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    Clinical Trial Results:
    A Phase 3 Evaluation of a daclatasvir/asunaprevir/BMS-791325 Fixed Dose Combination in Non-cirrhotic Subjects with Genotype 1 Chronic Hepatitis C

    Summary
    EudraCT number
    		 2013-002468-20
    Trial protocol
    		 FR  
    Global end of trial date
    18 Nov 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Apr 2016
    First version publication date
    28 Apr 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    AI443-102
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01979939
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol Myers Squibb
    Sponsor organisation address
    Chaussee de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    Bristol Myers Squibb Study Director, Bristol Myers Squibb, clinical.trials@bms.com
    Scientific contact
    Bristol Myers Squibb Study Director, Bristol Myers Squibb, 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
    18 Nov 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Nov 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the proportion of treatment-naive noncirrhotic subjects who achieved sustained virologic response at follow-up week 12, defined as hepatitis C virus RNA below lower limit of quantitation, target detected or target not detected at follow-up week 12, was significantly greater than the historical threshold of 79%.
    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
    16 Dec 2013
    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
    Australia: 64
    Country: Number of subjects enrolled
    Canada: 68
    Country: Number of subjects enrolled
    France: 41
    Country: Number of subjects enrolled
    United States: 291
    Country: Number of subjects enrolled
    Puerto Rico: 8
    Worldwide total number of subjects
    472
    EEA total number of subjects
    41
    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)
    438
    From 65 to 84 years
    34
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 66 sites in the United States, Puerto Rico, Canada, France and Australia.

    Pre-assignment
    Screening details
    		 A total of 472 subjects were enrolled and 415 were treated. Remaining 57 subjects did not receive any treatment.

    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
    		 Treatment-naive
    Arm description
    		 Previously untreated subjects received an oral fixed dose combination of daclatasvir 30 mg, asunaprevir 200 mg and beclabuvir 75 mg tablets twice daily with food for 12 weeks and followed-up for 24 weeks.
    Arm type
    		 Experimental

    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 30 mg was administered orally twice daily with food for 12 weeks by treatment naive subjects.

    Investigational medicinal product name
    Asunaprevir
    Investigational medicinal product code
    BMS-650032
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Asunaprevir 200 mg was administered orally twice daily with food for 12 weeks by treatment naive subjects.

    Investigational medicinal product name
    Beclabuvir
    Investigational medicinal product code
    BMS-791325
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Beclabuvir 75 mg was administered orally twice daily with food for 12 weeks by treatment naive subjects.

    Arm title
    		 Treatment-experienced
    Arm description
    		 Subjects previously treated with an interferon-containing regimen received an oral fixed dose combination of daclatasvir 30 mg, asunaprevir 200 mg and beclabuvir 75 mg tablets twice daily with food for 12 weeks and followed-up for 24 weeks.
    Arm type
    		 Experimental

    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 30 mg was administered orally twice daily with food for 12 weeks by treatment naive subjects.

    Investigational medicinal product name
    Asunaprevir
    Investigational medicinal product code
    BMS-650032
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Asunaprevir 200 mg was administered orally twice daily with food for 12 weeks by treatment naive subjects.

    Investigational medicinal product name
    Beclabuvir
    Investigational medicinal product code
    BMS-791325
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Beclabuvir 75 mg was administered orally twice daily with food for 12 weeks by treatment naive subjects.

    Number of subjects in period 1 [1]
    		Treatment-naive Treatment-experienced
    Started
    312
    103
    Completed
    305
    99
    Not completed
    7
    4
         Adverse event, non-fatal
    -
    3
         Pregnancy
    1
    -
         Lack of efficacy
    6
    1
    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: Of the 472 subjects enrolled, 415 subjects were treated with at least 1 dose of study therapy.
    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
    		 Treatment-naive
    Arm description
    		 Previously untreated subjects received an oral fixed dose combination of daclatasvir 30 mg, asunaprevir 200 mg and beclabuvir 75 mg tablets twice daily with food for 12 weeks and followed-up for 24 weeks.
    Arm type
    		 Experimental

    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 30 mg was administered orally twice daily with food for 12 weeks by treatment naive subjects.

    Investigational medicinal product name
    Asunaprevir
    Investigational medicinal product code
    BMS-650032
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Asunaprevir 200 mg was administered orally twice daily with food for 12 weeks by treatment naive subjects.

    Investigational medicinal product name
    Beclabuvir
    Investigational medicinal product code
    BMS-791325
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Beclabuvir 75 mg was administered orally twice daily with food for 12 weeks by treatment naive subjects.

    Arm title
    		 Treatment-experienced
    Arm description
    		 Subjects previously treated with an interferon-containing regimen received an oral fixed dose combination of daclatasvir 30 mg, asunaprevir 200 mg and beclabuvir 75 mg tablets twice daily with food for 12 weeks and followed-up for 24 weeks.
    Arm type
    		 Experimental

    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 30 mg was administered orally twice daily with food for 12 weeks by treatment naive subjects.

    Investigational medicinal product name
    Asunaprevir
    Investigational medicinal product code
    BMS-650032
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Asunaprevir 200 mg was administered orally twice daily with food for 12 weeks by treatment naive subjects.

    Investigational medicinal product name
    Beclabuvir
    Investigational medicinal product code
    BMS-791325
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Beclabuvir 75 mg was administered orally twice daily with food for 12 weeks by treatment naive subjects.

    Number of subjects in period 2
    		Treatment-naive Treatment-experienced
    Started
    305
    99
    Completed
    308
    98
    Not completed
    4
    5
         Consent withdrawn by subject
    1
    2
         Death
    -
    1
         Follow up no longer required per protocol
    1
    1
         Lost to follow-up
    2
    1
    Joined
    7
    4
         Rejoined for follow-up
    7
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment-naive
    Reporting group description
    		 Previously untreated subjects received an oral fixed dose combination of daclatasvir 30 mg, asunaprevir 200 mg and beclabuvir 75 mg tablets twice daily with food for 12 weeks and followed-up for 24 weeks.

    Reporting group title
    Treatment-experienced
    Reporting group description
    		 Subjects previously treated with an interferon-containing regimen received an oral fixed dose combination of daclatasvir 30 mg, asunaprevir 200 mg and beclabuvir 75 mg tablets twice daily with food for 12 weeks and followed-up for 24 weeks.

    Reporting group values
    		 Treatment-naive Treatment-experienced Total
    Number of subjects
    		 312 103 415
    Age categorical
    Units: Subjects
        < 65 years
    		 293 97 390
        >= 65 years
    		 19 6 25
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 50.8 ± 11.57 55.1 ± 8.09 -
    Gender categorical
    Units: Subjects
        Female
    		 137 39 176
        Male
    		 175 64 239

    End points

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    End points reporting groups
    Reporting group title
    Treatment-naive
    Reporting group description
    		 Previously untreated subjects received an oral fixed dose combination of daclatasvir 30 mg, asunaprevir 200 mg and beclabuvir 75 mg tablets twice daily with food for 12 weeks and followed-up for 24 weeks.

    Reporting group title
    Treatment-experienced
    Reporting group description
    		 Subjects previously treated with an interferon-containing regimen received an oral fixed dose combination of daclatasvir 30 mg, asunaprevir 200 mg and beclabuvir 75 mg tablets twice daily with food for 12 weeks and followed-up for 24 weeks.
    Reporting group title
    Treatment-naive
    Reporting group description
    		 Previously untreated subjects received an oral fixed dose combination of daclatasvir 30 mg, asunaprevir 200 mg and beclabuvir 75 mg tablets twice daily with food for 12 weeks and followed-up for 24 weeks.

    Reporting group title
    Treatment-experienced
    Reporting group description
    		 Subjects previously treated with an interferon-containing regimen received an oral fixed dose combination of daclatasvir 30 mg, asunaprevir 200 mg and beclabuvir 75 mg tablets twice daily with food for 12 weeks and followed-up for 24 weeks.

    Primary: Percentage of Treated Subjects in the Treatment-naive Cohort With Sustained Virologic Response at Follow-up Week 12 (SVR12)

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    End point title
    		 Percentage of Treated Subjects in the Treatment-naive Cohort With Sustained Virologic Response at Follow-up Week 12 (SVR12) [1] [2]
    End point description
    SVR12 was defined as hepatitis C virus (HCV) RNA levels <lower limit of quantitation (LLOQ), target detected or target not detected at follow-up week 12. The LLOQ was 25 international unit per milliliter. 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, the numerator was based on subjects meeting the response criteria and denominator based on all treated subjects. Missing values were imputed using Next Value Carried Backwards approach, i.e., missing HCV RNA in the follow-up Week 12 window was imputed using the next and closest available HCV RNA measurement after the follow-up Week 12 HCV RNA window.
    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 analysis was planned for this primary endpoint.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    		 Treatment-naive
    Number of subjects analysed
    312
    Units: Percentage of subjects
        number (confidence interval 95%)
    92.3 (89.4 to 95.3)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects in the Experienced Cohort With Sustained Virologic Response at Follow-up Week 12 (SVR12)

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    End point title
    		 Percentage of Subjects in the Experienced Cohort With Sustained Virologic Response at Follow-up Week 12 (SVR12) [3]
    End point description
    SVR12 was defined as hepatitis C virus (HCV) RNA levels <lower limit of quantitation (LLOQ), target detected or target not detected at follow-up week 12. The LLOQ was 25 international unit per milliliter, 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, the numerator was based on subjects meeting the response criteria and denominator based on all treated subjects. Missing values were imputed using Next Value Carried Backwards approach, i.e., missing HCV RNA in the follow-up Week 12 window was imputed using the next and closest available HCV RNA measurement after the follow-up Week 12 HCV RNA window.
    End point type
    Secondary
    End point timeframe
    Follow-up week 12
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    		 Treatment-experienced
    Number of subjects analysed
    103
    Units: Percentage of subjects
        number (confidence interval 95%)
    89.3 (83.4 to 95.3)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Hepatitis C Virus (HCV) RNA Levels Below Than Lower Limit of Quantitation (LLOQ) Target Detected (TD) or Target Not Detected (TND)

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    End point title
    		 Percentage of Subjects With Hepatitis C Virus (HCV) RNA Levels Below Than Lower Limit of Quantitation (LLOQ) Target Detected (TD) or Target Not Detected (TND)
    End point description
    Subjects who achieved HCV RNA levels <LLOQ, TD or TND. The LLOQ was 25 international unit per milliliter. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. The analysis was performed in modified intent-to-treat population, the numerator was based on subjects meeting the response criteria and denominator based on all treated subjects.
    End point type
    Secondary
    End point timeframe
    Week 1, 2, 4, 6, 8, 12; follow-up Week 4, 8 and 24.
    End point values
    		 Treatment-naive Treatment-experienced
    Number of subjects analysed
    312
    103
    Units: Percentage of Subjects
    number (not applicable)
        Week 1
    34.9
    28.2
        Week 2
    78.2
    74.8
        Week 4
    97.4
    97.1
        Week 6
    97.4
    97.1
        Week 8
    97.1
    96.1
        Week 12
    96.2
    95.1
        Follow-up week 4
    93.6
    89.3
        Follow-up week 8
    91
    88.3
        Follow-up week 24
    90.7
    88.3
    No statistical analyses for this end point

    Secondary: Percentage of Subjects in With Hepatitis C Virus (HCV) RNA Levels Below Than Lower Limit of Quantitation (LLOQ) Target Not Detected (TND)

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    End point title
    		 Percentage of Subjects in With Hepatitis C Virus (HCV) RNA Levels Below Than Lower Limit of Quantitation (LLOQ) Target Not Detected (TND)
    End point description
    Subjects who achieved HCV RNA levels <LLOQ, TND. The LLOQ was 25 international unit per milliliter, TND. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. The analysis was performed in modified intent-to-treat population, the numerator was based on subjects meeting the response criteria and denominator based on all treated subjects.
    End point type
    Secondary
    End point timeframe
    Week 1, 2, 4, 6, 8, 12; follow-up Week 4, 8, 12 and 24.
    End point values
    		 Treatment-naive Treatment-experienced
    Number of subjects analysed
    312
    103
    Units: Percentage of Subjects
    number (not applicable)
        Week 1
    6.1
    0
        Week 2
    32.4
    20.4
        Week 4
    79.5
    68.9
        Week 6
    92
    94.2
        Week 8
    93.6
    93.2
        Week 12
    95.5
    93.2
        Follow-up week 4
    92.9
    89.3
        Follow-up week 8
    91
    88.3
        Follow-up week 12
    92
    89.3
        Follow-up week 24
    90.7
    88.3
    No statistical analyses for this end point

    Secondary: Number of Subjects With On-treatment Serious Adverse Events (SAEs) and Discontinuations due to Adverse Events (AEs) in Each Cohort

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    End point title
    		 Number of Subjects With On-treatment Serious Adverse Events (SAEs) and Discontinuations due to Adverse Events (AEs) in Each Cohort
    End point description
    An AE was defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in a subject or clinical investigation subject administered an investigational (medicinal) product. An SAE was defined as any untoward medical occurrence that at any dose resulted in death, was life-threatening, required inpatient hospitalization or caused prolongation of existing hospitalization. The analysis was performed on all subjects who received at least 1 dose of study therapy.
    End point type
    Secondary
    End point timeframe
    Baseline through the last dose of study therapy plus 7 days
    End point values
    		 Treatment-naive Treatment-experienced
    Number of subjects analysed
    312
    103
    Units: Subjects
        SAEs
    4
    3
        Discontinuation due to AEs
    0
    3
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Anaemia on Treatment

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    End point title
    		 Percentage of Subjects With Anaemia on Treatment
    End point description
    Anaemia was defined as hemoglobin level less than 10 gram per deciliter (g/dL) on treatment for subjects who had hemoglobin level equal to or above 10 g/dL at baseline. The analysis was performed on all subjects who received at least 1 dose of study therapy.
    End point type
    Secondary
    End point timeframe
    Baseline through the last dose of study therapy plus 7 days
    End point values
    		 Treatment-naive Treatment-experienced
    Number of subjects analysed
    312
    103
    Units: Percentage of Subjects
        number (not applicable)
    0.3
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects With Selected Treatment Emergent Grade 3 to 4 Laboratory Test Abnormalities

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    End point title
    		 Number of Subjects With Selected Treatment Emergent Grade 3 to 4 Laboratory Test Abnormalities
    End point description
    Laboratory tests with Division of AIDS Version 1.0 toxicity criteria were performed and assessed. Assessment were done for following: Hemoglobin, Platelet count, International Normalized Ratio, Leukocytes, Lymphocytes, Neutrophils + bands, Total bilirubin, Alanine aminotransferase, Aspartate aminotransferase, Alkaline phosphatase, Albumin, Lipase Creatinine. Laboratory tests for which subjects had treatment emergent grade 3 to 4 abnormalities are reported below. The analysis was performed on all subjects who received at least 1 dose of study therapy.
    End point type
    Secondary
    End point timeframe
    Baseline through the last dose of study therapy plus 7 days
    End point values
    		 Treatment-naive Treatment-experienced
    Number of subjects analysed
    312
    103
    Units: Subjects
        International Normalized Ratio
    1
    0
        Lymphocytes
    0
    1
        Neutrophils + bands
    1
    1
        Alanine aminotransferase
    11
    8
        Aspartate aminotransferase
    4
    5
        Lipase
    11
    5
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Sustained Virologic Response at Follow-up Week 12 (SVR12) Associated With Hepatitis C Virus (HCV) Genotype Subtype 1a vs 1b

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    End point title
    		 Percentage of Subjects With Sustained Virologic Response at Follow-up Week 12 (SVR12) Associated With Hepatitis C Virus (HCV) Genotype Subtype 1a vs 1b
    End point description
    Subjects categorized into two genotype subtypes that were assessed for SVR12 defined as HCV RNA levels <lower limit of quantitation (LLOQ), target detected or target not detected at follow-up week 12. The LLOQ was 25 international unit per milliliter. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. The analysis was performed on treated subjects, the numerator was based on subjects meeting the response criteria and denominator based on all treated subjects. Here, ‘n’ signifies number of subjects evaluable at the specified subgroup. Missing values were imputed using Next Value Carried Backwards approach.
    End point type
    Secondary
    End point timeframe
    Follow-up week 12
    End point values
    		 Treatment-naive Treatment-experienced
    Number of subjects analysed
    312
    103
    Units: Percentage of Subjects
    number (confidence interval 95%)
        Genotype-1A (n= 229, 75)
    90.4 (86.6 to 94.2)
    85.3 (77.3 to 93.3)
        Genotype-1B (n= 83, 28)
    97.6 (91.6 to 99.7)
    100 (87.7 to 100)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With SVR12 Associated With IL28B rs12979860 Single Nucleotide Polymorphism (SNP) status (CC Genotype or Non-CC Genotype)

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    End point title
    		 Percentage of Subjects With SVR12 Associated With IL28B rs12979860 Single Nucleotide Polymorphism (SNP) status (CC Genotype or Non-CC Genotype)
    End point description
    Subjects categorized into two genotypes based on SNP in the IL28B gene were assessed for SVR12 defined as hepatitis c virus RNA levels <lower limit of quantitation, target detected or target not detected at follow-up week 12. The LLOQ was 25 international unit per milliliter. Here ‘’99999’’ signifies not available as data for the specified time point for this endpoint was not analyzed. The analysis was performed on treated subjects, the numerator was based on subjects meeting the response criteria and denominator based on all treated subjects. Missing values were imputed using Next Value Carried Backwards approach. Here, ‘n’ signifies number of subjects evaluable for the specified category and ‘99999’ signifies not applicable (NA) as no subject was analysed for that specified category.
    End point type
    Secondary
    End point timeframe
    Follow-up week 12
    End point values
    		 Treatment-naive Treatment-experienced
    Number of subjects analysed
    312
    103
    Units: Percentage of Subjects
    number (confidence interval 95%)
        CC Genotype (n= 90, 16)
    94.4 (89.7 to 99.2)
    93.8 (69.8 to 99.8)
        Non-CC Genotype (n=221, 87)
    91.4 (87.7 to 95.1)
    88.5 (81.8 to 95.2)
        Not Reported (n=1, 0)
    100 (2.5 to 100)
    99999 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Sustained Virologic Response at Follow-up Week 12 (SVR12) Associated With Stage of Liver Fibrosis

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    End point title
    		 Percentage of Subjects With Sustained Virologic Response at Follow-up Week 12 (SVR12) Associated With Stage of Liver Fibrosis
    End point description
    Liver Fibrosis was determined by the Fibro test. This test was helpful in determining the presence of cirrhosis by the fibro test scores which are as follows: F0: 0-0.27; F1: >0.27-0.48; F2: 0.48–0.58; F3: >0.58-0.74; F4: >0.74-1.00. Subjects were assessed for SVR12 defined as hepatitis c virus RNA levels <lower limit of quantitation, target detected or target not detected at follow-up week 12. The LLOQ was 25 international unit per milliliter. The analysis was performed on treated subjects, the numerator was based on subjects meeting the response criteria and denominator based on all treated subjects. Missing values were imputed using Next Value Carried Backwards approach. Here, ‘n’ signifies number of subjects evaluable for the specified category.
    End point type
    Secondary
    End point timeframe
    Follow-up week 12
    End point values
    		 Treatment-naive Treatment-experienced
    Number of subjects analysed
    312
    103
    Units: Percentage of Subjects
    number (confidence interval 95%)
        Fibrosis stage: F0 (n=150, 37)
    90.7 (86 to 95.3)
    94.6 (87.3 to 100)
        Fibrosis stage: F1 (n=73, 26)
    94.5 (89.3 to 99.7)
    100 (86.8 to 100)
        Fibrosis stage: F2 (n=31, 12)
    100 (88.8 to 100)
    66.7 (34.9 to 90.1)
        Fibrosis stage: F3 (n=41, 20)
    90.2 (81.2 to 99.3)
    80 (56.3 to 94.3)
        Fibrosis stage: F4 (n=17, 8)
    88.2 (63.6 to 98.5)
    87.5 (47.3 to 99.7)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline through the last dose of study therapy plus 7 days
    Adverse event reporting additional description
    On-treatment period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Treatment-experienced
    Reporting group description
    		 Subjects previously treated with an interferon-containing regimen received an oral fixed dose combination of daclatasvir 30 mg, asunaprevir 200 mg and beclabuvir 75 mg tablets twice daily with food for 12 weeks and followed-up for 24 weeks.

    Reporting group title
    Treatment-naive
    Reporting group description
    		 Previously untreated subjects received an oral fixed dose dose combination of daclatasvir 30 mg, asunaprevir 200 mg and beclabuvir 75 mg tablets twice daily with food for 12 weeks and followed-up for 24 weeks.

    Serious adverse events
    		 Treatment-experienced Treatment-naive
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 103 (2.91%)
    4 / 312 (1.28%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Overdose
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Enterovesical fistula
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic pseudocyst
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 312 (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
    0 / 103 (0.00%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 312 (0.00%)
         occurrences causally related to treatment / all
    0 / 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
    		 Treatment-experienced Treatment-naive
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    83 / 103 (80.58%)
    246 / 312 (78.85%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    29 / 103 (28.16%)
    77 / 312 (24.68%)
         occurrences all number
    36
    89
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    14 / 103 (13.59%)
    54 / 312 (17.31%)
         occurrences all number
    14
    57
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    14 / 103 (13.59%)
    44 / 312 (14.10%)
         occurrences all number
    14
    50
    Nausea
         subjects affected / exposed
    15 / 103 (14.56%)
    41 / 312 (13.14%)
         occurrences all number
    17
    44
    Abdominal pain
         subjects affected / exposed
    1 / 103 (0.97%)
    18 / 312 (5.77%)
         occurrences all number
    1
    18
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    7 / 103 (6.80%)
    26 / 312 (8.33%)
         occurrences all number
    7
    26
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 103 (2.91%)
    20 / 312 (6.41%)
         occurrences all number
    3
    21
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    9 / 103 (8.74%)
    15 / 312 (4.81%)
         occurrences all number
    9
    15
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 103 (7.77%)
    10 / 312 (3.21%)
         occurrences all number
    8
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Apr 2014
    An interim analysis was added after all subjects complete post-treatment Week 4. This interim database lock was to support pharmacokinetic modeling and simulations for exposure-response analysis.
    24 Jul 2014
    Historical threshold of sustained virologic response for treatment of chronic hepatitis c virus infection was updated.

    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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