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    Clinical Trial Results:
    A Phase 3 Evaluation of Daclatasvir in Combination with Peginterferon Lambda-1a and Ribavirin (RBV) or Telaprevir in Combination with Peginterferon Alfa-2a and RBV in Patients with Chronic Hepatitis C Genotype 1b who are Treatment Naïve or Prior Relapsers to Alfa/RBV Therapy.

    Summary
    EudraCT number
    		 2011-005409-65
    Trial protocol
    		 ES   IT   DE   PL   GB  
    Global end of trial date
    09 Oct 2014

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    AI452-021
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01718158
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Bristol-Myers Squibb International Corporation, Chaussée 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
    09 Oct 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Oct 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of the study was to compare the efficacy of pegylated interferon lambda-1a/ ribavirin/ daclatasvir (Lambda/RBV/DCV) to pegylated interferon alfa-2a/ ribavirin/ telaprevir (alfa-2a/RBV/TVR) in subjects with chronic hepatitis C virus (HCV) genotype-1b (GT-1b) infection, measured as the proportion of subjects in each treatment group.
    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
    		 Telaprevir (TVR), a directly acting antiviral (DAA) along with a backbone of alfa/RBV, is approved for treatment of chronic HCV GT-1 infection. The safety profile of TVR in subjects with chronic HCV GT-1 infection has been well characterized in both treatment-naive subjects and those with prior treatment failure to alfa-2a/RBV.
    Actual start date of recruitment
    29 Jan 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 65
    Country: Number of subjects enrolled
    Spain: 38
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    Germany: 39
    Country: Number of subjects enrolled
    Italy: 35
    Country: Number of subjects enrolled
    Argentina: 70
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Israel: 54
    Country: Number of subjects enrolled
    Japan: 120
    Country: Number of subjects enrolled
    Korea, Republic of: 45
    Country: Number of subjects enrolled
    Russian Federation: 72
    Country: Number of subjects enrolled
    Taiwan: 70
    Country: Number of subjects enrolled
    United States: 18
    Worldwide total number of subjects
    641
    EEA total number of subjects
    192
    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)
    568
    From 65 to 84 years
    73
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 85 sites in 13 countries.

    Pre-assignment
    Screening details
    		 A total of 641 subjects were enrolled, out of which 444 subjects were randomized and 440 were treated; Reasons for not being randomized: subject withdrew consent (17), poor/non-compliance (1), subject no longer met study criteria (167) and other reasons (12).

    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
    		 Lambda/RBV/DCV
    Arm description
    		 Subjects (treatment-naive or prior relapsers to alfa-2a/RBV) received daclatasvir (DCV) tablets 60 mg orally, once daily for 12 weeks, pegIFNlambda-1a injection 180 µg subcutaneously, once weekly and RBV tablets for a total daily dose of 1000-1200 mg orally twice daily for 24 weeks. Subjects were originally required to be followed-up for a minimum total period of 24 weeks post-treatment and subjects with any futility criteria or lack of efficacy [HCV RNA >=lower limit of quantitation (LLOQ) at Week 48] were required to be followed-up for a period of 48 weeks post-treatment. Following the Sponsor’s decision to terminate the Lambda development program, the follow-up requirements for all study subjects irrespective of treatment response were modified to a total period of 12 weeks post-treatment .
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pegylated interferon lambda-1a
    Investigational medicinal product code
    BMS-914143
    Other name
    Lambda
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received pegIFNlambda-1a solution for injection 180 µg subcutaneously, once weekly for 24 weeks.

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Ribasphere
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received ribavirin tablets for a total daily dose of 1000-1200 mg orally, twice daily for up to 24 weeks.

    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 60 mg tablet was administered orally once daily for 12 weeks.

    Arm title
    		 Alfa-2a/RBV/TVR
    Arm description
    		 Subjects (treatment-naive or prior relapsers to alfa-2a/RBV) received telaprevir tablets 375 mg orally, thrice daily for 12 weeks, pegIFNlalfa-2a injection 180 µg subcutaneously, once weekly and ribavirin tablets for a total daily dose of 1000-1200 mg orally twice daily for up to 48 weeks [duration of treatment based on eRVR response (HCV RNA < LLOQ at Weeks 4 and 12)]. At Week 24, subjects who achieved eRVR were discontinued from therapy versus subjects who failed to achieve eRVR yet continued to demonstrate benefit from therapy received an additional 24 weeks of pegIFNalfa-2a/RBV for a total treatment course of 48 weeks. Following discontinuation of study therapy, all subjects were originally planned to complete 24 weeks of post-treatment follow-up. Following the Sponsor’s decision to terminate the Lambda development program, the follow-up requirements for all study subjects irrespective of treatment response were modified to a total period of 12 weeks post-treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pegylated interferon alfa-2a
    Investigational medicinal product code
    Other name
    Pegasys
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received pegIFNalfa-2a solution for injection 180 µg subcutaneously, once weekly for 48 weeks.

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Ribasphere
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received ribavirin tablets for a total daily dose of 1000-1200 mg orally, twice daily for up to 48 weeks.

    Investigational medicinal product name
    Telaprevir
    Investigational medicinal product code
    Other name
    Incivek
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 2 telaprevir 375-mg tablets orally, three times daily for 12 weeks.

    Number of subjects in period 1 [1]
    		Lambda/RBV/DCV Alfa-2a/RBV/TVR
    Started
    294
    146
    Completed
    271
    99
    Not completed
    23
    47
         Consent withdrawn by subject
    1
    3
         Adverse event, non-fatal
    16
    28
         Other reason
    -
    1
         subject no longer meets study criteria
    -
    3
         Lost to follow-up
    -
    2
         Lack of efficacy
    4
    3
         Subject request to discontinue study therapy
    2
    7
    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 641 subjects who were enrolled in the study, 444 subjects were randomized and 440 subjects got the study treatment.
    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
    		 Lambda/RBV/DCV
    Arm description
    		 Subjects (treatment-naive or prior relapsers to alfa-2a/RBV) received daclatasvir (DCV) tablets 60 mg orally, once daily for 12 weeks, pegIFNlambda-1a injection 180 µg subcutaneously, once weekly and RBV tablets for a total daily dose of 1000-1200 mg orally twice daily for 24 weeks. Subjects were originally required to be followed-up for a minimum total period of 24 weeks post-treatment and subjects with any futility criteria or lack of efficacy [HCV RNA >=lower limit of quantitation (LLOQ) at Week 48] were required to be followed-up for a period of 48 weeks post-treatment. Following the Sponsor’s decision to terminate the Lambda development program, the follow-up requirements for all study subjects irrespective of treatment response were modified to a total period of 12 weeks post-treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pegylated interferon lambda-1a
    Investigational medicinal product code
    BMS-914143
    Other name
    Lambda
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received pegIFNlambda-1a solution for injection 180 µg subcutaneously, once weekly for 24 weeks.

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Ribasphere
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received ribavirin tablets for a total daily dose of 1000-1200 mg orally, twice daily for up to 24 weeks.

    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 60 mg tablet was administered orally once daily for 12 weeks.

    Arm title
    		 Alfa-2a/RBV/TVR
    Arm description
    		 Subjects (treatment-naive or prior relapsers to alfa-2a/RBV) received telaprevir tablets 375 mg orally, thrice daily for 12 weeks, pegIFNlalfa-2a injection 180 µg subcutaneously, once weekly and ribavirin tablets for a total daily dose of 1000-1200 mg orally twice daily for up to 48 weeks [duration of treatment based on eRVR response (HCV RNA < LLOQ at Weeks 4 and 12)]. At Week 24, subjects who achieved eRVR were discontinued from therapy versus subjects who failed to achieve eRVR yet continued to demonstrate benefit from therapy received an additional 24 weeks of pegIFNalfa-2a/RBV for a total treatment course of 48 weeks. Following discontinuation of study therapy, all subjects were originally planned to complete 24 weeks of post-treatment follow-up. Following the Sponsor’s decision to terminate the Lambda development program, the follow-up requirements for all study subjects irrespective of treatment response were modified to a total period of 12 weeks post-treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pegylated interferon alfa-2a
    Investigational medicinal product code
    Other name
    Pegasys
    Pharmaceutical forms
    Solution for infusion in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received pegIFNalfa-2a solution for injection 180 µg subcutaneously, once weekly for 48 weeks.

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Ribasphere
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received ribavirin tablets for a total daily dose of 1000-1200 mg orally, twice daily for up to 48 weeks.

    Investigational medicinal product name
    Telaprevir
    Investigational medicinal product code
    Other name
    Incivek
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 2 telaprevir 375-mg tablets orally, three times daily for 12 weeks.

    Number of subjects in period 2
    		Lambda/RBV/DCV Alfa-2a/RBV/TVR
    Started
    271
    99
    Completed
    284
    130
    Not completed
    7
    8
         Consent withdrawn by subject
    -
    3
         Death
    -
    1
         Follow up no longer required per protocol
    3
    1
         Other reason
    1
    2
         Lost to follow-up
    3
    1
    Joined
    20
    39
         Rejoined for follow-up
    20
    39

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lambda/RBV/DCV
    Reporting group description
    		 Subjects (treatment-naive or prior relapsers to alfa-2a/RBV) received daclatasvir (DCV) tablets 60 mg orally, once daily for 12 weeks, pegIFNlambda-1a injection 180 µg subcutaneously, once weekly and RBV tablets for a total daily dose of 1000-1200 mg orally twice daily for 24 weeks. Subjects were originally required to be followed-up for a minimum total period of 24 weeks post-treatment and subjects with any futility criteria or lack of efficacy [HCV RNA >=lower limit of quantitation (LLOQ) at Week 48] were required to be followed-up for a period of 48 weeks post-treatment. Following the Sponsor’s decision to terminate the Lambda development program, the follow-up requirements for all study subjects irrespective of treatment response were modified to a total period of 12 weeks post-treatment .

    Reporting group title
    Alfa-2a/RBV/TVR
    Reporting group description
    		 Subjects (treatment-naive or prior relapsers to alfa-2a/RBV) received telaprevir tablets 375 mg orally, thrice daily for 12 weeks, pegIFNlalfa-2a injection 180 µg subcutaneously, once weekly and ribavirin tablets for a total daily dose of 1000-1200 mg orally twice daily for up to 48 weeks [duration of treatment based on eRVR response (HCV RNA < LLOQ at Weeks 4 and 12)]. At Week 24, subjects who achieved eRVR were discontinued from therapy versus subjects who failed to achieve eRVR yet continued to demonstrate benefit from therapy received an additional 24 weeks of pegIFNalfa-2a/RBV for a total treatment course of 48 weeks. Following discontinuation of study therapy, all subjects were originally planned to complete 24 weeks of post-treatment follow-up. Following the Sponsor’s decision to terminate the Lambda development program, the follow-up requirements for all study subjects irrespective of treatment response were modified to a total period of 12 weeks post-treatment.

    Reporting group values
    		 Lambda/RBV/DCV Alfa-2a/RBV/TVR Total
    Number of subjects
    		 294 146 440
    Age categorical
    Units: Subjects
        < 65 years
    		 256 131 387
        >= 65 years
    		 38 15 53
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 50 ± 12.1 48 ± 13.2 -
    Gender categorical
    Units: Subjects
        Female
    		 137 76 213
        Male
    		 157 70 227

    End points

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    End points reporting groups
    Reporting group title
    Lambda/RBV/DCV
    Reporting group description
    		 Subjects (treatment-naive or prior relapsers to alfa-2a/RBV) received daclatasvir (DCV) tablets 60 mg orally, once daily for 12 weeks, pegIFNlambda-1a injection 180 µg subcutaneously, once weekly and RBV tablets for a total daily dose of 1000-1200 mg orally twice daily for 24 weeks. Subjects were originally required to be followed-up for a minimum total period of 24 weeks post-treatment and subjects with any futility criteria or lack of efficacy [HCV RNA >=lower limit of quantitation (LLOQ) at Week 48] were required to be followed-up for a period of 48 weeks post-treatment. Following the Sponsor’s decision to terminate the Lambda development program, the follow-up requirements for all study subjects irrespective of treatment response were modified to a total period of 12 weeks post-treatment .

    Reporting group title
    Alfa-2a/RBV/TVR
    Reporting group description
    		 Subjects (treatment-naive or prior relapsers to alfa-2a/RBV) received telaprevir tablets 375 mg orally, thrice daily for 12 weeks, pegIFNlalfa-2a injection 180 µg subcutaneously, once weekly and ribavirin tablets for a total daily dose of 1000-1200 mg orally twice daily for up to 48 weeks [duration of treatment based on eRVR response (HCV RNA < LLOQ at Weeks 4 and 12)]. At Week 24, subjects who achieved eRVR were discontinued from therapy versus subjects who failed to achieve eRVR yet continued to demonstrate benefit from therapy received an additional 24 weeks of pegIFNalfa-2a/RBV for a total treatment course of 48 weeks. Following discontinuation of study therapy, all subjects were originally planned to complete 24 weeks of post-treatment follow-up. Following the Sponsor’s decision to terminate the Lambda development program, the follow-up requirements for all study subjects irrespective of treatment response were modified to a total period of 12 weeks post-treatment.
    Reporting group title
    Lambda/RBV/DCV
    Reporting group description
    		 Subjects (treatment-naive or prior relapsers to alfa-2a/RBV) received daclatasvir (DCV) tablets 60 mg orally, once daily for 12 weeks, pegIFNlambda-1a injection 180 µg subcutaneously, once weekly and RBV tablets for a total daily dose of 1000-1200 mg orally twice daily for 24 weeks. Subjects were originally required to be followed-up for a minimum total period of 24 weeks post-treatment and subjects with any futility criteria or lack of efficacy [HCV RNA >=lower limit of quantitation (LLOQ) at Week 48] were required to be followed-up for a period of 48 weeks post-treatment. Following the Sponsor’s decision to terminate the Lambda development program, the follow-up requirements for all study subjects irrespective of treatment response were modified to a total period of 12 weeks post-treatment.

    Reporting group title
    Alfa-2a/RBV/TVR
    Reporting group description
    		 Subjects (treatment-naive or prior relapsers to alfa-2a/RBV) received telaprevir tablets 375 mg orally, thrice daily for 12 weeks, pegIFNlalfa-2a injection 180 µg subcutaneously, once weekly and ribavirin tablets for a total daily dose of 1000-1200 mg orally twice daily for up to 48 weeks [duration of treatment based on eRVR response (HCV RNA < LLOQ at Weeks 4 and 12)]. At Week 24, subjects who achieved eRVR were discontinued from therapy versus subjects who failed to achieve eRVR yet continued to demonstrate benefit from therapy received an additional 24 weeks of pegIFNalfa-2a/RBV for a total treatment course of 48 weeks. Following discontinuation of study therapy, all subjects were originally planned to complete 24 weeks of post-treatment follow-up. Following the Sponsor’s decision to terminate the Lambda development program, the follow-up requirements for all study subjects irrespective of treatment response were modified to a total period of 12 weeks post-treatment.

    Primary: Percentage of Subjects With Sustained Virologic Response at Follow-up Week 12 (SVR12)

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    End point title
    		 Percentage of Subjects With Sustained Virologic Response at Follow-up Week 12 (SVR12)
    End point description
    SVR12 was defined as Hepatitis C virus (HCV) RNA <LLOQ, target detected (TD) or target not detected (TND) at post-treatment follow-up Week 12. The LLOQ was 25 IU/mL. 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 (modified ITT) population, the numerator was based on subjects meeting the response criteria and denominator based on all treated subjects.
    End point type
    Primary
    End point timeframe
    Follow-up Week 12
    End point values
    		 Lambda/RBV/DCV Alfa-2a/RBV/TVR
    Number of subjects analysed
    294
    146
    Units: Percentage of subjects
        number (confidence interval 95%)
    88.8 (85.2 to 92.4)
    70.5 (63.2 to 77.9)
    Statistical analysis title
    		 Treatment difference in SVR12
    Statistical analysis description
    The treatment difference and its two-sided 95% confidence interval (CI) were estimated using stratum-adjusted Mantel-Haenszel approach stratified by IL28B rs12979860 host genotype (CC, non-CC), treatment naive or relapse status, and region (Japan vs rest of world), using modified ITT.
    Comparison groups
    Lambda/RBV/DCV v Alfa-2a/RBV/TVR
    Number of subjects included in analysis
    440
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.0001
    Method
    		 Stratum-adjusted Mantel-Haenszel
    Parameter type
    		 Percentage difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9.9
         upper limit
    		 25.7
    Notes
    [1] - Non-inferiority and superiority of Lambda/RBV/DCV to Alfa-2a/RBV/TVR were established because the P-value was < 0.05.

    Secondary: Percentage of Treatment-Naive Subjects With Sustained Virologic Response at Follow-up Week 12 (SVR12)

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    End point title
    		 Percentage of Treatment-Naive Subjects With Sustained Virologic Response at Follow-up Week 12 (SVR12)
    End point description
    SVR12 was defined as HCV RNA <LLOQ, TD or TND at follow-up Week 12. The LLOQ was 25 IU/mL. 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 ITT population, the numerator was based on subjects meeting the response criteria and denominator based on all treated subjects. Here, number of subjects analysed signifies number of treatment-naïve subjects in each reporting arm.
    End point type
    Secondary
    End point timeframe
    Follow-up week 12
    End point values
    		 Lambda/RBV/DCV Alfa-2a/RBV/TVR
    Number of subjects analysed
    235
    115
    Units: Percentage of subjects
        number (confidence interval 95%)
    89.8 (85.9 to 93.7)
    72.2 (64 to 80.4)
    Statistical analysis title
    		 Treatment difference in SVR12
    Statistical analysis description
    The treatment difference and its two-sided 95% CI were estimated using stratum-adjusted Mantel-Haenszel approach stratified by IL28B rs12979860 host genotype (CC, non-CC), treatment naive or relapse status, and region (Japan vs rest of world) using modified ITT.
    Comparison groups
    Lambda/RBV/DCV v Alfa-2a/RBV/TVR
    Number of subjects included in analysis
    350
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 < 0.0001
    Method
    		 Stratum-adjusted Mantel-Haenszel
    Parameter type
    		 Percentage difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.8
         upper limit
    		 26.3
    Notes
    [2] - Non-inferiority and superiority of Lambda/RBV/DCV to Alfa-2a/RBV/TVR were established because the P-value was < 0.05.

    Secondary: Percentage of subjects With Sustained Virologic Response at Follow-up Week 24 (SVR24)

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    End point title
    		 Percentage of subjects With Sustained Virologic Response at Follow-up Week 24 (SVR24)
    End point description
    SVR24 was defined as HCV RNA levels <LLOQ, TD or TND at follow-up Week 24. The LLOQ was 25 IU/mL. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. The analysis was performed in observed population, the numerator was based on subjects meeting the response criteria and denominator based on treated subjects with HCV RNA at follow-up Week 24. Here, number of subjects analysed signifies number of treated subjects with HCV RNA at follow-up Week 24 in each reporting arm. The modified ITT analysis was not performed because not all subjects had the opportunity to reach follow-up Week 24 due to early study termination.
    End point type
    Secondary
    End point timeframe
    Follow-up Week 24
    End point values
    		 Lambda/RBV/DCV Alfa-2a/RBV/TVR
    Number of subjects analysed
    268
    112
    Units: Percentage of subjects
        number (confidence interval 95%)
    82.7 (78.3 to 87)
    60.3 (52.3 to 68.2)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Rash Related Dermatologic Events

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    End point title
    		 Percentage of Subjects With Rash Related Dermatologic Events
    End point description
    Rash related dermatological events were graded as grade 1- mild, grade 2-moderate and grade 3- severe. The analysis was performed in modified ITT 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
    From Day 1 of study treatment up to Week 12
    End point values
    		 Lambda/RBV/DCV Alfa-2a/RBV/TVR
    Number of subjects analysed
    294
    146
    Units: Percentage of Subjects
        number (confidence interval 95%)
    26.5 (21.5 to 31.6)
    37 (29.2 to 44.8)
    Statistical analysis title
    		 Treatment difference for rash events
    Statistical analysis description
    The treatment difference and its two-sided 95% CI were estimated using stratum-adjusted Mantel-Haenszel approach stratified by IL28B rs12979860 host genotype (CC, non-CC), treatment naive or relapse status, and region (Japan vs rest of world).
    Comparison groups
    Lambda/RBV/DCV v Alfa-2a/RBV/TVR
    Number of subjects included in analysis
    440
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.0177
    Method
    		 Stratum-adjusted Mantel-Haenszel
    Parameter type
    		 Percentage difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -20.1
         upper limit
    		 -1.9
    Notes
    [3] - Superiority of Lambda/RBV/DCV to Alfa-2a/RBV/TVR was established because the P-value was < 0.05.

    Secondary: Percentage of Subjects With Treatment Emergent Cytopenic Abnormalities

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    End point title
    		 Percentage of Subjects With Treatment Emergent Cytopenic Abnormalities
    End point description
    Treatment emergent cytopenic abnormalities included anemia, defined as hemoglobin <10 grams/deciliters, neutropenia, defined as absolute neutrophil count <750/mm^3 and thrombocytopenia, defined as platelets <50,000/mm^3. The analysis was performed in modified ITT 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
    From Day 1 of study treatment up to Week 48
    End point values
    		 Lambda/RBV/DCV Alfa-2a/RBV/TVR
    Number of subjects analysed
    294
    146
    Units: Percentage of Subjects
        number (confidence interval 95%)
    10.2 (6.7 to 13.7)
    56.2 (48.1 to 64.2)
    Statistical analysis title
    		 Treatment difference in cytopenic abnormalities
    Statistical analysis description
    The treatment difference and its two-sided 95% CI were estimated using stratum-adjusted Mantel-Haenszel approach stratified by IL28B rs12979860 host genotype (CC, non-CC), treatment naive or relapse status, and region (Japan vs rest of world).
    Comparison groups
    Lambda/RBV/DCV v Alfa-2a/RBV/TVR
    Number of subjects included in analysis
    440
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 < 0.0001
    Method
    		 Stratum-adjusted Mantel-Haenszel
    Parameter type
    		 Percentage difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -54.4
         upper limit
    		 -37.5
    Notes
    [4] - Superiority of Lambda/RBV/DCV to Alfa-2a/RBV/TVR was established because the P-value was <0.05.

    Secondary: Percentage of Subjects With On-treatment Interferon (IFN)-Associated flu Like Symptoms

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    End point title
    		 Percentage of Subjects With On-treatment Interferon (IFN)-Associated flu Like Symptoms
    End point description
    Subjects were assessed for flu-like symptoms like pyrexia, chills or pain. The analysis was performed in modified ITT 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
    From Day 1 of study treatment up to Week 48
    End point values
    		 Lambda/RBV/DCV Alfa-2a/RBV/TVR
    Number of subjects analysed
    294
    146
    Units: Percentage of subjects
        number (confidence interval 95%)
    9.9 (6.5 to 13.3)
    27.4 (20.2 to 34.6)
    Statistical analysis title
    		 Treatment difference for flu like symptoms
    Statistical analysis description
    The treatment difference and its two-sided 95% CI were estimated using stratum-adjusted Mantel-Haenszel approach stratified by IL28B rs12979860 host genotype (CC, non-CC), treatment-naive or prior relapse to alfa-2a/RBV, and region (Japan vs rest of world).
    Comparison groups
    Lambda/RBV/DCV v Alfa-2a/RBV/TVR
    Number of subjects included in analysis
    440
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 < 0.0001
    Method
    		 Stratum-adjusted Mantel-Haenszel
    Parameter type
    		 Percentage difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -24.9
         upper limit
    		 -9.2
    Notes
    [5] - Superiority of Lambda/RBV/DCV to Alfa-2a/RBV/TVR was established because the P-value was <0.05.

    Secondary: Percentage of Subjects With On-treatment Interferon (IFN) Associated Musculoskeletal Symptoms

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    End point title
    		 Percentage of Subjects With On-treatment Interferon (IFN) Associated Musculoskeletal Symptoms
    End point description
    Subjects were assessed for musculoskeletal symptoms which includes arthralgia, myalgia or back pain. The analysis was performed in modified ITT 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
    From Day 1 of study treatment up to Week 48
    End point values
    		 Lambda/RBV/DCV Alfa-2a/RBV/TVR
    Number of subjects analysed
    294
    146
    Units: Percentage of subjects
        number (confidence interval 95%)
    17.7 (13.3 to 22)
    19.9 (13.4 to 26.3)
    Statistical analysis title
    		 Treatment difference for musculoskeletal symptoms
    Statistical analysis description
    The treatment difference and its two-sided 95% CI were estimated using stratum-adjusted Mantel-Haenszel approach stratified by IL28B rs12979860 host genotype (CC, non-CC), treatment naive or relapse status, and region (Japan vs rest of world).
    Comparison groups
    Lambda/RBV/DCV v Alfa-2a/RBV/TVR
    Number of subjects included in analysis
    440
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.584
    Method
    		 Stratum-adjusted Mantel-Haenszel
    Parameter type
    		 Percentage difference
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.8
         upper limit
    		 5.5
    Notes
    [6] - Superiority of Lambda/RBV/DCV to Alfa-2a/RBV/TVR was not established because the P-value was >=0.05. No further hierachical testing of secondary endpoints (eg, SVR14) was conducted.

    Secondary: Number of Subjects With Adverse events (AEs), Serious Adverse Events (SAEs), Dose Reductions, and Discontinuations due to AEs during treatment period

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    End point title
    		 Number of Subjects With Adverse events (AEs), Serious Adverse Events (SAEs), Dose Reductions, and Discontinuations due to AEs during treatment period
    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
    From Day 1 of study treatment up to Week 48
    End point values
    		 Lambda/RBV/DCV Alfa-2a/RBV/TVR
    Number of subjects analysed
    294
    146
    Units: Subjects
        AEs
    254
    138
        SAEs
    11
    16
        Dose reduction
    26
    33
        Discontinuations due to AEs
    16
    41
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Extended Rapid Virologic Response (eRVR)

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    End point title
    		 Percentage of Subjects With Extended Rapid Virologic Response (eRVR)
    End point description
    eRVR was defined as HCV RNA <LLOQ TND at Weeks 4 and 12 of treatment. The LLOQ was 25 IU/mL. 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 ITT population, the numerator was based on subjects meeting the response criteria and denominator based on all treated subjects. Missing values were imputed using backward imputation technique.
    End point type
    Secondary
    End point timeframe
    Weeks 4, 12
    End point values
    		 Lambda/RBV/DCV Alfa-2a/RBV/TVR
    Number of subjects analysed
    294
    146
    Units: Percentage of subjects
        number (confidence interval 95%)
    76.9 (72.1 to 81.7)
    67.1 (59.5 to 74.7)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Rapid Virologic Response (RVR)

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    End point title
    		 Percentage of Subjects With Rapid Virologic Response (RVR)
    End point description
    RVR was defined as HCV RNA <LLOQ TND at Week 4 of treatment. The LLOQ was 25 IU/mL. 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 ITT 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 4
    End point values
    		 Lambda/RBV/DCV Alfa-2a/RBV/TVR
    Number of subjects analysed
    294
    146
    Units: Percentage of subjects
        number (confidence interval 95%)
    79.3 (74.6 to 83.9)
    75.3 (68.4 to 82.3)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Complete Early Virologic Response (cEVR)

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    End point title
    		 Percentage of Subjects With Complete Early Virologic Response (cEVR)
    End point description
    cEVR was defined as HCV RNA <LLOQ TND at Week 12 of treatment. The LLOQ was 25 IU/mL. 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 ITT 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 12
    End point values
    		 Lambda/RBV/DCV Alfa-2a/RBV/TVR
    Number of subjects analysed
    294
    146
    Units: Percentage of subjects
        number (confidence interval 95%)
    93.5 (90.7 to 96.3)
    80.1 (73.7 to 86.6)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With End of Treatment Response (EOTR)

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    End point title
    		 Percentage of Subjects With End of Treatment Response (EOTR)
    End point description
    EOTR was defined as HCV RNA <LLOQ TND at end of treatment. The LLOQ was 25 IU/mL. 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 ITT 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
    End of treatment (up to Week 48)
    End point values
    		 Lambda/RBV/DCV Alfa-2a/RBV/TVR
    Number of subjects analysed
    294
    146
    Units: Percentage of subjects
        number (confidence interval 95%)
    95.6 (93.2 to 97.9)
    89 (84 to 94.1)
    No statistical analyses for this end point

    Secondary: Number of Subjects with Treatment Emergent Grade 3 to 4 Laboratory Abnormalities

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    End point title
    		 Number of Subjects with Treatment Emergent Grade 3 to 4 Laboratory Abnormalities
    End point description
    On-treatment emergent abnormalities were those with a higher toxicity grade than the baseline toxicity grade. Laboratory abnormalities were determined and graded using the Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, version 1.0. Hemoglobin: <7.5 g/dL; Platelet count: <50,000/mm^3; International Normalized Ratio (INR) : >2.0*Upper limit of normal (ULN); Leukocytes: <1,500/mm^3; Lymphocytes (Absolute) : <500/mm^3; Neutrophils + bands (absolute): <750/mm^3; Alanine aminotransferase (ALT) : >5*ULN; Aspartate aminotransferase (AST): >5*ULN; Bilirubin (Total) : >2.5*ULN; G-Glutamyl transferase (GGT): >5*ULN; Amylase: >2.0*ULN; Lipase: >3*ULN; Creatinine: >1.8*ULN. The analysis was performed on all subjects who received at least 1 dose of study therapy.
    End point type
    Secondary
    End point timeframe
    From Day 1 of study treatment up to Week 48
    End point values
    		 Lambda/RBV/DCV Alfa-2a/RBV/TVR
    Number of subjects analysed
    294
    146
    Units: Subjects
        Hemoglobin
    6
    30
        INR
    2
    1
        Leukocytes
    2
    19
        Lymphocytes
    10
    30
        Neutrophils + bands
    3
    36
        ALT
    13
    2
        AST
    26
    4
        Bilirubin (Total)
    28
    3
        Bilirubin (Direct)
    18
    1
        GGT
    40
    7
        Amylase
    5
    5
        Lipase
    1
    3
        Creatinine
    0
    2
        Platelet count
    1
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 of study treatment up to Week 48
    Adverse event reporting additional description
    On-treatment period (1 death reported at follow-up week 12).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Lambda/RBV/DCV
    Reporting group description
    		 Subjects (treatment-naive or prior relapsers to alfa-2a/RBV) received daclatasvir (DCV) tablets 60 mg orally, once daily for 12 weeks, pegIFNlambda-1a injection 180 µg subcutaneously, once weekly and RBV tablets for a total daily dose of 1000-1200 mg orally twice daily for 24 weeks. Subjects were originally required to be followed-up for a minimum total period of 24 weeks post-treatment and subjects with any futility criteria or lack of efficacy [HCV RNA >=lower limit of quantitation (LLOQ) at Week 48] were required to be followed-up for a period of 48 weeks post-treatment. Following the Sponsor’s decision to terminate the Lambda development program, the follow-up requirements for all study subjects irrespective of treatment response were modified to a total period of 12 weeks post-treatment .

    Reporting group title
    Alfa-2a/RBV/TVR
    Reporting group description
    		 Subjects (treatment-naive or prior relapsers to alfa-2a/RBV) received telaprevir tablets 375 mg orally, thrice daily for 12 weeks, pegIFNlalfa-2a injection 180 µg subcutaneously, once weekly and ribavirin tablets for a total daily dose of 1000-1200 mg orally twice daily for up to 48 weeks [duration of treatment based on eRVR response (HCV RNA < LLOQ at Weeks 4 and 12)]. At Week 24, subjects who achieved eRVR were discontinued from therapy versus subjects who failed to achieve eRVR yet continued to demonstrate benefit from therapy received an additional 24 weeks of pegIFNalfa-2a/RBV for a total treatment course of 48 weeks. Following discontinuation of study therapy, all subjects were originally planned to complete 24 weeks of post-treatment follow-up. Following the Sponsor’s decision to terminate the Lambda development program, the follow-up requirements for all study subjects irrespective of treatment response were modified to a total period of 12 weeks post-treatment.

    Serious adverse events
    		 Lambda/RBV/DCV Alfa-2a/RBV/TVR
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 294 (3.74%)
    16 / 146 (10.96%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 294 (0.34%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Malaise
         subjects affected / exposed
    0 / 294 (0.00%)
    2 / 146 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis acute
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Jaundice
         subjects affected / exposed
    3 / 294 (1.02%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Interstitial lung disease
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 294 (0.00%)
    5 / 146 (3.42%)
         occurrences causally related to treatment / all
    0 / 0
    5 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash generalised
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 146 (0.68%)
         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
    0 / 294 (0.00%)
    2 / 146 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Acinetobacter bacteraemia
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    1 / 294 (0.34%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 294 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Lambda/RBV/DCV Alfa-2a/RBV/TVR
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    235 / 294 (79.93%)
    136 / 146 (93.15%)
    Investigations
    Blood uric acid increased
         subjects affected / exposed
    8 / 294 (2.72%)
    11 / 146 (7.53%)
         occurrences all number
    8
    11
    Creatinine renal clearance decreased
         subjects affected / exposed
    1 / 294 (0.34%)
    9 / 146 (6.16%)
         occurrences all number
    1
    9
    Alanine aminotransferase increased
         subjects affected / exposed
    20 / 294 (6.80%)
    4 / 146 (2.74%)
         occurrences all number
    21
    4
    Aspartate aminotransferase increased
         subjects affected / exposed
    24 / 294 (8.16%)
    3 / 146 (2.05%)
         occurrences all number
    26
    3
    Blood bilirubin increased
         subjects affected / exposed
    20 / 294 (6.80%)
    3 / 146 (2.05%)
         occurrences all number
    22
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    38 / 294 (12.93%)
    27 / 146 (18.49%)
         occurrences all number
    69
    41
    Dizziness
         subjects affected / exposed
    23 / 294 (7.82%)
    22 / 146 (15.07%)
         occurrences all number
    39
    24
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    55 / 294 (18.71%)
    44 / 146 (30.14%)
         occurrences all number
    65
    48
    Pyrexia
         subjects affected / exposed
    23 / 294 (7.82%)
    31 / 146 (21.23%)
         occurrences all number
    29
    50
    Asthenia
         subjects affected / exposed
    58 / 294 (19.73%)
    27 / 146 (18.49%)
         occurrences all number
    66
    34
    Malaise
         subjects affected / exposed
    13 / 294 (4.42%)
    17 / 146 (11.64%)
         occurrences all number
    13
    17
    Chills
         subjects affected / exposed
    9 / 294 (3.06%)
    14 / 146 (9.59%)
         occurrences all number
    18
    27
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    31 / 294 (10.54%)
    75 / 146 (51.37%)
         occurrences all number
    35
    79
    Neutropenia
         subjects affected / exposed
    3 / 294 (1.02%)
    35 / 146 (23.97%)
         occurrences all number
    3
    40
    Leukopenia
         subjects affected / exposed
    0 / 294 (0.00%)
    13 / 146 (8.90%)
         occurrences all number
    0
    19
    Thrombocytopenia
         subjects affected / exposed
    1 / 294 (0.34%)
    9 / 146 (6.16%)
         occurrences all number
    1
    10
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    43 / 294 (14.63%)
    41 / 146 (28.08%)
         occurrences all number
    56
    50
    Anal pruritus
         subjects affected / exposed
    2 / 294 (0.68%)
    14 / 146 (9.59%)
         occurrences all number
    2
    16
    Diarrhoea
         subjects affected / exposed
    32 / 294 (10.88%)
    14 / 146 (9.59%)
         occurrences all number
    35
    14
    Vomiting
         subjects affected / exposed
    14 / 294 (4.76%)
    11 / 146 (7.53%)
         occurrences all number
    17
    16
    Epigastric discomfort
         subjects affected / exposed
    1 / 294 (0.34%)
    9 / 146 (6.16%)
         occurrences all number
    1
    9
    Dry mouth
         subjects affected / exposed
    2 / 294 (0.68%)
    8 / 146 (5.48%)
         occurrences all number
    2
    10
    Dyspepsia
         subjects affected / exposed
    16 / 294 (5.44%)
    8 / 146 (5.48%)
         occurrences all number
    16
    8
    Abdominal pain upper
         subjects affected / exposed
    16 / 294 (5.44%)
    5 / 146 (3.42%)
         occurrences all number
    19
    6
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    19 / 294 (6.46%)
    25 / 146 (17.12%)
         occurrences all number
    22
    31
    Cough
         subjects affected / exposed
    18 / 294 (6.12%)
    19 / 146 (13.01%)
         occurrences all number
    19
    20
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    106 / 294 (36.05%)
    59 / 146 (40.41%)
         occurrences all number
    120
    69
    Rash
         subjects affected / exposed
    49 / 294 (16.67%)
    58 / 146 (39.73%)
         occurrences all number
    54
    64
    Alopecia
         subjects affected / exposed
    13 / 294 (4.42%)
    17 / 146 (11.64%)
         occurrences all number
    13
    18
    Dry skin
         subjects affected / exposed
    22 / 294 (7.48%)
    17 / 146 (11.64%)
         occurrences all number
    22
    17
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    60 / 294 (20.41%)
    33 / 146 (22.60%)
         occurrences all number
    64
    36
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    37 / 294 (12.59%)
    23 / 146 (15.75%)
         occurrences all number
    47
    35
    Arthralgia
         subjects affected / exposed
    34 / 294 (11.56%)
    15 / 146 (10.27%)
         occurrences all number
    43
    22
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    16 / 294 (5.44%)
    3 / 146 (2.05%)
         occurrences all number
    23
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    32 / 294 (10.88%)
    37 / 146 (25.34%)
         occurrences all number
    34
    41

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Oct 2012
    The recommendations from the Food and Drug Administration following their review of the protocol at the end of phase-2 meeting on 15-Oct-2012, to clarify some inclusion/exclusion criteria and study procedures and to incorporate some administrative changes.
    20 Feb 2013
    New safety information on telaprevir was added in to the protocol along with the clarifications on the list of prohibited medications during dosing with daclatasvir, new cardiac safety monitoring procedures and guidelines for subjects who develop clinically significant symptoms suggestive of cardiac pathology and clarify some study.

    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.
    The study was terminated after all subjects completed the post-dosing Week 12 follow-up visit.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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