achieved SVR12 and those who did not using ANCOVA analyses. SVR12 status was included as a factor and baseline FibroScan score was included as a covariate in the ANCOVA model.
    Comparison groups
    Subjects in study M14-423 who did not achieve SVR12 v Subjects in study M14-423 who achieved SVR12
    Number of subjects included in analysis
    1209
    Analysis specification
    Pre-specified
    Analysis type
    superiority [29]
    P-value
    = 0.172
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -1.36
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.32
         upper limit
    0.59
    Variability estimate
    Standard error of the mean
    Dispersion value
    1
    Notes
    [29] - Difference = with SVR12 minus without SVR12
    Statistical analysis title
    Post-Treatment Week 260
    Statistical analysis description
    The effect of sustained virologic response on change from baseline in FibroScan score was evaluated by comparing mean change from baseline between subjects who achieved SVR12 and those who did not using ANCOVA analyses. SVR12 status was included as a factor and baseline FibroScan score was included as a covariate in the ANCOVA model.
    Comparison groups
    Subjects in study M14-423 who achieved SVR12 v Subjects in study M14-423 who did not achieve SVR12
    Number of subjects included in analysis
    1209
    Analysis specification
    Pre-specified
    Analysis type
    superiority [30]
    P-value
    = 0.322
    Method
    ANCOVA
    Parameter type
    LS Mean Difference
    Point estimate
    -1.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.35
         upper limit
    1.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.14
    Notes
    [30] - Difference = with SVR12 minus without SVR12

    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) [31]
    End point description
    SVR12 is defined as hepatitis C virus ribonucleic acid (HCV RNA) less than the lower limit of quantification (LLOQ) 12 weeks after the last actual dose of study drug. Flanking imputation, where applicable, was used to impute missing data. After applying flanking imputation, if there was no value in the window but there was an HCV RNA value from a local laboratory present, then it was to be imputed into the SVR window. Otherwise, participants with missing data were counted as failures.
    End point type
    Secondary
    End point timeframe
    12 weeks after the last actual dose of study drug
    Notes
    [31] - 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: Per protocol, this is a secondary endpoint specific to study M14-423.
    End point values
    M14-423: ABT-450/r/ABT-267 plus ABT-333 +/- Ribavirin (RBV)
    Number of subjects analysed
    1596 [32]
    Units: percentage of participants
        number (confidence interval 95%)
    97.0 (96.0 to 97.7)
    Notes
    [32] - All enrolled subjects in study M14-423 who received at least 1 dose of study drug
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality reported from study enrollment to end, up to 5 yrs. TEAEs and TESAEs collected from 1st dose of study drug until 30 d after the last administration, up to 203 d. From PT Week 4 to the end of the study, only SAE of death was collected.
    Adverse event reporting additional description
    All-cause mortality and adverse events: all study M14-423 participants who received at least one dose of study drug
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    M14-423: ABT-450/r/ABT-267 plus ABT-333 +/- Ribavirin (RBV)
    Reporting group description
    Study M14-423: Participants with HCV GT1b without cirrhosis received the 3-DAA (ABT-450/ritonavir/ABT-267 and ABT-333) regimen: two 75 mg ABT 450/50 mg ritonavir/12.5 mg ABT-267 tablets taken orally every morning (QD) and one ABT-333 250 mg tablet taken orally twice a day (BID) for 12 weeks. Participants with HCV GT1a without cirrhosis and those with HCV GT1b with cirrhosis received the 3-DAA regimen for 12 weeks. Participants with HCV GT1a with cirrhosis received the 3-DAA regimen for 24 weeks.

    Serious adverse events
    M14-423: ABT-450/r/ABT-267 plus ABT-333 +/- Ribavirin (RBV)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    40 / 1596 (2.51%)
         number of deaths (all causes)
    28
         number of deaths resulting from adverse events
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    HEPATOCELLULAR CARCINOMA
         subjects affected / exposed
    2 / 1596 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    MALIGNANT MELANOMA
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    PANCREATIC NEOPLASM
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    PAPILLARY THYROID CANCER
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    TUMOUR THROMBOSIS
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    ABORTION SPONTANEOUS
         subjects affected / exposed
    1 / 1596 (0.06%)
         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 / 1596 (0.06%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    DRUG INTERACTION
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    ANGER
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    AFFECT LABILITY
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    INSOMNIA
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    SCHIZOAFFECTIVE DISORDER
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    MANIA
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    HEAD INJURY
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    RADIUS FRACTURE
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    TENDON RUPTURE
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    ANGINA UNSTABLE
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    PALPITATIONS
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    DIZZINESS POSTURAL
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    ENCEPHALOPATHY
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    PARAESTHESIA
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    PSYCHOMOTOR SKILLS IMPAIRED
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    SYNCOPE
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    ANAL FISSURE
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    ASCITES
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    CONSTIPATION
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    COLITIS
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    DENTAL CARIES
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    GASTRIC ULCER
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    OESOPHAGEAL VARICES HAEMORRHAGE
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    VARICES OESOPHAGEAL
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    HEPATIC FAILURE
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    HEPATORENAL SYNDROME
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    ECZEMA
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    CALCULUS URINARY
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    NEPHROLITHIASIS
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    RENAL COLIC
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    PATHOLOGICAL FRACTURE
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    APPENDICITIS
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    DERMATITIS INFECTED
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    ERYSIPELAS
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    INFLUENZA
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    PERITONITIS BACTERIAL
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    2 / 1596 (0.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    PYELONEPHRITIS
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    1 / 1596 (0.06%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    DIABETES MELLITUS
         subjects affected / exposed
    1 / 1596 (0.06%)
         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
    M14-423: ABT-450/r/ABT-267 plus ABT-333 +/- Ribavirin (RBV)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    805 / 1596 (50.44%)
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    291 / 1596 (18.23%)
         occurrences all number
    319
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    165 / 1596 (10.34%)
         occurrences all number
    179
    FATIGUE
         subjects affected / exposed
    300 / 1596 (18.80%)
         occurrences all number
    331
    Gastrointestinal disorders
    DIARRHOEA
         subjects affected / exposed
    103 / 1596 (6.45%)
         occurrences all number
    112
    NAUSEA
         subjects affected / exposed
    186 / 1596 (11.65%)
         occurrences all number
    200
    Skin and subcutaneous tissue disorders
    PRURITUS
         subjects affected / exposed
    199 / 1596 (12.47%)
         occurrences all number
    209
    Psychiatric disorders
    INSOMNIA
         subjects affected / exposed
    179 / 1596 (11.22%)
         occurrences all number
    183

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Jan 2015
    Protocol Amendment 2 ● Updated treatment duration for subjects with GT1a infection and compensated cirrhosis (F4 fibrosis stage) from 12 to 24 weeks, with 12 weeks considered for some patients where consistent with the local label. ● Updated Introduction to remove language detailing effects of ABT-450/ritonavir, ABT-267 (and it major, inactive human metabolites) and ABT-333 on embryo-fetal development. ● Updated Introduction to refer investigators to locally approved labels for preclinical toxicology (including reproductive and development toxicity), metabolism, pharmacokinetics and drug-drug interactions in countries that have received marketing approval. ● Clarified elevated ALT risk associated with ethinyl estradiol therapy in Section 3.0 Introduction; Integrated Safety Results. ● Clarified enrollment caps for cirrhotic subjects. ● Updated Contraindicated Medication list in Synopsis and Exclusion 3 (Table 6)\ to refer investigators to locally approved labels were AbbVie product containing the regimen for this study has been approved. ● Updated Schedule of Activities (Table 7) removing duplicate "Study Drug Returned for IRT Reconciliation" entry. ● Updated Schedule of Activities (Table 7, footnote "j.") and Section 5.3.1.1 to clarify urine pregnancy testing requirements for subjects on DAA regimen only. ● Added AFP to the list of Clinical Laboratory Tests collected at the Screening Visit. ● Updated Table 12 to allow for RBV dose modifications in management of hemoglobin decreases per local label. ● Updated Section 9.1 to include submission of amendments to Regulatory Authority(ies) as applicable. ● Updated Table 4 (Baseline Fibrosis Stage) to correct administrative error for F4 FibroScan range. ● Added back-up Sponsor contact phone number to Title Page and Section 6.5.

    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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