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    Clinical Trial Results:
    A Phase 3, Open-Label Study with Asunaprevir and Daclatasvir Plus Peginterferon Alfa-2a (Pegasys) and Ribavirin (Copegus) (P/R) (QUAD) for Subjects Who Are Null or Partial Responders to Peginterferon Alfa-2a or -2b Plus Ribavirin with Chronic Hepatitis C Genotypes 1 or 4 Infection

    Summary
    EudraCT number
    		 2011-005422-21
    Trial protocol
    		 SE   DE   NL   ES   DK   IT  
    Global end of trial date
    09 Dec 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Oct 2016
    First version publication date
    30 Oct 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    AI447-029
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01573351
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb International Corporation
    Sponsor organisation address
    Chaussee de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb International Corporation, clinical.trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb International Corporation, clinical.trials@bms.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
    09 Dec 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Dec 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to assess efficacy, as determined by the proportion of subjects with sustained virologic response at follow-up Week 12 (SVR12), defined as hepatitis C virus (HCV) ribonucleic acid (RNA) < limit of quantitation (LOQ) at post-treatment Week 12.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 May 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 8
    Country: Number of subjects enrolled
    Spain: 23
    Country: Number of subjects enrolled
    Sweden: 11
    Country: Number of subjects enrolled
    Denmark: 8
    Country: Number of subjects enrolled
    France: 87
    Country: Number of subjects enrolled
    Germany: 47
    Country: Number of subjects enrolled
    Italy: 21
    Country: Number of subjects enrolled
    Argentina: 12
    Country: Number of subjects enrolled
    Canada: 27
    Country: Number of subjects enrolled
    Korea, Republic of: 37
    Country: Number of subjects enrolled
    Mexico: 7
    Country: Number of subjects enrolled
    Russian Federation: 23
    Country: Number of subjects enrolled
    Switzerland: 5
    Country: Number of subjects enrolled
    Taiwan: 24
    Country: Number of subjects enrolled
    United States: 156
    Worldwide total number of subjects
    496
    EEA total number of subjects
    205
    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)
    451
    From 65 to 84 years
    45
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study was conducted at 79 sites in 15 countries.

    Pre-assignment
    Screening details
    		 496 enrolled; 398 treated. 98 did not enter treatment because 81 did not meet the study criteria during the screening period, 13 withdrew consent, 4 other.

    Period 1
    Period 1 title
    Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 GT-1: Asunaprevir/Daclatasvir/Peginterferon Alfa-2a/Ribavirin
    Arm description
    		 Subjects with chronic HCV infection (genotype 1 [GT-1]) who were null or partial responders to peginterferon alfa-2a (pegINFα-2a) or peginterferon alfa-2b (pegINFα-2b) plus ribavirin were treated for 24 weeks with daclatasvir (DCV) Quad regimen followed by 24 weeks of follow-up after completion or early discontinuation of treatment. The DCV Quad regimen included daclatasvir 60 mg tablet once daily by mouth, asunaprevir 100-mg soft gel capsule twice daily by mouth, pegIFNα-2a 180 μg subcutaneous once weekly, and RBV (for subjects weighing < 75 kg the total dose was 1000 mg per day and for those weighing ≥ 75 kg the dose was 1200 mg per day; therefore, subjects were to take either 400 mg [2 tablets for subjects < 75 kg] or 600 mg [3 tablets for subjects ≥ 75 kg] in the morning with food and 600 mg [3 tablets] in the evening with food) for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Asunaprevir
    Investigational medicinal product code
    BMS-650032
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Asunaprevir 100mg softgel capsule was administered orally twice daily.

    Investigational medicinal product name
    Daclatasvir
    Investigational medicinal product code
    BMS-790052
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Daclatasvir 60mg film coated tablet was administered orally once daily.

    Investigational medicinal product name
    Peginterferon Alfa-2a
    Investigational medicinal product code
    Other name
    PEGASYS
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Peginterferon Alfa-2a 180 micrograms/0.5 mL was administered once per week.

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    COPEGUS
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ribavirin administered at a daily dose of 1000 to 1200 mg orally in two divided doses.

    Arm title
    		 GT-4: Asunaprevir/Daclatasvir/Peginterferon Alfa-2a/Ribavirin
    Arm description
    		 Subjects with chronic HCV infection (genotype 4 [GT-4]) who were null or partial responders to peginterferon alfa-2a (pegINFα-2a) or peginterferon alfa-2b (pegINFα-2b) plus ribavirin were treated for 24 weeks with daclatasvir (DCV) Quad regimen followed by 24 weeks of follow-up after completion or early discontinuation of treatment. The DCV Quad regimen included daclatasvir 60 mg tablet once daily by mouth, asunaprevir 100-mg soft gel capsule twice daily by mouth, pegIFNα-2a 180 μg subcutaneous once weekly, and RBV (for subjects weighing < 75 kg the total dose was 1000 mg per day and for those weighing ≥ 75 kg the dose was 1200 mg per day; therefore, subjects were to take either 400 mg [2 tablets for subjects < 75 kg] or 600 mg [3 tablets for subjects ≥ 75 kg] in the morning with food and 600 mg [3 tablets] in the evening with food) for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Asunaprevir
    Investigational medicinal product code
    BMS-650032
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Asunaprevir 100mg softgel capsule was administered orally twice daily.

    Investigational medicinal product name
    Daclatasvir
    Investigational medicinal product code
    BMS-790052
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Daclatasvir 60mg film coated tablet was administered orally once daily.

    Investigational medicinal product name
    Peginterferon Alfa-2a
    Investigational medicinal product code
    Other name
    PEGASYS
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Peginterferon Alfa-2a 180 micrograms/0.5 mL was administered once per week.

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    COPEGUS
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ribavirin was administered at a daily dose of 1000 to 1200 mg orally in two divided doses.

    Number of subjects in period 1 [1]
    		GT-1: Asunaprevir/Daclatasvir/Peginterferon Alfa-2a/Ribavirin GT-4: Asunaprevir/Daclatasvir/Peginterferon Alfa-2a/Ribavirin
    Started
    354
    44
    Completed
    335
    44
    Not completed
    19
    0
         Adverse event, non-fatal
    7
    -
         Lost to follow-up
    1
    -
         Lack of efficacy
    11
    -
    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: Out of 496 subjects who were enrolled, only 398 were treated. Remaining 98 subjects did not receive any treatment. 81 subjects no longer met the study criteria, 13 subjects withdrew consent to participate, and 4 due to other reasons.
    Period 2
    Period 2 title
    Follow-Up Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 GT-1: Asunaprevir/Daclatasvir/Peginterferon Alfa-2a/Ribavirin
    Arm description
    		 Subjects received no treatment during 24 weeks of follow-up after completion of treatment or upon early discontinuation of treatment. Treatment included 24 weeks with DCV Quad regimen followed by 24 weeks of follow-up after completion or early discontinuation of treatment. The DCV Quad regimen included daclatasvir 60 mg tablet once daily by mouth, asunaprevir 100-mg soft gel capsule twice daily by mouth, pegIFNα-2a 180 μg subcutaneous once weekly, and ribavirin (for subjects weighing < 75 kg the total dose was 1000 mg per day and for those weighing ≥ 75 kg the dose was 1200 mg per day; therefore, subjects were to take either 400 mg [2 tablets for subjects < 75 kg] or 600 mg [3 tablets for subjects ≥ 75 kg] in the morning with food and 600 mg [3 tablets] in the evening with food) for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Asunaprevir
    Investigational medicinal product code
    BMS-650032
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Asunaprevir 100mg softgel capsule was administered orally twice daily.

    Investigational medicinal product name
    Daclatasvir
    Investigational medicinal product code
    BMS-790052
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Daclatasvir 60mg film coated tablet was administered orally once daily.

    Investigational medicinal product name
    Peginterferon Alfa-2a
    Investigational medicinal product code
    Other name
    PEGASYS
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Peginterferon Alfa-2a 180 micrograms/0.5 mL was administered once per week.

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    COPEGUS
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ribavirin administered at a daily dose of 1000 to 1200 mg orally in two divided doses.

    Arm title
    		 GT-4: Asunaprevir/Daclatasvir/Peginterferon Alfa-2a/Ribavirin
    Arm description
    		 Subjects received no treatment during 24 weeks of follow-up after completion of treatment or upon early discontinuation of treatment. Treatment included 24 weeks with DCV Quad regimen followed by 24 weeks of follow-up after completion or early discontinuation of treatment. The DCV Quad regimen included daclatasvir 60 mg tablet once daily by mouth, asunaprevir 100-mg soft gel capsule twice daily by mouth, pegIFNα-2a 180 μg subcutaneous once weekly, and ribavirin (for subjects weighing < 75 kg the total dose was 1000 mg per day and for those weighing ≥ 75 kg the dose was 1200 mg per day; therefore, subjects were to take either 400 mg [2 tablets for subjects < 75 kg] or 600 mg [3 tablets for subjects ≥ 75 kg] in the morning with food and 600 mg [3 tablets] in the evening with food) for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Asunaprevir
    Investigational medicinal product code
    BMS-650032
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Asunaprevir 100mg softgel capsule was administered orally twice daily.

    Investigational medicinal product name
    Daclatasvir
    Investigational medicinal product code
    BMS-790052
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Daclatasvir 60mg film coated tablet was administered orally once daily.

    Investigational medicinal product name
    Peginterferon Alfa-2a
    Investigational medicinal product code
    Other name
    PEGASYS
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Peginterferon Alfa 180 micrograms/0.5 mL was administered once per week.

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    COPEGUS
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ribavirin administered at a daily dose of 1000 to 1200 mg orally in two divided doses.

    Number of subjects in period 2
    		GT-1: Asunaprevir/Daclatasvir/Peginterferon Alfa-2a/Ribavirin GT-4: Asunaprevir/Daclatasvir/Peginterferon Alfa-2a/Ribavirin
    Started
    335
    44
    Completed
    344
    44
    Not completed
    8
    0
         Consent withdrawn by subject
    3
    -
         Death
    1
    -
         Other
    2
    -
         Lost to follow-up
    2
    -
    Joined
    17
    0
         Re-entering for follow-up
    17
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    GT-1: Asunaprevir/Daclatasvir/Peginterferon Alfa-2a/Ribavirin
    Reporting group description
    		 Subjects with chronic HCV infection (genotype 1 [GT-1]) who were null or partial responders to peginterferon alfa-2a (pegINFα-2a) or peginterferon alfa-2b (pegINFα-2b) plus ribavirin were treated for 24 weeks with daclatasvir (DCV) Quad regimen followed by 24 weeks of follow-up after completion or early discontinuation of treatment. The DCV Quad regimen included daclatasvir 60 mg tablet once daily by mouth, asunaprevir 100-mg soft gel capsule twice daily by mouth, pegIFNα-2a 180 μg subcutaneous once weekly, and RBV (for subjects weighing < 75 kg the total dose was 1000 mg per day and for those weighing ≥ 75 kg the dose was 1200 mg per day; therefore, subjects were to take either 400 mg [2 tablets for subjects < 75 kg] or 600 mg [3 tablets for subjects ≥ 75 kg] in the morning with food and 600 mg [3 tablets] in the evening with food) for 24 weeks.

    Reporting group title
    GT-4: Asunaprevir/Daclatasvir/Peginterferon Alfa-2a/Ribavirin
    Reporting group description
    		 Subjects with chronic HCV infection (genotype 4 [GT-4]) who were null or partial responders to peginterferon alfa-2a (pegINFα-2a) or peginterferon alfa-2b (pegINFα-2b) plus ribavirin were treated for 24 weeks with daclatasvir (DCV) Quad regimen followed by 24 weeks of follow-up after completion or early discontinuation of treatment. The DCV Quad regimen included daclatasvir 60 mg tablet once daily by mouth, asunaprevir 100-mg soft gel capsule twice daily by mouth, pegIFNα-2a 180 μg subcutaneous once weekly, and RBV (for subjects weighing < 75 kg the total dose was 1000 mg per day and for those weighing ≥ 75 kg the dose was 1200 mg per day; therefore, subjects were to take either 400 mg [2 tablets for subjects < 75 kg] or 600 mg [3 tablets for subjects ≥ 75 kg] in the morning with food and 600 mg [3 tablets] in the evening with food) for 24 weeks.

    Reporting group values
    		 GT-1: Asunaprevir/Daclatasvir/Peginterferon Alfa-2a/Ribavirin GT-4: Asunaprevir/Daclatasvir/Peginterferon Alfa-2a/Ribavirin Total
    Number of subjects
    		 354 44 398
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 320 41 361
        From 65-84 years
    		 34 3 37
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 52.9 (19 to 76) 50.8 (20 to 71) -
    Gender categorical
    Units: Subjects
        Female
    		 114 11 125
        Male
    		 240 33 273

    End points

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    End points reporting groups
    Reporting group title
    GT-1: Asunaprevir/Daclatasvir/Peginterferon Alfa-2a/Ribavirin
    Reporting group description
    		 Subjects with chronic HCV infection (genotype 1 [GT-1]) who were null or partial responders to peginterferon alfa-2a (pegINFα-2a) or peginterferon alfa-2b (pegINFα-2b) plus ribavirin were treated for 24 weeks with daclatasvir (DCV) Quad regimen followed by 24 weeks of follow-up after completion or early discontinuation of treatment. The DCV Quad regimen included daclatasvir 60 mg tablet once daily by mouth, asunaprevir 100-mg soft gel capsule twice daily by mouth, pegIFNα-2a 180 μg subcutaneous once weekly, and RBV (for subjects weighing < 75 kg the total dose was 1000 mg per day and for those weighing ≥ 75 kg the dose was 1200 mg per day; therefore, subjects were to take either 400 mg [2 tablets for subjects < 75 kg] or 600 mg [3 tablets for subjects ≥ 75 kg] in the morning with food and 600 mg [3 tablets] in the evening with food) for 24 weeks.

    Reporting group title
    GT-4: Asunaprevir/Daclatasvir/Peginterferon Alfa-2a/Ribavirin
    Reporting group description
    		 Subjects with chronic HCV infection (genotype 4 [GT-4]) who were null or partial responders to peginterferon alfa-2a (pegINFα-2a) or peginterferon alfa-2b (pegINFα-2b) plus ribavirin were treated for 24 weeks with daclatasvir (DCV) Quad regimen followed by 24 weeks of follow-up after completion or early discontinuation of treatment. The DCV Quad regimen included daclatasvir 60 mg tablet once daily by mouth, asunaprevir 100-mg soft gel capsule twice daily by mouth, pegIFNα-2a 180 μg subcutaneous once weekly, and RBV (for subjects weighing < 75 kg the total dose was 1000 mg per day and for those weighing ≥ 75 kg the dose was 1200 mg per day; therefore, subjects were to take either 400 mg [2 tablets for subjects < 75 kg] or 600 mg [3 tablets for subjects ≥ 75 kg] in the morning with food and 600 mg [3 tablets] in the evening with food) for 24 weeks.
    Reporting group title
    GT-1: Asunaprevir/Daclatasvir/Peginterferon Alfa-2a/Ribavirin
    Reporting group description
    		 Subjects received no treatment during 24 weeks of follow-up after completion of treatment or upon early discontinuation of treatment. Treatment included 24 weeks with DCV Quad regimen followed by 24 weeks of follow-up after completion or early discontinuation of treatment. The DCV Quad regimen included daclatasvir 60 mg tablet once daily by mouth, asunaprevir 100-mg soft gel capsule twice daily by mouth, pegIFNα-2a 180 μg subcutaneous once weekly, and ribavirin (for subjects weighing < 75 kg the total dose was 1000 mg per day and for those weighing ≥ 75 kg the dose was 1200 mg per day; therefore, subjects were to take either 400 mg [2 tablets for subjects < 75 kg] or 600 mg [3 tablets for subjects ≥ 75 kg] in the morning with food and 600 mg [3 tablets] in the evening with food) for 24 weeks.

    Reporting group title
    GT-4: Asunaprevir/Daclatasvir/Peginterferon Alfa-2a/Ribavirin
    Reporting group description
    		 Subjects received no treatment during 24 weeks of follow-up after completion of treatment or upon early discontinuation of treatment. Treatment included 24 weeks with DCV Quad regimen followed by 24 weeks of follow-up after completion or early discontinuation of treatment. The DCV Quad regimen included daclatasvir 60 mg tablet once daily by mouth, asunaprevir 100-mg soft gel capsule twice daily by mouth, pegIFNα-2a 180 μg subcutaneous once weekly, and ribavirin (for subjects weighing < 75 kg the total dose was 1000 mg per day and for those weighing ≥ 75 kg the dose was 1200 mg per day; therefore, subjects were to take either 400 mg [2 tablets for subjects < 75 kg] or 600 mg [3 tablets for subjects ≥ 75 kg] in the morning with food and 600 mg [3 tablets] in the evening with food) for 24 weeks.

    Primary: Percentage of Genotype 1 Chronic Hepatitis C Infected Subjects Who Were Prior Null or Partial Responders to Peginterferon Alfa/Ribavirin Achieving a Sustained Virologic Response at Follow-Up Week 12

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    End point title
    		 Percentage of Genotype 1 Chronic Hepatitis C Infected Subjects Who Were Prior Null or Partial Responders to Peginterferon Alfa/Ribavirin Achieving a Sustained Virologic Response at Follow-Up Week 12 [1]
    End point description
    Sustained Virologic Response at follow-up (post treatment) Week 12 defined as hepatitis C Virus (HCV) RNA levels to be <lower limit of quantitation i.e., 25 international unit per milliliter, target detected or target not detected, at Follow-up Week 12 for subjects with genotype 1 who were prior null or partial responders to Peginterferon Alfa/Ribavirin. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. The analysis was based on all treated subjects. Subjects missing follow-up Week 12 measurements and subjects who received non-study anti-HCV medication prior to follow-up Week 12 were counted as non-responders.
    End point type
    Primary
    End point timeframe
    Follow-Up Week 12
    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: Only descriptive summary statistics were planned for this outcome measure.
    End point values
    		 GT-1: Asunaprevir/Daclatasvir/Peginterferon Alfa-2a/Ribavirin GT-4: Asunaprevir/Daclatasvir/Peginterferon Alfa-2a/Ribavirin
    Number of subjects analysed
    354
    44
    Units: Percentage of Subjects
        number (confidence interval 95%)
    92.9 (90.3 to 95.6)
    97.7 (93.3 to 100)
    No statistical analyses for this end point

    Secondary: Percentage of Genotype 1 Chronic Hepatitis C Infected Subjects Who Were Prior Null or Partial Responders to Peginterferon Alfa/Ribavirin With Hepatitis C Virus (HCV) RNA <Lower Limit of Quantitation (LLOQ), Target not Detected

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    End point title
    		 Percentage of Genotype 1 Chronic Hepatitis C Infected Subjects Who Were Prior Null or Partial Responders to Peginterferon Alfa/Ribavirin With Hepatitis C Virus (HCV) RNA <Lower Limit of Quantitation (LLOQ), Target not Detected
    End point description
    HCV RNA levels to be <LLOQ i.e. 25 international unit per milliliter, target not detected. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. The analysis was performed on all treated subjects who received at least 1 dose of study therapy.
    End point type
    Secondary
    End point timeframe
    Week 2, 4, 6, 8, 12, 24, follow-up week 12, and follow-up week 24
    End point values
    		 GT-1: Asunaprevir/Daclatasvir/Peginterferon Alfa-2a/Ribavirin GT-4: Asunaprevir/Daclatasvir/Peginterferon Alfa-2a/Ribavirin
    Number of subjects analysed
    354
    44
    Units: Percentage of Subjects
    number (confidence interval 95%)
        Week 2
    28 (23.3 to 32.6)
    27.3 (14.1 to 40.4)
        Week 4
    82.5 (78.5 to 86.4)
    81.8 (70.4 to 93.2)
        Week 6
    93.2 (90.6 to 95.8)
    90.9 (82.4 to 99.4)
        Week 8
    95.5 (93.3 to 97.4)
    97.7 (93.3 to 100)
        Week 12
    95.2 (93 to 97.4)
    97.7 (93.3 to 100)
        Week 24
    91 (88 to 93.9)
    97.7 (93.3 to 100)
        Follow-Up Week 12
    91.5 (88.6 to 94.4)
    97.7 (93.3 to 100)
        Follow-Up Week 24
    88.1 (84.8 to 91.5)
    93.2 (85.7 to 100)
    No statistical analyses for this end point

    Secondary: Percentage of Genotype 1 Chronic Hepatitis C Infected Subjects Who Were Prior Null or Partial Responders to Peginterferon Alfa/Ribavirin with Hepatitis C Virus (HCV) RNA <Lower Limit of Quantitation (LLOQ), Target Detected or Target not Detected

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    End point title
    		 Percentage of Genotype 1 Chronic Hepatitis C Infected Subjects Who Were Prior Null or Partial Responders to Peginterferon Alfa/Ribavirin with Hepatitis C Virus (HCV) RNA <Lower Limit of Quantitation (LLOQ), Target Detected or Target not Detected
    End point description
    HCV RNA levels to be <LLOQ i.e., 25 international unit per milliliter, target detected or target not detected. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. The analysis was performed on all treated subjects who received at least 1 dose of study therapy.
    End point type
    Secondary
    End point timeframe
    Week 2, 4, 6, 8, 12, 24, and follow-up Week 24
    End point values
    		 GT-1: Asunaprevir/Daclatasvir/Peginterferon Alfa-2a/Ribavirin GT-4: Asunaprevir/Daclatasvir/Peginterferon Alfa-2a/Ribavirin
    Number of subjects analysed
    354
    44
    Units: Percentage of Subjects
    number (confidence interval 95%)
        Week 2
    81.4 (77.3 to 85.4)
    86.4 (76.2 to 96.5)
        Week 4
    97.7 (96.2 to 99.3)
    100 (100 to 100)
        Weel 6
    94.4 (91.9 to 96.8)
    95.5 (89.3 to 100)
        Week 8
    97.5 (95.8 to 99.1)
    97.7 (93.3 to 100)
        Week 12
    97.2 (95.4 to 98.9)
    100 (100 to 100)
        Week 24
    92.4 (89.6 to 95.1)
    100 (100 to 100)
        Follow-Up Week 24
    88.4 (85.1 to 91.8)
    95.5 (89.3 to 100)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), Grade 3 to 4 AEs, and Who Died During Treatment Period

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    End point title
    		 Number of Subjects With Serious Adverse Events (SAEs), Discontinuations Due to Adverse Events (AEs), Grade 3 to 4 AEs, and Who Died During Treatment Period
    End point description
    AE was defined as any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not has a causal relationship with treatment. SAE was defined as a medical event that at any dose resulted in death, persistent or significant disability/incapacity, or drug dependency/abuse; was life-threatening, an important medical event, or a congenital anomaly/birth defect; or required or prolonged hospitalisation. Grade 3 to 4 AE were also reported. The analysis was performed on all treated subjects who received at least 1 dose of study therapy.
    End point type
    Secondary
    End point timeframe
    From start of study treatment up to 7 days post last dose of study treatment
    End point values
    		 GT-1: Asunaprevir/Daclatasvir/Peginterferon Alfa-2a/Ribavirin GT-4: Asunaprevir/Daclatasvir/Peginterferon Alfa-2a/Ribavirin
    Number of subjects analysed
    354
    44
    Units: Subjects
        SAEs
    19
    3
        AEs Leading to Discontinuation
    15
    3
        Grade 3/4 AEs
    86
    11
        Deaths
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study treatment up to 7 days post last dose of study treatment
    Adverse event reporting additional description
    On-treatment
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    GT-1:Asunaprevir/Daclatasvir/ Peginterferon Alfa-2a/Ribaviri
    Reporting group description
    		 Subjects with chronic HCV infection (genotype 1 [GT-1]) who were null or partial responders to peginterferon alfa-2a (pegINFα-2a) or peginterferon alfa-2b (pegINFα-2b) plus ribavirin were treated for 24 weeks with daclatasvir (DCV) Quad regimen followed by 24 weeks of follow-up after completion or early discontinuation of treatment. The DCV Quad regimen included daclatasvir 60 mg tablet once daily by mouth, asunaprevir 100-mg soft gel capsule twice daily by mouth, pegIFNα-2a 180 μg subcutaneous once weekly, and RBV (for subjects weighing < 75 kg the total dose was 1000 mg per day and for those weighing ≥ 75 kg the dose was 1200 mg per day; therefore, subjects were to take either 400 mg [2 tablets for subjects < 75 kg] or 600 mg [3 tablets for subjects ≥ 75 kg] in the morning with food and 600 mg [3 tablets] in the evening with food) for 24 weeks.

    Reporting group title
    GT-4:Asunaprevir/Daclatasvir/ Peginterferon Alfa-2a/Ribaviri
    Reporting group description
    		 Subjects with chronic HCV infection (genotype 4 [GT-4]) who were null or partial responders to peginterferon alfa-2a (pegINFα-2a) or peginterferon alfa-2b (pegINFα-2b) plus ribavirin were treated for 24 weeks with daclatasvir (DCV) Quad regimen followed by 24 weeks of follow-up after completion or early discontinuation of treatment. The DCV Quad regimen included daclatasvir 60 mg tablet once daily by mouth, asunaprevir 100-mg soft gel capsule twice daily by mouth, pegIFNα-2a 180 μg subcutaneous once weekly, and RBV (for subjects weighing < 75 kg the total dose was 1000 mg per day and for those weighing ≥ 75 kg the dose was 1200 mg per day; therefore, subjects were to take either 400 mg [2 tablets for subjects < 75 kg] or 600 mg [3 tablets for subjects ≥ 75 kg] in the morning with food and 600 mg [3 tablets] in the evening with food) for 24 weeks.

    Serious adverse events
    		 GT-1:Asunaprevir/Daclatasvir/ Peginterferon Alfa-2a/Ribaviri GT-4:Asunaprevir/Daclatasvir/ Peginterferon Alfa-2a/Ribaviri
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 354 (5.37%)
    3 / 44 (6.82%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Major depression
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Spinal column injury
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic ulcer
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 354 (0.56%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    0 / 354 (0.00%)
    1 / 44 (2.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Calculus ureteric
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 354 (0.85%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 354 (0.56%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 354 (0.28%)
    0 / 44 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 GT-1:Asunaprevir/Daclatasvir/ Peginterferon Alfa-2a/Ribaviri GT-4:Asunaprevir/Daclatasvir/ Peginterferon Alfa-2a/Ribaviri
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    350 / 354 (98.87%)
    43 / 44 (97.73%)
    Investigations
    Weight decreased
         subjects affected / exposed
    19 / 354 (5.37%)
    7 / 44 (15.91%)
         occurrences all number
    19
    7
    Nervous system disorders
    Headache
         subjects affected / exposed
    111 / 354 (31.36%)
    13 / 44 (29.55%)
         occurrences all number
    122
    17
    Dizziness
         subjects affected / exposed
    30 / 354 (8.47%)
    2 / 44 (4.55%)
         occurrences all number
    31
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    146 / 354 (41.24%)
    19 / 44 (43.18%)
         occurrences all number
    155
    21
    Asthenia
         subjects affected / exposed
    79 / 354 (22.32%)
    17 / 44 (38.64%)
         occurrences all number
    85
    18
    Influenza like illness
         subjects affected / exposed
    79 / 354 (22.32%)
    10 / 44 (22.73%)
         occurrences all number
    90
    10
    Irritability
         subjects affected / exposed
    57 / 354 (16.10%)
    7 / 44 (15.91%)
         occurrences all number
    58
    7
    Pyrexia
         subjects affected / exposed
    57 / 354 (16.10%)
    7 / 44 (15.91%)
         occurrences all number
    62
    7
    Injection site erythema
         subjects affected / exposed
    22 / 354 (6.21%)
    1 / 44 (2.27%)
         occurrences all number
    22
    1
    Pain
         subjects affected / exposed
    14 / 354 (3.95%)
    7 / 44 (15.91%)
         occurrences all number
    14
    7
    Chills
         subjects affected / exposed
    16 / 354 (4.52%)
    3 / 44 (6.82%)
         occurrences all number
    18
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    67 / 354 (18.93%)
    10 / 44 (22.73%)
         occurrences all number
    78
    12
    Neutropenia
         subjects affected / exposed
    56 / 354 (15.82%)
    3 / 44 (6.82%)
         occurrences all number
    77
    6
    Thrombocytopenia
         subjects affected / exposed
    21 / 354 (5.93%)
    3 / 44 (6.82%)
         occurrences all number
    26
    3
    Eye disorders
    Dry eye
         subjects affected / exposed
    17 / 354 (4.80%)
    4 / 44 (9.09%)
         occurrences all number
    17
    4
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    63 / 354 (17.80%)
    7 / 44 (15.91%)
         occurrences all number
    68
    13
    Nausea
         subjects affected / exposed
    61 / 354 (17.23%)
    5 / 44 (11.36%)
         occurrences all number
    69
    7
    Abdominal pain upper
         subjects affected / exposed
    18 / 354 (5.08%)
    3 / 44 (6.82%)
         occurrences all number
    18
    5
    Vomiting
         subjects affected / exposed
    14 / 354 (3.95%)
    4 / 44 (9.09%)
         occurrences all number
    14
    4
    Dry mouth
         subjects affected / exposed
    11 / 354 (3.11%)
    3 / 44 (6.82%)
         occurrences all number
    11
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    67 / 354 (18.93%)
    6 / 44 (13.64%)
         occurrences all number
    69
    6
    Dyspnoea
         subjects affected / exposed
    41 / 354 (11.58%)
    8 / 44 (18.18%)
         occurrences all number
    42
    8
    Dyspnoea exertional
         subjects affected / exposed
    18 / 354 (5.08%)
    3 / 44 (6.82%)
         occurrences all number
    19
    3
    Epistaxis
         subjects affected / exposed
    10 / 354 (2.82%)
    4 / 44 (9.09%)
         occurrences all number
    10
    5
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    88 / 354 (24.86%)
    16 / 44 (36.36%)
         occurrences all number
    93
    17
    Rash
         subjects affected / exposed
    75 / 354 (21.19%)
    7 / 44 (15.91%)
         occurrences all number
    78
    8
    Dry skin
         subjects affected / exposed
    65 / 354 (18.36%)
    6 / 44 (13.64%)
         occurrences all number
    68
    7
    Alopecia
         subjects affected / exposed
    60 / 354 (16.95%)
    4 / 44 (9.09%)
         occurrences all number
    60
    4
    Eczema
         subjects affected / exposed
    10 / 354 (2.82%)
    3 / 44 (6.82%)
         occurrences all number
    11
    3
    Erythema
         subjects affected / exposed
    10 / 354 (2.82%)
    3 / 44 (6.82%)
         occurrences all number
    11
    3
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    77 / 354 (21.75%)
    12 / 44 (27.27%)
         occurrences all number
    81
    14
    Depression
         subjects affected / exposed
    30 / 354 (8.47%)
    4 / 44 (9.09%)
         occurrences all number
    30
    5
    Sleep disorder
         subjects affected / exposed
    11 / 354 (3.11%)
    4 / 44 (9.09%)
         occurrences all number
    12
    4
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    55 / 354 (15.54%)
    6 / 44 (13.64%)
         occurrences all number
    65
    7
    Arthralgia
         subjects affected / exposed
    35 / 354 (9.89%)
    5 / 44 (11.36%)
         occurrences all number
    37
    5
    Back pain
         subjects affected / exposed
    29 / 354 (8.19%)
    0 / 44 (0.00%)
         occurrences all number
    31
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    41 / 354 (11.58%)
    6 / 44 (13.64%)
         occurrences all number
    45
    7

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Mar 2012
    Permitted collection and storage of blood samples for use in future exploratory pharmacogenetic research.
    31 May 2012
    Added a safety update and guidance regarding the management of patients exposed to DCV/ASV (Dual therapy), who presented with unexplained pyrexia. In addition, subjects with hemophilia were excluded following Health Authorities commitments as this population is at high risk.
    30 Mar 2013
    Corrected grammatical and typographical errors as well as protocol inconsistencies with program standards. Additionally, table numbers were slightly modified to reflect a new template.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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