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    Clinical Trial Results:
    A Phase 2B, randomized study to evaluate the safety and efficacy of Pegylated Interferon Lambda (BMS-914143) administered with Ribavirin plus a single direct antiviral agent (BMS-790052 or BMS-650032) versus Pegasys administered with Ribavirin (Part A) and of Pegylated Interferon Lambda (BMS-914143) administered with or without Ribavirin plus 2 direct antiviral agents (BMS 790052 and BMS-650032) (Part B) in chronic hepatitis C genotype-1 treatment naive subjects

    Summary
    EudraCT number
    		 2010-022568-11
    Trial protocol
    		 DE   IT   ES  
    Global end of trial date
    01 Sep 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
    AI452-008
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01309932
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    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
    01 Sep 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main purpose of the trial was to evaluate the safety and tolerability (as measured by the frequency of serious adverse events, dose reductions and discontinuations due to adverse events) of Peginterferon Lambda-1a administered with Ribavirin + a single direct antiviral agent (BMS-790052 or BMS-650032) and describe the antiviral activity as determined by the proportion of hepatitis C virus genotype 1 subjects with SVR24.
    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
    31 Mar 2011
    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
    France: 42
    Country: Number of subjects enrolled
    Australia: 23
    Country: Number of subjects enrolled
    Germany: 22
    Country: Number of subjects enrolled
    Italy: 28
    Country: Number of subjects enrolled
    Japan: 22
    Country: Number of subjects enrolled
    New Zealand: 13
    Country: Number of subjects enrolled
    Puerto Rico: 12
    Country: Number of subjects enrolled
    Spain: 10
    Country: Number of subjects enrolled
    United States: 61
    Worldwide total number of subjects
    233
    EEA total number of subjects
    102
    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)
    222
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Part A: The study was conducted at 40 sites in 9 countries. Sub-study C: The study was conducted at 6 sites in 3 countries.

    Pre-assignment
    Screening details
    		 A total of 233 subjects were enrolled. Of which 140 subjects were treated (119 subjects in Global study and 21 subjects in Japan sub-study) in Part A. A total of 24 subjects were treated in Sub-study C.

    Period 1
    Period 1 title
    Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Carer
    Blinding implementation details
    BMS personnel and investigators were blinded, with the exception of a designated member of the staff at each investigational site (who was unblinded only to dispense study medications as well as required dose reductions.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Lambda + Ribavirin + Asunaprevir (Part A-Global Study)
    Arm description
    		 Pegylated Interferon Lambda: solution, subcutaneous, 180 µg/mL, once weekly for up to 24 or 48 weeks (depending upon response); Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Asunaprevir: tablets, oral, 200 mg, twice daily for up to 24 weeks; Placebo: Daclatasvir matching­ placebo, tablets, oral, once daily for up to 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pegylated Interferon Lambda
    Investigational medicinal product code
    BMS-914143
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received Pegylated Interferon Lambda 180-μg/ml as subcutaneous injection once weekly for up to 24 or 48 weeks depending upon the response.

    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 200-mg tablets, orally, twice daily to make the final dose of 1000 mg or 1200 mg per day (depending upon the body weight) for up to 48 weeks.

    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
    Subjects received Asunaprevir 200-mg tablets, orally, twice daily for up to 24 weeks.

    Investigational medicinal product name
    Daclatasvir matching-placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 daclatasvir matching-placebo tablets were administered, orally, once daily, for up to 24 weeks.

    Arm title
    		 Lambda + Ribavirin + Daclatasvir (Part A-Global Study)
    Arm description
    		 Pegylated Interferon Lambda: solution, subcutaneous, 180 µg/mL, once weekly for up to 24 or 48 weeks (depending upon response); Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Daclatasvir: tablets, oral, 60 mg, once daily for up to 24 weeks; Placebo: Asunaprevir matching-placebo, tablets, oral, twice daily for up to 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pegylated Interferon Lambda
    Investigational medicinal product code
    BMS-914143
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received Pegylated Interferon Lambda 180-μg/ml as subcutaneous injection once weekly for up to 24 or 48 weeks depending upon the response.

    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 200-mg tablets, orally, twice daily to make the final dose of 1000 mg or 1200 mg per day (depending upon the body weight) for up to 48 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
    2 daclatasvir 30-mg tablets were administered orally, once daily for up to 24 weeks.

    Investigational medicinal product name
    Asunaprevir matching-placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received asunaprevir matching-placebo tablets, orally, twice daily for up to 24 weeks.

    Arm title
    		 Alfa-2a + Ribavirin (Part A-Global Study)
    Arm description
    		 Pegylated Interferon Alfa-2a: solution, subcutaneous, 180 µg/mL, once weekly for up to 48 weeks; Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Asunaprevir matching-placebo: tablets, oral, twice daily for up to 24 weeks; Daclatasvir matching-placebo: tablets, oral, once daily for up to 24 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Pegylated Interferon Alfa-2a
    Investigational medicinal product code
    Other name
    Pegasys ®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received Pegylated Interferon Alfa-2a 180-μg/mL as subcutaneous injection once weekly for up to 24 or 48 weeks depending upon the response.

    Investigational medicinal product name
    Daclatasvir matching-placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 daclatasvir matching-placebo tablets were administered, orally, once daily, for up to 24 weeks.

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Ribasphere
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Ribavirin 200-mg tablets, orally, twice daily to make the final dose of 1000 mg or 1200 mg per day (depending upon the body weight) for up to 48 weeks.

    Investigational medicinal product name
    Asunaprevir matching-placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received asunaprevir matching-placebo tablets, orally, twice daily for up to 24 weeks.

    Arm title
    		 Lambda + Ribavirin + Asunaprevir (Japan Substudy)
    Arm description
    		 Pegylated Interferon Lambda: solution, subcutaneous, 180 µg/mL, once weekly for up to 24 or 48 weeks (depending upon response); Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Asunaprevir: tablets, oral, 200 mg, twice daily for up to 24 weeks; Placebo: Daclatasvir matching-placebo, tablets, oral, once daily for up to 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pegylated Interferon Lambda
    Investigational medicinal product code
    BMS-914143
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received Pegylated Interferon Lambda 180-μg/ml as subcutaneous injection once weekly for up to 24 or 48 weeks depending upon the response.

    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 200-mg tablets, orally, twice daily to make the final dose of 1000 mg or 1200 mg per day (depending upon the body weight) for up to 48 weeks.

    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
    Subjects received Asunaprevir 200-mg tablets, orally, twice daily for up to 24 weeks.

    Investigational medicinal product name
    Daclatasvir matching-placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 daclatasvir matching-placebo tablets were administered, orally, once daily, for up to 24 weeks.

    Arm title
    		 Lambda + Ribavirin + Daclatasvir (Japan Substudy)
    Arm description
    		 Pegylated Interferon Lambda: solution, subcutaneous, 180 µg/mL, once weekly for up to 24 or 48 weeks (depending upon response); Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Daclatasvir: tablets, oral, 60 mg, once daily for up to 24 weeks; Placebo: Asunaprevir matching-placebo, tablets, oral, twice daily for up to 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pegylated Interferon Lambda
    Investigational medicinal product code
    BMS-914143
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received Pegylated Interferon Lambda 180-μg/ml as subcutaneous injection once weekly for up to 24 or 48 weeks depending upon the response.

    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
    2 daclatasvir 30-mg tablets were administered orally, once daily for up to 24 weeks.

    Investigational medicinal product name
    Asunaprevir matching-placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received asunaprevir matching-placebo tablets, orally, twice daily for up to 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 200-mg tablets, orally, twice daily to make the final dose of 1000 mg or 1200 mg per day (depending upon the body weight) for up to 48 weeks.

    Arm title
    		 Alfa-2a + Ribavirin (Japan Substudy)
    Arm description
    		 Pegylated Interferon Alfa-2a: solution, subcutaneous, 180 µg/mL, once weekly for up to 48 weeks; Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Asunaprevir matching-placebo: tablets, oral, twice daily for up to 24 weeks; Daclatasvir matching-placebo: tablets, oral, once daily for up to 24 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Pegylated Interferon Alfa-2a
    Investigational medicinal product code
    Other name
    Pegasys ®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received Pegylated Interferon Alfa-2a 180-μg/mL as subcutaneous injection once weekly for up to 24 or 48 weeks depending upon the response.

    Investigational medicinal product name
    Asunaprevir matching-placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received asunaprevir matching-placebo tablets, orally, twice daily for up to 24 weeks.

    Investigational medicinal product name
    Daclatasvir matching-placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 daclatasvir matching-placebo tablets were administered, orally, once daily, for up to 24 weeks.

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Ribasphere
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Ribavirin 200-mg tablets, orally, twice daily to make the final dose of 1000 mg or 1200 mg per day (depending upon the body weight) for up to 48 weeks.

    Arm title
    		 Lambda + Ribavirin + Daclatasvir (Substudy C)
    Arm description
    		 Pegylated Interferon Lambda: solution, subcutaneous, 180 µg/mL, once weekly for 12 weeks; Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for 12 weeks; Daclatasvir: tablets, oral, 6 once daily for up to 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pegylated Interferon Lambda
    Investigational medicinal product code
    BMS-914143
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received Pegylated Interferon Lambda 180-μg/ml as subcutaneous injection once weekly for 12 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 200-mg tablets, orally, twice daily to make the final dose of 1000 mg or 1200 mg per day (depending upon the body weight) for up to 12 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
    2 daclatasvir 30-mg tablets were administered orally, once daily for up to 12 weeks.

    Number of subjects in period 1 [1]
    		Lambda + Ribavirin + Asunaprevir (Part A-Global Study) Lambda + Ribavirin + Daclatasvir (Part A-Global Study) Alfa-2a + Ribavirin (Part A-Global Study) Lambda + Ribavirin + Asunaprevir (Japan Substudy) Lambda + Ribavirin + Daclatasvir (Japan Substudy) Alfa-2a + Ribavirin (Japan Substudy) Lambda + Ribavirin + Daclatasvir (Substudy C)
    Started
    38
    41
    40
    6
    8
    7
    24
    Completed
    29
    35
    18
    3
    8
    5
    24
    Not completed
    9
    6
    22
    3
    0
    2
    0
         Consent withdrawn by subject
    -
    -
    1
    -
    -
    -
    -
         Adverse event, non-fatal
    6
    2
    5
    3
    -
    1
    -
         Subject's request to discontinue study treatment
    1
    1
    4
    -
    -
    -
    -
         Poor/Non-compliance
    1
    1
    -
    -
    -
    -
    -
         Subject no longer meets study criteria
    -
    -
    1
    -
    -
    -
    -
         Lack of efficacy
    1
    2
    11
    -
    -
    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: The number of subjects reported in the baseline period are different from the worldwide number enrolled in the trial, as out of 233 subjects only 164 subjects received treatment during the study.
    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 + Ribavirin + Asunaprevir (Part A-Global Study)
    Arm description
    		 Pegylated Interferon Lambda: solution, subcutaneous, 180 µg/mL, once weekly for up to 24 or 48 weeks (depending upon response); Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Asunaprevir: tablets, oral, 200 mg, twice daily for up to 24 weeks; Placebo: Daclatasvir matching ­placebo, tablets, oral, once daily for up to 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pegylated Interferon Lambda
    Investigational medicinal product code
    BMS-914143
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received Pegylated Interferon Lambda 180-μg/ml as subcutaneous injection once weekly for up to 24 or 48 weeks depending upon the response.

    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 200-mg tablets, orally, twice daily to make the final dose of 1000 mg or 1200 mg per day (depending upon the body weight) for up to 48 weeks.

    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
    Subjects received Asunaprevir 200-mg tablets, orally, twice daily for up to 24 weeks.

    Investigational medicinal product name
    Daclatasvir matching-placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 daclatasvir matching-placebo tablets were administered, orally, once daily, for up to 24 weeks.

    Arm title
    		 Lambda + Ribavirin + Daclatasvir (Part A-Global Study)
    Arm description
    		 Pegylated Interferon Lambda: solution, subcutaneous, 180 µg/mL, once weekly for up to 24 or 48 weeks (depending upon response); Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Daclatasvir: tablets, oral, 60 mg, once daily for up to 24 weeks; Placebo: Asunaprevir matching-placebo, tablets, oral, twice daily for up to 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pegylated Interferon Lambda
    Investigational medicinal product code
    BMS-914143
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received Pegylated Interferon Lambda 180-μg/ml as subcutaneous injection once weekly for up to 24 or 48 weeks depending upon the response.

    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 200-mg tablets, orally, twice daily to make the final dose of 1000 mg or 1200 mg per day (depending upon the body weight) for up to 48 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
    2 daclatasvir 30-mg tablets were administered orally, once daily for up to 24 weeks.

    Investigational medicinal product name
    Asunaprevir matching-placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received asunaprevir matching-placebo tablets, orally, twice daily for up to 24 weeks.

    Arm title
    		 Alfa-2a + Ribavirin (Part A-Global Study)
    Arm description
    		 Pegylated Interferon Alfa-2a: solution, subcutaneous, 180 µg/mL, once weekly for up to 48 weeks; Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Asunaprevir matching-placebo: tablets, oral, twice daily for up to 24 weeks; Daclatasvir matching-placebo: tablets, oral, once daily for up to 24 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Pegylated Interferon Alfa-2a
    Investigational medicinal product code
    Other name
    Pegasys ®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received Pegylated Interferon Alfa-2a 180-μg/mL as subcutaneous injection once weekly for up to 24 or 48 weeks depending upon the response.

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Ribasphere
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Ribavirin 200-mg tablets, orally, twice daily to make the final dose of 1000 mg or 1200 mg per day (depending upon the body weight) for up to 48 weeks.

    Investigational medicinal product name
    Asunaprevir matching-placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received asunaprevir matching-placebo tablets, orally, twice daily for up to 24 weeks.

    Investigational medicinal product name
    Daclatasvir matching-placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 daclatasvir matching-placebo tablets were administered, orally, once daily, for up to 24 weeks.

    Arm title
    		 Lambda + Ribavirin + Asunaprevir (Japan Substudy)
    Arm description
    		 Pegylated Interferon Lambda: solution, subcutaneous, 180 µg/mL, once weekly for up to 24 or 48 weeks (depending upon response); Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Asunaprevir: tablets, oral, 200 mg, twice daily for up to 24 weeks; Placebo: Daclatasvir matching-placebo, tablets, oral, once daily for up to 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pegylated Interferon Lambda
    Investigational medicinal product code
    BMS-914143
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received Pegylated Interferon Lambda 180-μg/ml as subcutaneous injection once weekly for up to 24 or 48 weeks depending upon the response.

    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 200-mg tablets, orally, twice daily to make the final dose of 1000 mg or 1200 mg per day (depending upon the body weight) for up to 48 weeks.

    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
    Subjects received Asunaprevir 200-mg tablets, orally, twice daily for up to 24 weeks.

    Investigational medicinal product name
    Daclatasvir matching-placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 daclatasvir matching-placebo tablets were administered, orally, once daily, for up to 24 weeks.

    Arm title
    		 Lambda + Ribavirin + Daclatasvir (Japan Substudy)
    Arm description
    		 Pegylated Interferon Lambda: solution, subcutaneous, 180 µg/mL, once weekly for up to 24 or 48 weeks (depending upon response); Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Daclatasvir: tablets, oral, 60 mg, once daily for up to 24 weeks; Placebo: Asunaprevir matching-placebo, tablets, oral, twice daily for up to 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pegylated Interferon Lambda
    Investigational medicinal product code
    BMS-914143
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received Pegylated Interferon Lambda 180-μg/ml as subcutaneous injection once weekly for up to 24 or 48 weeks depending upon the response.

    Investigational medicinal product name
    Asunaprevir matching-placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received asunaprevir matching-placebo tablets, orally, twice daily for up to 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 200-mg tablets, orally, twice daily to make the final dose of 1000 mg or 1200 mg per day (depending upon the body weight) for up to 48 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
    2 daclatasvir 30-mg tablets were administered orally, once daily for up to 24 weeks.

    Arm title
    		 Alfa-2a + Ribavirin (Japan Substudy)
    Arm description
    		 Pegylated Interferon Alfa-2a: solution, subcutaneous, 180 µg/mL, once weekly for up to 48 weeks; Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Asunaprevir matching-placebo: tablets, oral, twice daily for up to 24 weeks; Daclatasvir matching-placebo: tablets, oral, once daily for up to 24 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Pegylated Interferon Alfa-2a
    Investigational medicinal product code
    Other name
    Pegasys ®
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received Pegylated Interferon Alfa-2a 180-μg/mL as subcutaneous injection once weekly for up to 24 or 48 weeks depending upon the response.

    Investigational medicinal product name
    Asunaprevir matching-placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received asunaprevir matching-placebo tablets, orally, twice daily for up to 24 weeks.

    Investigational medicinal product name
    Daclatasvir matching-placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 daclatasvir matching-placebo tablets were administered, orally, once daily, for up to 24 weeks.

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Ribasphere
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Ribavirin 200-mg tablets, orally, twice daily to make the final dose of 1000 mg or 1200 mg per day (depending upon the body weight) for up to 48 weeks.

    Arm title
    		 Lambda + Ribavirin + Daclatasvir (Substudy C)
    Arm description
    		 Pegylated Interferon Lambda: solution, subcutaneous, 180 µg/mL, once weekly for 12 weeks; Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for 12 weeks; Daclatasvir: tablets, oral, 6 once daily for up to 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pegylated Interferon Lambda
    Investigational medicinal product code
    BMS-914143
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects received Pegylated Interferon Lambda 180-μg/ml as subcutaneous injection once weekly for 12 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 200-mg tablets, orally, twice daily to make the final dose of 1000 mg or 1200 mg per day (depending upon the body weight) for up to 12 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
    2 daclatasvir 30-mg tablets were administered orally, once daily for up to 12 weeks.

    Number of subjects in period 2
    		Lambda + Ribavirin + Asunaprevir (Part A-Global Study) Lambda + Ribavirin + Daclatasvir (Part A-Global Study) Alfa-2a + Ribavirin (Part A-Global Study) Lambda + Ribavirin + Asunaprevir (Japan Substudy) Lambda + Ribavirin + Daclatasvir (Japan Substudy) Alfa-2a + Ribavirin (Japan Substudy) Lambda + Ribavirin + Daclatasvir (Substudy C)
    Started
    29
    35
    18
    3
    8
    5
    24
    Completed
    36
    39
    34
    6
    8
    6
    23
    Not completed
    2
    2
    6
    0
    0
    1
    1
         Consent withdrawn by subject
    1
    -
    5
    -
    -
    -
    -
         Subject's request to discontinue study treatment
    -
    -
    -
    -
    -
    1
    -
         Poor/Non-compliance
    -
    1
    -
    -
    -
    -
    -
         Lost to follow-up
    -
    -
    -
    -
    -
    -
    1
         Administrative reason by sponsor
    1
    -
    -
    -
    -
    -
    -
         Lack of efficacy
    -
    1
    1
    -
    -
    -
    -
    Joined
    9
    6
    22
    3
    0
    2
    0
         Subjects rejoined in follow-up period
    9
    6
    22
    3
    -
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Lambda + Ribavirin + Asunaprevir (Part A-Global Study)
    Reporting group description
    		 Pegylated Interferon Lambda: solution, subcutaneous, 180 µg/mL, once weekly for up to 24 or 48 weeks (depending upon response); Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Asunaprevir: tablets, oral, 200 mg, twice daily for up to 24 weeks; Placebo: Daclatasvir matching­ placebo, tablets, oral, once daily for up to 24 weeks.

    Reporting group title
    Lambda + Ribavirin + Daclatasvir (Part A-Global Study)
    Reporting group description
    		 Pegylated Interferon Lambda: solution, subcutaneous, 180 µg/mL, once weekly for up to 24 or 48 weeks (depending upon response); Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Daclatasvir: tablets, oral, 60 mg, once daily for up to 24 weeks; Placebo: Asunaprevir matching-placebo, tablets, oral, twice daily for up to 24 weeks.

    Reporting group title
    Alfa-2a + Ribavirin (Part A-Global Study)
    Reporting group description
    		 Pegylated Interferon Alfa-2a: solution, subcutaneous, 180 µg/mL, once weekly for up to 48 weeks; Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Asunaprevir matching-placebo: tablets, oral, twice daily for up to 24 weeks; Daclatasvir matching-placebo: tablets, oral, once daily for up to 24 weeks.

    Reporting group title
    Lambda + Ribavirin + Asunaprevir (Japan Substudy)
    Reporting group description
    		 Pegylated Interferon Lambda: solution, subcutaneous, 180 µg/mL, once weekly for up to 24 or 48 weeks (depending upon response); Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Asunaprevir: tablets, oral, 200 mg, twice daily for up to 24 weeks; Placebo: Daclatasvir matching-placebo, tablets, oral, once daily for up to 24 weeks.

    Reporting group title
    Lambda + Ribavirin + Daclatasvir (Japan Substudy)
    Reporting group description
    		 Pegylated Interferon Lambda: solution, subcutaneous, 180 µg/mL, once weekly for up to 24 or 48 weeks (depending upon response); Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Daclatasvir: tablets, oral, 60 mg, once daily for up to 24 weeks; Placebo: Asunaprevir matching-placebo, tablets, oral, twice daily for up to 24 weeks.

    Reporting group title
    Alfa-2a + Ribavirin (Japan Substudy)
    Reporting group description
    		 Pegylated Interferon Alfa-2a: solution, subcutaneous, 180 µg/mL, once weekly for up to 48 weeks; Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Asunaprevir matching-placebo: tablets, oral, twice daily for up to 24 weeks; Daclatasvir matching-placebo: tablets, oral, once daily for up to 24 weeks.

    Reporting group title
    Lambda + Ribavirin + Daclatasvir (Substudy C)
    Reporting group description
    		 Pegylated Interferon Lambda: solution, subcutaneous, 180 µg/mL, once weekly for 12 weeks; Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for 12 weeks; Daclatasvir: tablets, oral, 6 once daily for up to 12 weeks.

    Reporting group values
    		 Lambda + Ribavirin + Asunaprevir (Part A-Global Study) Lambda + Ribavirin + Daclatasvir (Part A-Global Study) Alfa-2a + Ribavirin (Part A-Global Study) Lambda + Ribavirin + Asunaprevir (Japan Substudy) Lambda + Ribavirin + Daclatasvir (Japan Substudy) Alfa-2a + Ribavirin (Japan Substudy) Lambda + Ribavirin + Daclatasvir (Substudy C) Total
    Number of subjects
    		 38 41 40 6 8 7 24 164
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 47.9 ± 10.7 45.6 ± 9.96 46.7 ± 10.71 52.7 ± 12.23 58.5 ± 7.5 56.6 ± 5.26 54.5 ± 9.979 -
    Gender categorical
    Units: Subjects
        Female
    		 12 21 14 4 6 4 13 74
        Male
    		 26 20 26 2 2 3 11 90

    End points

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    End points reporting groups
    Reporting group title
    Lambda + Ribavirin + Asunaprevir (Part A-Global Study)
    Reporting group description
    		 Pegylated Interferon Lambda: solution, subcutaneous, 180 µg/mL, once weekly for up to 24 or 48 weeks (depending upon response); Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Asunaprevir: tablets, oral, 200 mg, twice daily for up to 24 weeks; Placebo: Daclatasvir matching­ placebo, tablets, oral, once daily for up to 24 weeks.

    Reporting group title
    Lambda + Ribavirin + Daclatasvir (Part A-Global Study)
    Reporting group description
    		 Pegylated Interferon Lambda: solution, subcutaneous, 180 µg/mL, once weekly for up to 24 or 48 weeks (depending upon response); Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Daclatasvir: tablets, oral, 60 mg, once daily for up to 24 weeks; Placebo: Asunaprevir matching-placebo, tablets, oral, twice daily for up to 24 weeks.

    Reporting group title
    Alfa-2a + Ribavirin (Part A-Global Study)
    Reporting group description
    		 Pegylated Interferon Alfa-2a: solution, subcutaneous, 180 µg/mL, once weekly for up to 48 weeks; Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Asunaprevir matching-placebo: tablets, oral, twice daily for up to 24 weeks; Daclatasvir matching-placebo: tablets, oral, once daily for up to 24 weeks.

    Reporting group title
    Lambda + Ribavirin + Asunaprevir (Japan Substudy)
    Reporting group description
    		 Pegylated Interferon Lambda: solution, subcutaneous, 180 µg/mL, once weekly for up to 24 or 48 weeks (depending upon response); Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Asunaprevir: tablets, oral, 200 mg, twice daily for up to 24 weeks; Placebo: Daclatasvir matching-placebo, tablets, oral, once daily for up to 24 weeks.

    Reporting group title
    Lambda + Ribavirin + Daclatasvir (Japan Substudy)
    Reporting group description
    		 Pegylated Interferon Lambda: solution, subcutaneous, 180 µg/mL, once weekly for up to 24 or 48 weeks (depending upon response); Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Daclatasvir: tablets, oral, 60 mg, once daily for up to 24 weeks; Placebo: Asunaprevir matching-placebo, tablets, oral, twice daily for up to 24 weeks.

    Reporting group title
    Alfa-2a + Ribavirin (Japan Substudy)
    Reporting group description
    		 Pegylated Interferon Alfa-2a: solution, subcutaneous, 180 µg/mL, once weekly for up to 48 weeks; Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Asunaprevir matching-placebo: tablets, oral, twice daily for up to 24 weeks; Daclatasvir matching-placebo: tablets, oral, once daily for up to 24 weeks.

    Reporting group title
    Lambda + Ribavirin + Daclatasvir (Substudy C)
    Reporting group description
    		 Pegylated Interferon Lambda: solution, subcutaneous, 180 µg/mL, once weekly for 12 weeks; Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for 12 weeks; Daclatasvir: tablets, oral, 6 once daily for up to 12 weeks.
    Reporting group title
    Lambda + Ribavirin + Asunaprevir (Part A-Global Study)
    Reporting group description
    		 Pegylated Interferon Lambda: solution, subcutaneous, 180 µg/mL, once weekly for up to 24 or 48 weeks (depending upon response); Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Asunaprevir: tablets, oral, 200 mg, twice daily for up to 24 weeks; Placebo: Daclatasvir matching ­placebo, tablets, oral, once daily for up to 24 weeks.

    Reporting group title
    Lambda + Ribavirin + Daclatasvir (Part A-Global Study)
    Reporting group description
    		 Pegylated Interferon Lambda: solution, subcutaneous, 180 µg/mL, once weekly for up to 24 or 48 weeks (depending upon response); Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Daclatasvir: tablets, oral, 60 mg, once daily for up to 24 weeks; Placebo: Asunaprevir matching-placebo, tablets, oral, twice daily for up to 24 weeks.

    Reporting group title
    Alfa-2a + Ribavirin (Part A-Global Study)
    Reporting group description
    		 Pegylated Interferon Alfa-2a: solution, subcutaneous, 180 µg/mL, once weekly for up to 48 weeks; Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Asunaprevir matching-placebo: tablets, oral, twice daily for up to 24 weeks; Daclatasvir matching-placebo: tablets, oral, once daily for up to 24 weeks.

    Reporting group title
    Lambda + Ribavirin + Asunaprevir (Japan Substudy)
    Reporting group description
    		 Pegylated Interferon Lambda: solution, subcutaneous, 180 µg/mL, once weekly for up to 24 or 48 weeks (depending upon response); Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Asunaprevir: tablets, oral, 200 mg, twice daily for up to 24 weeks; Placebo: Daclatasvir matching-placebo, tablets, oral, once daily for up to 24 weeks.

    Reporting group title
    Lambda + Ribavirin + Daclatasvir (Japan Substudy)
    Reporting group description
    		 Pegylated Interferon Lambda: solution, subcutaneous, 180 µg/mL, once weekly for up to 24 or 48 weeks (depending upon response); Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Daclatasvir: tablets, oral, 60 mg, once daily for up to 24 weeks; Placebo: Asunaprevir matching-placebo, tablets, oral, twice daily for up to 24 weeks.

    Reporting group title
    Alfa-2a + Ribavirin (Japan Substudy)
    Reporting group description
    		 Pegylated Interferon Alfa-2a: solution, subcutaneous, 180 µg/mL, once weekly for up to 48 weeks; Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Asunaprevir matching-placebo: tablets, oral, twice daily for up to 24 weeks; Daclatasvir matching-placebo: tablets, oral, once daily for up to 24 weeks.

    Reporting group title
    Lambda + Ribavirin + Daclatasvir (Substudy C)
    Reporting group description
    		 Pegylated Interferon Lambda: solution, subcutaneous, 180 µg/mL, once weekly for 12 weeks; Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for 12 weeks; Daclatasvir: tablets, oral, 6 once daily for up to 12 weeks.

    Primary: Number of Subjects With Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation of Study Drug, and Grade 3 or 4 AEs

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    End point title
    		 Number of Subjects With Serious Adverse Events (SAEs), Adverse Events (AEs) Leading to Discontinuation of Study Drug, and Grade 3 or 4 AEs [1] [2]
    End point description
    AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or unknown relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4=Life-threatening or disabling. Analysis population included all the randomised subjects who received at least 1 dose of the study drug.
    End point type
    Primary
    End point timeframe
    Baseline up to end of treatment (Week 16, 24 or 48)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive summary statistics were planned for this outcome measure.
    [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
    		 Lambda + Ribavirin + Asunaprevir (Part A-Global Study) Lambda + Ribavirin + Daclatasvir (Part A-Global Study) Alfa-2a + Ribavirin (Part A-Global Study) Lambda + Ribavirin + Asunaprevir (Japan Substudy) Lambda + Ribavirin + Daclatasvir (Japan Substudy) Alfa-2a + Ribavirin (Japan Substudy)
    Number of subjects analysed
    38
    41
    40
    6
    8
    7
    Units: Subjects
        SAEs
    3
    2
    0
    1
    0
    0
        AEs leading to discontinuation of study drug
    6
    2
    5
    3
    0
    1
        Grade 3 or 4 AEs
    11
    7
    8
    5
    1
    5
    No statistical analyses for this end point

    Primary: Percentage of Hepatitis C Virus (HCV) Genotype 1 Subjects With 24-Week Sustained Virologic Response (SVR24)

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    End point title
    		 Percentage of Hepatitis C Virus (HCV) Genotype 1 Subjects With 24-Week Sustained Virologic Response (SVR24) [3] [4]
    End point description
    HCV RNA was measured by the Roche COBAS TaqMan HCV Test v2.0 from the central laboratory. The lower and upper limits of quantitation (LLOQ and ULOQ) of the assay were 25 IU/mL and 3.91 x 10^8 IU/mL. SVR24 was defined as undetectable HCV RNA at end of treatment (maximum of 48 weeks) and undetectable HCV RNA at follow-up Week 24. Analysis population included all treated subjects, ie, randomised subjects who received at least 1 dose of the study drug. Response rates were assessed using modified Intent-to-Treat algorithm. The numerator was based on subjects meeting the response criteria, that is, undetectable HCV RNA at end of treatment and undetectable HCV RNA at follow-up Week 24. The denominator was based on all treated subjects.
    End point type
    Primary
    End point timeframe
    Baseline up to follow-up Week 24
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive summary statistics were planned for this outcome measure.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    		 Lambda + Ribavirin + Asunaprevir (Part A-Global Study) Lambda + Ribavirin + Daclatasvir (Part A-Global Study) Alfa-2a + Ribavirin (Part A-Global Study) Lambda + Ribavirin + Asunaprevir (Japan Substudy) Lambda + Ribavirin + Daclatasvir (Japan Substudy) Alfa-2a + Ribavirin (Japan Substudy)
    Number of subjects analysed
    38
    41
    40
    6
    8
    7
    Units: Percentage of subjects
        number (confidence interval 80%)
    68.4 (56.9 to 78.4)
    63.4 (52.2 to 73.6)
    35 (24.9 to 46.3)
    83.3 (49 to 98.3)
    100 (75 to 100)
    28.6 (7.9 to 59.6)
    No statistical analyses for this end point

    Primary: Substudy C: Percentage of Subjects With 12-Week Sustained Virologic Response (SVR12)

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    End point title
    		 Substudy C: Percentage of Subjects With 12-Week Sustained Virologic Response (SVR12) [5] [6]
    End point description
    SVR12 was defined as undetectable Hepatitis C Virus (HCV) RNA at end of treatment and undetectable HCV RNA at follow-up Week 12. Analysis population included all treated subjects, ie, randomised subjects who received at least 1 dose of the study drug. Response rates were assessed using modified Intent-to-Treat algorithm. The numerator was based on subjects meeting the response criteria, that is, undetectable HCV RNA at end of treatment and undetectable HCV RNA at follow-up Week 12. The denominator was based on all treated subjects.
    End point type
    Primary
    End point timeframe
    Baseline to follow-up Week 12
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive summary statistics were planned for this outcome measure.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    		 Lambda + Ribavirin + Daclatasvir (Substudy C)
    Number of subjects analysed
    24
    Units: Percentage of Subjects
        number (confidence interval 80%)
    79.2 (64.8 to 89.5)
    No statistical analyses for this end point

    Secondary: Part A: Percentage of Subjects With Protocol Defined Response (PDR)

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    End point title
    		 Part A: Percentage of Subjects With Protocol Defined Response (PDR) [7]
    End point description
    PDR was defined as Hepatitis C Virus (HCV) RNA < LLOQ at Week 4 and undetectable HCV RNA at Week 12. The analysis was performed in all treated subjects, ie, randomised subjects who received at least 1 dose of the study drug. Response rates were assessed using modified Intent-to-Treat algorithm. The numerator was based on subjects meeting the response criteria and the denominator was based on all treated subjects.
    End point type
    Secondary
    End point timeframe
    Week 4 and Week 12
    Notes
    [7] - 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
    		 Lambda + Ribavirin + Asunaprevir (Part A-Global Study) Lambda + Ribavirin + Daclatasvir (Part A-Global Study) Alfa-2a + Ribavirin (Part A-Global Study) Lambda + Ribavirin + Asunaprevir (Japan Substudy) Lambda + Ribavirin + Daclatasvir (Japan Substudy) Alfa-2a + Ribavirin (Japan Substudy)
    Number of subjects analysed
    38
    41
    40
    6
    8
    7
    Units: Percentage of subjects
        number (confidence interval 80%)
    84.2 (73.9 to 91.5)
    90.2 (81.4 to 95.7)
    12.5 (6.2 to 22)
    83.3 (49 to 98.3)
    87.5 (59.4 to 98.7)
    14.3 (1.5 to 45.3)
    No statistical analyses for this end point

    Secondary: Part A: Serum Hepatitis C Virus (HCV) RNA Levels Over Time

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    End point title
    		 Part A: Serum Hepatitis C Virus (HCV) RNA Levels Over Time [8]
    End point description
    HCV RNA values outside ULOQ (LLOQ) were assigned a value of 1 more (or 1 less) than the limit. Then HCV RNA was transformed on the log10 scale. The analysis was performed in all treated subjects, ie, randomised subjects who received at least 1 dose of the study drug. Here, ‘n’ signifies the number of subjects with observed HCV RNA values at the specified time point for each arm, respectively. Here, 99999 signifies data not applicable.
    End point type
    Secondary
    End point timeframe
    Days 1, 3, Weeks 1, 2, 4, 6, 8, 12, 16, 20, and end of treatment (Week 16, 24 or 48 depending on treatment assignment)
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    		 Lambda + Ribavirin + Asunaprevir (Part A-Global Study) Lambda + Ribavirin + Daclatasvir (Part A-Global Study) Alfa-2a + Ribavirin (Part A-Global Study) Lambda + Ribavirin + Asunaprevir (Japan Substudy) Lambda + Ribavirin + Daclatasvir (Japan Substudy) Alfa-2a + Ribavirin (Japan Substudy)
    Number of subjects analysed
    38
    41
    40
    6
    8
    7
    Units: log10 IU/mL
    arithmetic mean (standard deviation)
        Day 1 (n=38, 41, 40, 6, 8, 7)
    6.34 ± 0.682
    6.33 ± 0.607
    6.31 ± 0.678
    6.54 ± 0.443
    6.24 ± 0.981
    6.54 ± 0.398
        Day 3 (n=35, 30, 31, 6, 8, 7)
    2.56 ± 0.616
    2.61 ± 0.618
    5.5 ± 1.045
    2.33 ± 0.346
    2.17 ± 0.572
    5.64 ± 0.917
        Week 1 (n=36, 40, 37, 6, 8, 7)
    1.95 ± 0.726
    1.9 ± 0.664
    5.41 ± 1.127
    1.52 ± 0.259
    1.47 ± 0.176
    5.23 ± 1.198
        Week 2 (n=37, 40, 40, 6, 8, 7)
    1.48 ± 0.406
    1.48 ± 0.223
    4.87 ± 1.486
    1.38 ± 0
    1.38 ± 0
    4.52 ± 1.704
        Week 4 (n=37, 41, 38, 6, 7, 7)
    1.47 ± 0.526
    1.38 ± 0
    3.99 ± 1.822
    1.38 ± 0
    1.38 ± 0
    3.36 ± 1.723
        Week 6 (n=36, 39, 39, 5, 8, 7)
    1.47 ± 0.514
    1.4 ± 0.129
    3.55 ± 1.893
    1.38 ± 0
    1.38 ± 0
    2.65 ± 1.416
        Week 8 (n=35, 39, 36, 5, 8, 7)
    1.48 ± 0.575
    1.38 ± 0
    3.08 ± 1.838
    1.38 ± 0
    1.38 ± 0
    2.2 ± 1.12
        Week 12 (n=35, 39, 37, 5, 8, 6)
    1.46 ± 0.474
    1.39 ± 0.048
    2.76 ± 1.761
    1.38 ± 0
    1.38 ± 0
    1.8 ± 0.786
        Week 16 (n=26, 32, 28, 3, 8, 6)
    1.38 ± 0
    1.54 ± 0.758
    2.35 ± 1.622
    1.38 ± 0
    1.38 ± 0
    1.67 ± 0.72
        Week 20 (n=28, 31, 26, 3, 8, 6)
    1.4 ± 0.108
    1.59 ± 0.854
    1.57 ± 0.637
    1.38 ± 0
    1.38 ± 0
    1.7 ± 0.777
        Week 24 (n=31, 37, 24, 3, 8, 6)
    1.54 ± 0.704
    1.68 ± 1.085
    1.7 ± 1.128
    1.38 ± 0
    1.38 ± 0
    1.75 ± 0.907
        Week 48 (n=1, 0, 17, 0, 0, 5)
    1 ± 99999
    99999 ± 99999
    1.56 ± 0.754
    99999 ± 99999
    99999 ± 99999
    1.38 ± 0
    No statistical analyses for this end point

    Secondary: Part A: Percentage of Subjects With Undetectable Hepatitis C Virus (HCV) RNA Over Time

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    End point title
    		 Part A: Percentage of Subjects With Undetectable Hepatitis C Virus (HCV) RNA Over Time [9]
    End point description
    The analysis was performed in all treated subjects, ie, randomised subjects who received at least 1 dose of the study drug. Response rates were assessed using modified Intent-to-­Treat algorithm. The numerator was based on subjects meeting the response criteria, and the denominator was based on all treated subjects.
    End point type
    Secondary
    End point timeframe
    Days 1, 3, Weeks 1, 2, 4, 6, 8, 12, 16, 20, and end of treatment (24 or 48 depending on treatment assignment)
    Notes
    [9] - 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
    		 Lambda + Ribavirin + Asunaprevir (Part A-Global Study) Lambda + Ribavirin + Daclatasvir (Part A-Global Study) Alfa-2a + Ribavirin (Part A-Global Study) Lambda + Ribavirin + Asunaprevir (Japan Substudy) Lambda + Ribavirin + Daclatasvir (Japan Substudy) Alfa-2a + Ribavirin (Japan Substudy)
    Number of subjects analysed
    38
    41
    40
    6
    8
    7
    Units: Percentage of subjects
    number (confidence interval 80%)
        Day 1
    0 (0 to 5.9)
    0 (0 to 5.5)
    0 (0 to 5.6)
    0 (0 to 31.9)
    0 (0 to 25)
    0 (0 to 28)
        Week 1
    0 (0 to 5.9)
    0 (0 to 5.5)
    2.5 (0.3 to 9.4)
    0 (0 to 31.9)
    12.5 (1.3 to 40.6)
    0 (0 to 28)
        Week 2
    31.6 (21.6 to 43.1)
    24.4 (15.7 to 35.1)
    2.5 (0.3 to 9.4)
    50 (20.1 to 79.9)
    62.5 (34.5 to 85.3)
    0 (0 to 28)
        Week 4
    81.6 (71 to 89.4)
    70.7 (59.8 to 80.1)
    5 (1.3 to 12.8)
    83.3 (49 to 98.3)
    87.5 (59.4 to 98.7)
    14.3 (1.5 to 45.3)
        Week 6
    86.8 (77 to 93.5)
    90.2 (81.4 to 95.7)
    12.5 (6.2 to 22)
    83.3 (49 to 98.3)
    100 (75 to 100)
    14.3 (1.5 to 45.3)
        Week 8
    86.8 (77 to 93.5)
    90.2 (81.4 to 95.7)
    22.5 (14.1 to 33.2)
    83.3 (49 to 98.3)
    87.5 (59.4 to 98.7)
    42.9 (17 to 72.1)
        Week 12
    84.2 (73.9 to 91.5)
    90.2 (81.4 to 95.7)
    37.5 (27.1 to 48.9)
    83.3 (49 to 98.3)
    100 (75 to 100)
    42.9 (17 to 72.1)
        Week 16
    63.2 (51.5 to 73.7)
    70.7 (59.8 to 80.1)
    32.5 (22.7 to 43.8)
    50 (20.1 to 79.9)
    100 (75 to 100)
    42.9 (17 to 72.1)
        Week 20
    65.8 (54.2 to 76.1)
    65.9 (54.7 to 75.8)
    45 (34.1 to 56.3)
    50 (20.1 to 79.9)
    100 (75 to 100)
    42.9 (17 to 72.1)
        Week 24
    68.4 (56.9 to 78.4)
    80.5 (70.2 to 88.3)
    50 (38.8 to 61.2)
    50 (20.1 to 79.9)
    100 (75 to 100)
    71.4 (40.4 to 92.1)
        Week 48
    0 (0 to 5.9)
    0 (0 to 5.5)
    40 (29.4 to 51.4)
    0 (0 to 31.9)
    0 (0 to 25)
    71.4 (40.4 to 92.1)
    No statistical analyses for this end point

    Secondary: Part A: Percentage of Subjects With 12 ­Week Sustained Virologic Response (SVR12)

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    End point title
    		 Part A: Percentage of Subjects With 12 ­Week Sustained Virologic Response (SVR12) [10]
    End point description
    SVR12 was defined as undetectable Hepatitis C Virus (HCV) RNA at end of treatment and undetectable HCV RNA at follow­-up Week 12. Analysis population included all treated subjects, ie, randomised subjects who received at least 1 dose of the study drug. Response rates were assessed using modified Intent-to-Treat algorithm. The numerator was based on subjects meeting the response criteria, that is, undetectable HCV RNA at end of treatment and undetectable HCV RNA at follow-­up Week 12. The denominator was based on all treated subjects.
    End point type
    Secondary
    End point timeframe
    Baseline to follow-up Week 12
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to evaluate for the specified arm only.
    End point values
    		 Lambda + Ribavirin + Asunaprevir (Part A-Global Study) Lambda + Ribavirin + Daclatasvir (Part A-Global Study) Alfa-2a + Ribavirin (Part A-Global Study) Lambda + Ribavirin + Asunaprevir (Japan Substudy) Lambda + Ribavirin + Daclatasvir (Japan Substudy) Alfa-2a + Ribavirin (Japan Substudy)
    Number of subjects analysed
    38
    41
    40
    6
    8
    7
    Units: Percentage of subjects
        number (confidence interval 80%)
    65.8 (54.2 to 76.1)
    68.3 (57.2 to 77.9)
    37.5 (27.1 to 48.9)
    83.3 (49 to 98.3)
    100 (75 to 100)
    28.6 (7.9 to 59.6)
    No statistical analyses for this end point

    Secondary: Part A: Time to Viral Clearance

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    End point title
    		 Part A: Time to Viral Clearance [11]
    End point description
    Time to viral clearance was measured by time to confirmed undetectable HCV RNA from the first dose of study therapy to the first of 2 consecutive undetectable HCV RNA measurements using all available data on treatment. For subjects who never achieved confirmed undetectable HCV RNA while on treatment, time was set to the maximum planned duration of study (72 weeks). The analysis was performed in all treated subjects, ie, randomised subjects who received at least 1 dose of the study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to end of treatment
    Notes
    [11] - 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
    		 Lambda + Ribavirin + Asunaprevir (Part A-Global Study) Lambda + Ribavirin + Daclatasvir (Part A-Global Study) Alfa-2a + Ribavirin (Part A-Global Study) Lambda + Ribavirin + Asunaprevir (Japan Substudy) Lambda + Ribavirin + Daclatasvir (Japan Substudy) Alfa-2a + Ribavirin (Japan Substudy)
    Number of subjects analysed
    38
    41
    40
    6
    8
    7
    Units: Number of subjects with events
        Weeks 0-4
    10
    8
    1
    4
    5
    0
        Weeks 4-8
    33
    37
    5
    6
    8
    1
        Weeks 8-12
    34
    37
    9
    6
    8
    2
        Weeks 12-16
    34
    37
    14
    6
    8
    3
        Weeks 16-20
    34
    37
    17
    6
    8
    4
        Weeks 20-24
    34
    37
    20
    6
    8
    4
        Weeks 24-28
    34
    37
    21
    6
    8
    5
        Weeks 28-32
    34
    37
    21
    6
    8
    5
        Weeks 32-36
    34
    37
    21
    6
    8
    5
        Weeks 36-72
    34
    37
    22
    6
    8
    5
    No statistical analyses for this end point

    Secondary: Part A: Percentage of Subjects With Viral Breakthrough

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    End point title
    		 Part A: Percentage of Subjects With Viral Breakthrough [12]
    End point description
    Viral breakthrough was defined as confirmed >1 log10 increase in HCV RNA over nadir or confirmed HCV RNA >= LLOQ after confirmed undetectable HCV RNA while on treatment. The analysis was performed in all treated subjects, ie, randomised subjects who received at least 1 dose of the study drug. Response rates were assessed using modified Intent-to-Treat algorithm. The numerator was based on subjects with viral breakthrough, and the denominator was based on all treated subjects.
    End point type
    Secondary
    End point timeframe
    Baseline up to end of treatment
    Notes
    [12] - 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
    		 Lambda + Ribavirin + Asunaprevir (Part A-Global Study) Lambda + Ribavirin + Daclatasvir (Part A-Global Study) Alfa-2a + Ribavirin (Part A-Global Study) Lambda + Ribavirin + Asunaprevir (Japan Substudy) Lambda + Ribavirin + Daclatasvir (Japan Substudy) Alfa-2a + Ribavirin (Japan Substudy)
    Number of subjects analysed
    38
    41
    40
    6
    8
    7
    Units: Percentage of subjects
        number (not applicable)
    5.3
    4.9
    7.5
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Part A: Percentage of Subjects With Relapse

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    End point title
    		 Part A: Percentage of Subjects With Relapse [13]
    End point description
    Relapse was defined as undetectable HCV RNA at EOT followed by HCV RNA >=LLOQ in any follow-up visit. The analysis was performed in all treated subjects, ie, randomised subjects who received at least 1 dose of the study drug. Relapse rates were assessed using modified Intent-to-Treat algorithm. The numerator was based on subjects with relapse, and the denominator was based on all treated subjects.
    End point type
    Secondary
    End point timeframe
    Baseline up to Follow-up Week 24
    Notes
    [13] - 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
    		 Lambda + Ribavirin + Asunaprevir (Part A-Global Study) Lambda + Ribavirin + Daclatasvir (Part A-Global Study) Alfa-2a + Ribavirin (Part A-Global Study) Lambda + Ribavirin + Asunaprevir (Japan Substudy) Lambda + Ribavirin + Daclatasvir (Japan Substudy) Alfa-2a + Ribavirin (Japan Substudy)
    Number of subjects analysed
    38
    41
    40
    6
    8
    7
    Units: Percentage of subjects
        number (not applicable)
    13.2
    17.1
    10
    16.7
    0
    42.9
    No statistical analyses for this end point

    Secondary: Part A: Maximum Observed Plasma Concentration (Cmax)

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    End point title
    		 Part A: Maximum Observed Plasma Concentration (Cmax) [14]
    End point description
    Cmax was defined as the peak plasma concentration of a drug after administration, obtained directly from the plasma concentration-time curve. The analysis was performed in subjects who received at least 1 dose of study drug with any plasma concentration data. The Cmax was derived by using non compartmental method. Here, “Number of subjects analysed” signifies number of subjects evaluated for this outcome measure. Here, ‘n’ signifies evaluable subjects for specified categories in respective treatment arms, and '99999' represents not estimable data for specified categories in respective arms.
    End point type
    Secondary
    End point timeframe
    Baseline to 0-12 h for Asunaprevir, 0-24 h for Daclatasvir, and 0-168 h for pegIFNλ and pegIFNα-2a at Week 4
    Notes
    [14] - 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
    		 Lambda + Ribavirin + Asunaprevir (Part A-Global Study) Lambda + Ribavirin + Daclatasvir (Part A-Global Study) Alfa-2a + Ribavirin (Part A-Global Study) Lambda + Ribavirin + Asunaprevir (Japan Substudy) Lambda + Ribavirin + Daclatasvir (Japan Substudy) Alfa-2a + Ribavirin (Japan Substudy)
    Number of subjects analysed
    6
    4
    4
    2
    4
    3
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Lambda (n=6, 4, 0, 2, 4, 0)
    2.51 ± 103.46
    3.19 ± 26.15
    99999 ± 99999
    2.12 ± 37.35
    1.85 ± 33.83
    99999 ± 99999
        Daclatasvir (n=0, 4, 0, 0, 4, 0)
    99999 ± 99999
    1414 ± 24.54
    99999 ± 99999
    99999 ± 99999
    1512 ± 16.02
    99999 ± 99999
        Asunaprevir (n=6, 0, 0, 2, 0, 0)
    337.46 ± 127.18
    99999 ± 99999
    99999 ± 99999
    660.06 ± 48.15
    99999 ± 99999
    99999 ± 99999
        Alfa-2a (n=0, 0, 4, 0, 0, 3)
    99999 ± 99999
    99999 ± 99999
    15.21 ± 48.27
    99999 ± 99999
    99999 ± 99999
    18.9 ± 3.89
    No statistical analyses for this end point

    Secondary: Time of Maximum Observed Plasma Concentration (Tmax)

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    End point title
    		 Time of Maximum Observed Plasma Concentration (Tmax) [15]
    End point description
    Time to reach the maximum plasma concentration was directly determined from concentration time data. The analysis was performed in subjects who received at least 1 dose of study drug with any plasma concentration data. The Tmax was derived by using non compartmental method. Here, “Number of subjects analysed” signifies number of subjects evaluated for this outcome measure. Here, ‘n’ signifies evaluable subjects for specified categories in respective treatment arms, and ‘99999’ represents not estimable data for specified categories in respective arms.
    End point type
    Secondary
    End point timeframe
    Baseline to 0-12 h for Asunaprevir, 0-24 h for Daclatasvir, and 0-168 h for pegIFNλ and pegIFNα-2a at Week 4
    Notes
    [15] - 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
    		 Lambda + Ribavirin + Asunaprevir (Part A-Global Study) Lambda + Ribavirin + Daclatasvir (Part A-Global Study) Alfa-2a + Ribavirin (Part A-Global Study) Lambda + Ribavirin + Asunaprevir (Japan Substudy) Lambda + Ribavirin + Daclatasvir (Japan Substudy) Alfa-2a + Ribavirin (Japan Substudy)
    Number of subjects analysed
    6
    4
    4
    2
    4
    3
    Units: hour
    median (full range (min-max))
        Lambda (n=6, 4, 0, 2, 4, 0)
    23.79 (12 to 71.6)
    10.58 (8 to 48)
    99999 (-99999 to 99999)
    21.46 (20.2 to 22.8)
    22.98 (22 to 24)
    99999 (-99999 to 99999)
        Daclatasvir (n=0, 4, 0, 0, 4, 0)
    99999 (-99999 to 99999)
    1 (1 to 2)
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    2.94 (1 to 4)
    99999 (-99999 to 99999)
        Asunaprevir (n=6, 0, 0, 2, 0, 0)
    3.99 (1 to 8)
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    2.04 (2 to 2.1)
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
        Alfa-2a (n=0, 0, 4, 0, 0, 3)
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    35.44 (11.9 to 72.6)
    99999 (-99999 to 99999)
    99999 (-99999 to 99999)
    47.97 (45.7 to 94)
    No statistical analyses for this end point

    Secondary: Minimal Observed Plasma Concentration (Cmin)

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    End point title
    		 Minimal Observed Plasma Concentration (Cmin) [16]
    End point description
    Cmin was observed directly from 12-hour and 24-hour post-dose concentration depending upon the dosing schedule (once daily or twice daily). The analysis was performed in subjects who received at least 1 dose of study drug with any plasma concentration data. The Cmin was derived by using non compartmental method. Here, “Number of subjects analysed” signifies number of subjects evaluated for this outcome measure. Here, ‘n’ signifies evaluable subjects for specified categories in respective treatment arms, and '99999' represents not estimable data for specified categories in respective arms.
    End point type
    Secondary
    End point timeframe
    Baseline to 0-12 h for Asunaprevir, 0-24 h for Daclatasvir, and 0-168 h for pegIFNλ and pegIFNα-2a at Week 4
    Notes
    [16] - 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
    		 Lambda + Ribavirin + Asunaprevir (Part A-Global Study) Lambda + Ribavirin + Daclatasvir (Part A-Global Study) Alfa-2a + Ribavirin (Part A-Global Study) Lambda + Ribavirin + Asunaprevir (Japan Substudy) Lambda + Ribavirin + Daclatasvir (Japan Substudy) Alfa-2a + Ribavirin (Japan Substudy)
    Number of subjects analysed
    6
    4
    4
    2
    4
    3
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Lambda (n=6, 4, 0, 2, 4, 0)
    0.42 ± 41.85
    0.72 ± 36.92
    99999 ± 99999
    0.72 ± 47.08
    0.3 ± 63.77
    99999 ± 99999
        Daclatasvir (n=0, 4, 0, 0, 4, 0)
    99999 ± 99999
    283.13 ± 53.2
    99999 ± 99999
    99999 ± 99999
    352.94 ± 29.43
    99999 ± 99999
        Asunaprevir (n=6, 0, 0, 2, 0, 0)
    98.4 ± 140.55
    99999 ± 99999
    99999 ± 99999
    52.96 ± 57.15
    99999 ± 99999
    99999 ± 99999
        Alfa-2a (n=0, 0, 4, 0, 0, 3)
    99999 ± 99999
    99999 ± 99999
    4.17 ± 81.36
    99999 ± 99999
    99999 ± 99999
    13.66 ± 4.87
    No statistical analyses for this end point

    Secondary: Area Under the Plasma Concentration-Time Curve in 1 Dosing Interval, From time 0 to 24 Hours Post-dose [AUC(TAU)]

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    End point title
    		 Area Under the Plasma Concentration-Time Curve in 1 Dosing Interval, From time 0 to 24 Hours Post-dose [AUC(TAU)] [17]
    End point description
    AUC (TAU)=Area under concentration time profile from time 0 to tau, where tau was the dosing interval of 12 or 24 hours depending upon the dosing schedule (once daily or twice daily). The analysis was performed in subjects who received at least 1 dose of study drug with any plasma concentration data. The AUC(TAU) was derived by using non compartmental method. Here, “Number of subjects analysed” signifies number of subjects evaluated for this outcome measure. Here, ‘n’ signifies evaluable subjects for specified categories in respective treatment arms, and '99999' represents not estimable data for specified categories in respective arms.
    End point type
    Secondary
    End point timeframe
    Baseline to 0-12 h for Asunaprevir, 0-24 h for Daclatasvir, and 0-168 h for pegIFNλ and pegIFNα-2a at Week 4
    Notes
    [17] - 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
    		 Lambda + Ribavirin + Asunaprevir (Part A-Global Study) Lambda + Ribavirin + Daclatasvir (Part A-Global Study) Alfa-2a + Ribavirin (Part A-Global Study) Lambda + Ribavirin + Asunaprevir (Japan Substudy) Lambda + Ribavirin + Daclatasvir (Japan Substudy) Alfa-2a + Ribavirin (Japan Substudy)
    Number of subjects analysed
    6
    4
    4
    2
    4
    3
    Units: ng*hr/mL
    geometric mean (geometric coefficient of variation)
        Lambda (n=6, 4, 0, 2, 4, 0)
    214.04 ± 75.57
    291.97 ± 23.9
    99999 ± 99999
    243.49 ± 37.06
    187.8 ± 22.48
    99999 ± 99999
        Daclatasvir (n=0, 4, 0, 0, 4, 0)
    99999 ± 99999
    20592.61 ± 57.98
    99999 ± 99999
    99999 ± 99999
    21783.59 ± 18.65
    99999 ± 99999
        Asunaprevir (n=6, 0, 0, 2, 0, 0)
    1739.97 ± 159.4
    99999 ± 99999
    99999 ± 99999
    2007.03 ± 15.72
    99999 ± 99999
    99999 ± 99999
        Alfa-2a (n=0, 0, 4, 0, 0, 3)
    99999 ± 99999
    99999 ± 99999
    1923.13 ± 41.76
    99999 ± 99999
    99999 ± 99999
    2748.88 ± 4.8
    No statistical analyses for this end point

    Secondary: Observed Trough Plasma Concentration (Ctrough)

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    End point title
    		 Observed Trough Plasma Concentration (Ctrough) [18]
    End point description
    Geometric mean of a subject’s trough concentrations through Week 24, was summarised by treatment regimen. The analysis was performed in subjects who received at least 1 dose of study drug with any plasma concentration data. The Ctrough was derived by using non compartmental method. Here, “Number of subjects analysed” signifies number of subjects evaluated for this outcome measure. Here, ‘n’ signifies evaluable subjects for specified categories in respective treatment arms, and '99999' represents not estimable data for specified categories in respective arms.
    End point type
    Secondary
    End point timeframe
    Baseline to 0-12 h for Asunaprevir, 0-24 h for Daclatasvir, and 0-168 h for pegIFNλ and pegIFNα-2a at Week 4
    Notes
    [18] - 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
    		 Lambda + Ribavirin + Asunaprevir (Part A-Global Study) Lambda + Ribavirin + Daclatasvir (Part A-Global Study) Alfa-2a + Ribavirin (Part A-Global Study) Lambda + Ribavirin + Asunaprevir (Japan Substudy) Lambda + Ribavirin + Daclatasvir (Japan Substudy) Alfa-2a + Ribavirin (Japan Substudy)
    Number of subjects analysed
    37
    41
    37
    6
    8
    7
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        Lambda (n=37, 41, 0, 6, 8, 0)
    0.187 ± 69.2
    0.285 ± 96.52
    99999 ± 99999
    0.735 ± 31.79
    0.332 ± 37.92
    99999 ± 99999
        Daclatasvir (n=0, 41, 0, 0, 8, 0)
    99999 ± 99999
    198.1 ± 112.1
    99999 ± 99999
    99999 ± 99999
    272.316 ± 41.7
    99999 ± 99999
        Asunaprevir (n=37, 0, 0, 6, 0, 0)
    81.716 ± 118.51
    99999 ± 99999
    99999 ± 99999
    99.808 ± 148
    99999 ± 99999
    99999 ± 99999
        Alfa-2a (n=0, 0, 37, 0, 0, 7)
    99999 ± 99999
    99999 ± 99999
    7.208 ± 49.84
    99999 ± 99999
    99999 ± 99999
    9.911 ± 54.92
    No statistical analyses for this end point

    Secondary: Substudy C: Percentage of Hepatitis C Virus (HCV) Subjects With Sustained Virologic Response (SVR24)

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    End point title
    		 Substudy C: Percentage of Hepatitis C Virus (HCV) Subjects With Sustained Virologic Response (SVR24) [19]
    End point description
    HCV RNA was measured by the Roche COBAS TaqMan HCV Test v2.0 from the central laboratory. The lower and upper limits of quantitation (LLOQ and ULOQ) of the assay were 25 IU/mL and 3.91 x 108 IU/mL. SVR24 was defined as undetectable HCV RNA at end of treatment (maximum of 48 weeks) and undetectable HCV RNA at follow-up Week 24. Analysis population included all treated subjects, ie, randomised subjects who received at least 1 dose of the study drug. Response rates were assessed using modified Intent-to-Treat algorithm. The numerator was based on subjects meeting the response criteria, that is, undetectable HCV RNA at end of treatment and undetectable HCV RNA at follow-up Week 24. The denominator was based on all treated subjects.
    End point type
    Secondary
    End point timeframe
    Baseline up to follow-up Week 24
    Notes
    [19] - 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
    		 Lambda + Ribavirin + Daclatasvir (Substudy C)
    Number of subjects analysed
    24
    Units: Percentage of Subjects
        number (confidence interval 80%)
    79.2 (64.8 to 89.5)
    No statistical analyses for this end point

    Secondary: Substudy C: Percentage of Non-Cirrhotic Genotype-1b Subjects With Extended Rapid Virologic Response (eRVR)

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    End point title
    		 Substudy C: Percentage of Non-Cirrhotic Genotype-1b Subjects With Extended Rapid Virologic Response (eRVR) [20]
    End point description
    eRVR was defined as undetectable Hepatitis C virus RNA at Week 4 and Week 12 of treatment. Analysis population included all treated subjects, ie, randomised subjects who received at least 1 dose of the study drug. Response rates were assessed using modified Intent-to-Treat algorithm. The numerator was based on subjects meeting the response criteria, and the denominator was based on all treated subjects.
    End point type
    Secondary
    End point timeframe
    Weeks 4 and 12
    Notes
    [20] - 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
    		 Lambda + Ribavirin + Daclatasvir (Substudy C)
    Number of subjects analysed
    24
    Units: Percentage of subjects
        number (confidence interval 80%)
    79.2 (64.8 to 89.5)
    No statistical analyses for this end point

    Secondary: Substudy C: Percentage of Non-Cirrhotic Genotype-1b Subjects With Treatment-Emergent Cytopenic Abnormalities on Treatment (Maximum of 12 Weeks)

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    End point title
    		 Substudy C: Percentage of Non-Cirrhotic Genotype-1b Subjects With Treatment-Emergent Cytopenic Abnormalities on Treatment (Maximum of 12 Weeks) [21]
    End point description
    Cytopenic abnormalities were defined as anemia as defined by haemoglobin <10 g/dL, and/or neutropenia as defined by absolute neutrophil count <750 mm^3, and/or thrombocytopenia as defined by platelets < 50,000 mm^3. Analysis population included all treated subjects, ie, randomised subjects who received at least 1 dose of the study drug. Response rates were assessed using modified Intent-to-Treat algorithm. The numerator was based on subjects with abnormalities, and the denominator was based on all treated subjects.
    End point type
    Secondary
    End point timeframe
    On-treatment up to Week 12
    Notes
    [21] - 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
    		 Lambda + Ribavirin + Daclatasvir (Substudy C)
    Number of subjects analysed
    24
    Units: Percentage of subjects
        number (confidence interval 80%)
    4.2 (0.4 to 15.3)
    No statistical analyses for this end point

    Secondary: Substudy C: Percentage of Non-Cirrhotic Genotype-1b Subjects With On-Treatment (Maximum of 12 Weeks) Interferon-Associated Symptoms

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    End point title
    		 Substudy C: Percentage of Non-Cirrhotic Genotype-1b Subjects With On-Treatment (Maximum of 12 Weeks) Interferon-Associated Symptoms [22]
    End point description
    Interferon-associated symptoms were evaluated as flu-like symptoms defined by pyrexia or chills or pain and musculoskeletal symptoms as defined by arthralgia or myalgia or back pain. Analysis population included all treated subjects, ie, randomised subjects who received at least 1 dose of the study drug. Response rates were assessed using modified Intent-to-Treat algorithm. The numerator was based on subjects with symptoms, and the denominator was based on all treated subjects.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    Notes
    [22] - 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
    		 Lambda + Ribavirin + Daclatasvir (Substudy C)
    Number of subjects analysed
    24
    Units: Percentage of subjects
    number (confidence interval 80%)
        Flu-like symptoms
    8.3 (2.2 to 20.7)
        Musculoskeletal symptoms
    12.5 (4.7 to 25.8)
    No statistical analyses for this end point

    Secondary: Substudy C: Number of Subjects With Adverse events (AEs), Deaths and Serious Adverse Events (SAEs)

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    End point title
    		 Substudy C: Number of Subjects With Adverse events (AEs), Deaths and Serious Adverse Events (SAEs) [23]
    End point description
    AE = any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE = a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalisation. Analysis population included all treated subjects, ie, randomised subjects who received at least 1 dose of the study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to end of treatment
    Notes
    [23] - 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
    		 Lambda + Ribavirin + Daclatasvir (Substudy C)
    Number of subjects analysed
    24
    Units: Number of Subjects
        AEs
    20
        SAEs
    0
        Deaths
    0
    No statistical analyses for this end point

    Secondary: Substudy C: Number of Subjects With Drug Related Adverse Events (AEs), Dose Reductions And Discontinuations Due to AE

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    End point title
    		 Substudy C: Number of Subjects With Drug Related Adverse Events (AEs), Dose Reductions And Discontinuations Due to AE [24]
    End point description
    AE = any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. Treatment-related = having certain, probable, possible, or unknown relationship to study drug. Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4=Life-threatening or disabling. Analysis population included all treated subjects, ie, randomised subjects who received at least 1 dose of the study drug.
    End point type
    Secondary
    End point timeframe
    Baseline up to end of treatment
    Notes
    [24] - 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
    		 Lambda + Ribavirin + Daclatasvir (Substudy C)
    Number of subjects analysed
    24
    Units: Number of Subjects
        Grade 2 to 4 Drug related AEs
    6
        Dose reduction
    1
        Discontinuation due to AEs
    0
    No statistical analyses for this end point

    Secondary: Substudy C: Percentage of Non-Cirrhotic Hepatitis C Virus (HCV) Genotype-1b Subjects With Psychiatric Symptoms (Depression or Irritability or Insomnia) Through The End of Treatment (Maximum of 12 Weeks)

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    End point title
    		 Substudy C: Percentage of Non-Cirrhotic Hepatitis C Virus (HCV) Genotype-1b Subjects With Psychiatric Symptoms (Depression or Irritability or Insomnia) Through The End of Treatment (Maximum of 12 Weeks) [25]
    End point description
    Interferon-associated symptoms were evaluated for psychiatric, neurologic, constitutional symptoms defined as depression or irritability or insomnia, headache or dizziness and fatigue or asthenia, respectively. Analysis population included all treated subjects, ie, randomised subjects who received at least 1 dose of the study drug. Response rates were assessed using modified Intent-to-Treat algorithm. The numerator was based on subjects with symptoms, and the denominator was based on all treated subjects.
    End point type
    Secondary
    End point timeframe
    Baseline up to Week 12
    Notes
    [25] - 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
    		 Lambda + Ribavirin + Daclatasvir (Substudy C)
    Number of subjects analysed
    24
    Units: Percentage of subjects
    number (confidence interval 80%)
        Psychiatric symptoms
    16.7 (7.5 to 30.6)
        Neurologic symptoms
    8.3 (2.2 to 20.7)
        Constitutional symptoms
    41.7 (27.7 to 56.7)
    No statistical analyses for this end point

    Secondary: Substudy C: Number of Subjects With Treatment Emergent Grade 3-4 Laboratory Abnormalities

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    End point title
    		 Substudy C: Number of Subjects With Treatment Emergent Grade 3-4 Laboratory Abnormalities [26]
    End point description
    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. International Normalized Ratio (INR): >2.0*Upper limit of normal (ULN); Hemoglobin: <9.0 g/dL; Alanine aminotransferase (ALT) : >5*ULN; Aspartate aminotransferase (AST): >5*ULN; Bilirubin (Total): >2.5*ULN. The analysis was performed on all subjects who received at least 1 dose of study therapy.
    End point type
    Secondary
    End point timeframe
    Baseline up to end of treatment
    Notes
    [26] - 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
    		 Lambda + Ribavirin + Daclatasvir (Substudy C)
    Number of subjects analysed
    24
    Units: Number of Subjects
        Hemoglobin (n=24)
    1
        Alanine aminotransferase (ALT) (n=24)
    1
        Aspartate aminotransferase (AST) (n=24)
    1
        Bilirubin, Total (n=24)
    1
        Bilirubin, Direct (n=11)
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to end of treatment
    Adverse event reporting additional description
    On-treatment period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Lambda + Ribavirin+ Asunaprevir (Global study +Japan substudy)
    Reporting group description
    		 Pegylated Interferon Lambda: solution, subcutaneous, 180 µg/mL, once weekly for up to 24 or 48 weeks (depending upon response); Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks ; Asunaprevir: tablets, oral, 200 mg, twice daily for up to 24 weeks; Placebo: Daclatasvir matching placebo, tablets, oral, once daily for up to 24 weeks. The arm consists of subjects from global study and Japan substudy.

    Reporting group title
    Lambda + Ribavirin+ Daclatasvir (Global study +Japan substudy)
    Reporting group description
    		 Pegylated Interferon Lambda: solution, subcutaneous, 180 µg/mL, once weekly for up to 24 or 48 weeks (depending upon response);Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Daclatasvir: tablets, oral, 60 mg, once daily for up to 24 weeks; Placebo: Asunaprevir matching placebo, tablets, oral, twice daily for up to 24 weeks. The arm consists of subjects from global study and Japan substudy.

    Reporting group title
    Alfa­2a +Ribavirin (Global study + Japan substudy)
    Reporting group description
    		 Pegylated Interferon Alfa­2a: solution, subcutaneous, 180 µg/mL, once weekly for up to 48 weeks; Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for up to 48 weeks; Asunaprevir matching placebo: tablets, oral, twice daily for up to 24 weeks; Daclatasvir matching ­placebo: tablets, oral, once daily for up to 24 weeks. The arm consists of subjects from global study and japan substudy.

    Reporting group title
    Lambda +Ribavirin +Daclatasvir (Substudy C)
    Reporting group description
    		 Pegylated Interferon Lambda: solution, subcutaneous, 180 µg/mL, once weekly for 12 weeks; Ribavirin: tablets, oral, 1000 or 1200 mg based on weight, twice daily for 12 weeks; Daclatasvir: tablets, oral, 60 mg, once daily for up to 12 weeks.

    Serious adverse events
    		 Lambda + Ribavirin+ Asunaprevir (Global study +Japan substudy) Lambda + Ribavirin+ Daclatasvir (Global study +Japan substudy) Alfa­2a +Ribavirin (Global study + Japan substudy) Lambda +Ribavirin +Daclatasvir (Substudy C)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 44 (9.09%)
    2 / 49 (4.08%)
    0 / 47 (0.00%)
    0 / 24 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    3 / 44 (6.82%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    2 / 44 (4.55%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases abnormal
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 49 (2.04%)
    0 / 47 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer in situ
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 49 (2.04%)
    0 / 47 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 44 (2.27%)
    1 / 49 (2.04%)
    0 / 47 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Enterocolitis infectious
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Lambda + Ribavirin+ Asunaprevir (Global study +Japan substudy) Lambda + Ribavirin+ Daclatasvir (Global study +Japan substudy) Alfa­2a +Ribavirin (Global study + Japan substudy) Lambda +Ribavirin +Daclatasvir (Substudy C)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    39 / 44 (88.64%)
    47 / 49 (95.92%)
    47 / 47 (100.00%)
    18 / 24 (75.00%)
    General disorders and administration site conditions
    Dry mouth
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 49 (0.00%)
    3 / 47 (6.38%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Fatigue
         subjects affected / exposed
    12 / 44 (27.27%)
    15 / 49 (30.61%)
    19 / 47 (40.43%)
    2 / 24 (8.33%)
         occurrences all number
    12
    16
    19
    2
    Asthenia
         subjects affected / exposed
    7 / 44 (15.91%)
    9 / 49 (18.37%)
    7 / 47 (14.89%)
    8 / 24 (33.33%)
         occurrences all number
    7
    10
    9
    8
    Injection site erythema
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 49 (4.08%)
    6 / 47 (12.77%)
    1 / 24 (4.17%)
         occurrences all number
    0
    2
    7
    1
    Chills
         subjects affected / exposed
    0 / 44 (0.00%)
    2 / 49 (4.08%)
    7 / 47 (14.89%)
    1 / 24 (4.17%)
         occurrences all number
    0
    2
    7
    1
    Malaise
         subjects affected / exposed
    4 / 44 (9.09%)
    1 / 49 (2.04%)
    7 / 47 (14.89%)
    1 / 24 (4.17%)
         occurrences all number
    4
    1
    7
    1
    Pyrexia
         subjects affected / exposed
    2 / 44 (4.55%)
    3 / 49 (6.12%)
    10 / 47 (21.28%)
    1 / 24 (4.17%)
         occurrences all number
    5
    5
    12
    3
    Feeling Hot
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 49 (0.00%)
    3 / 47 (6.38%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Influenza like illness
         subjects affected / exposed
    4 / 44 (9.09%)
    0 / 49 (0.00%)
    8 / 47 (17.02%)
    0 / 24 (0.00%)
         occurrences all number
    4
    0
    8
    0
    Injection site rash
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 49 (2.04%)
    3 / 47 (6.38%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Injection site reaction
         subjects affected / exposed
    1 / 44 (2.27%)
    2 / 49 (4.08%)
    3 / 47 (6.38%)
    0 / 24 (0.00%)
         occurrences all number
    1
    2
    3
    0
    Pain
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 49 (0.00%)
    3 / 47 (6.38%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    4 / 44 (9.09%)
    1 / 49 (2.04%)
    8 / 47 (17.02%)
    2 / 24 (8.33%)
         occurrences all number
    4
    1
    8
    2
    Cough
         subjects affected / exposed
    3 / 44 (6.82%)
    7 / 49 (14.29%)
    10 / 47 (21.28%)
    1 / 24 (4.17%)
         occurrences all number
    3
    7
    10
    1
    Oropharyngeal pain
         subjects affected / exposed
    3 / 44 (6.82%)
    0 / 49 (0.00%)
    6 / 47 (12.77%)
    0 / 24 (0.00%)
         occurrences all number
    3
    0
    7
    0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 49 (2.04%)
    3 / 47 (6.38%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    3
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    9 / 44 (20.45%)
    13 / 49 (26.53%)
    13 / 47 (27.66%)
    3 / 24 (12.50%)
         occurrences all number
    9
    14
    13
    3
    Irritability
         subjects affected / exposed
    7 / 44 (15.91%)
    10 / 49 (20.41%)
    10 / 47 (21.28%)
    1 / 24 (4.17%)
         occurrences all number
    7
    10
    10
    1
    Sleep disorder
         subjects affected / exposed
    1 / 44 (2.27%)
    3 / 49 (6.12%)
    5 / 47 (10.64%)
    1 / 24 (4.17%)
         occurrences all number
    1
    3
    5
    1
    Depressed mood
         subjects affected / exposed
    1 / 44 (2.27%)
    3 / 49 (6.12%)
    5 / 47 (10.64%)
    0 / 24 (0.00%)
         occurrences all number
    1
    3
    5
    0
    Depression
         subjects affected / exposed
    2 / 44 (4.55%)
    5 / 49 (10.20%)
    3 / 47 (6.38%)
    0 / 24 (0.00%)
         occurrences all number
    2
    5
    3
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 44 (13.64%)
    1 / 49 (2.04%)
    0 / 47 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    6
    1
    0
    0
    Blood bilirubin increased
         subjects affected / exposed
    3 / 44 (6.82%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    4
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    7 / 44 (15.91%)
    1 / 49 (2.04%)
    0 / 47 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    7
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 44 (0.00%)
    3 / 49 (6.12%)
    6 / 47 (12.77%)
    0 / 24 (0.00%)
         occurrences all number
    0
    3
    6
    0
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    2 / 44 (4.55%)
    4 / 49 (8.16%)
    6 / 47 (12.77%)
    2 / 24 (8.33%)
         occurrences all number
    2
    4
    7
    2
    Dizziness
         subjects affected / exposed
    6 / 44 (13.64%)
    1 / 49 (2.04%)
    6 / 47 (12.77%)
    1 / 24 (4.17%)
         occurrences all number
    6
    1
    6
    1
    Headache
         subjects affected / exposed
    7 / 44 (15.91%)
    15 / 49 (30.61%)
    24 / 47 (51.06%)
    1 / 24 (4.17%)
         occurrences all number
    12
    20
    24
    1
    Hyperaesthesia
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 49 (0.00%)
    3 / 47 (6.38%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Lethargy
         subjects affected / exposed
    1 / 44 (2.27%)
    0 / 49 (0.00%)
    3 / 47 (6.38%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    3
    0
    Syncope
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 49 (0.00%)
    3 / 47 (6.38%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 44 (4.55%)
    5 / 49 (10.20%)
    3 / 47 (6.38%)
    1 / 24 (4.17%)
         occurrences all number
    2
    5
    3
    1
    Neutropenia
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 49 (0.00%)
    11 / 47 (23.40%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    12
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    4 / 44 (9.09%)
    2 / 49 (4.08%)
    4 / 47 (8.51%)
    0 / 24 (0.00%)
         occurrences all number
    4
    3
    4
    0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    8 / 44 (18.18%)
    7 / 49 (14.29%)
    12 / 47 (25.53%)
    4 / 24 (16.67%)
         occurrences all number
    10
    7
    14
    15
    Abdominal pain upper
         subjects affected / exposed
    5 / 44 (11.36%)
    6 / 49 (12.24%)
    2 / 47 (4.26%)
    3 / 24 (12.50%)
         occurrences all number
    5
    6
    2
    3
    Nausea
         subjects affected / exposed
    12 / 44 (27.27%)
    14 / 49 (28.57%)
    9 / 47 (19.15%)
    2 / 24 (8.33%)
         occurrences all number
    14
    15
    9
    2
    Toothache
         subjects affected / exposed
    0 / 44 (0.00%)
    1 / 49 (2.04%)
    3 / 47 (6.38%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    4
    1
    Vomiting
         subjects affected / exposed
    5 / 44 (11.36%)
    4 / 49 (8.16%)
    5 / 47 (10.64%)
    1 / 24 (4.17%)
         occurrences all number
    6
    6
    9
    1
    Abdominal Discomfort
         subjects affected / exposed
    4 / 44 (9.09%)
    1 / 49 (2.04%)
    0 / 47 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    4
    1
    0
    0
    Cheilitis
         subjects affected / exposed
    0 / 44 (0.00%)
    3 / 49 (6.12%)
    3 / 47 (6.38%)
    0 / 24 (0.00%)
         occurrences all number
    0
    3
    3
    0
    Abdominal pain
         subjects affected / exposed
    1 / 44 (2.27%)
    2 / 49 (4.08%)
    4 / 47 (8.51%)
    0 / 24 (0.00%)
         occurrences all number
    1
    2
    5
    0
    Constipation
         subjects affected / exposed
    2 / 44 (4.55%)
    2 / 49 (4.08%)
    5 / 47 (10.64%)
    0 / 24 (0.00%)
         occurrences all number
    2
    2
    5
    0
    Gastroesophageal reflux disease
         subjects affected / exposed
    1 / 44 (2.27%)
    4 / 49 (8.16%)
    2 / 47 (4.26%)
    0 / 24 (0.00%)
         occurrences all number
    1
    4
    2
    0
    Dyspepsia
         subjects affected / exposed
    4 / 44 (9.09%)
    1 / 49 (2.04%)
    4 / 47 (8.51%)
    0 / 24 (0.00%)
         occurrences all number
    4
    1
    4
    0
    Mouth ulceration
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 49 (0.00%)
    4 / 47 (8.51%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    9
    0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    6 / 44 (13.64%)
    3 / 49 (6.12%)
    0 / 47 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    10
    3
    0
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    8 / 44 (18.18%)
    17 / 49 (34.69%)
    16 / 47 (34.04%)
    5 / 24 (20.83%)
         occurrences all number
    10
    19
    19
    5
    Dry skin
         subjects affected / exposed
    3 / 44 (6.82%)
    8 / 49 (16.33%)
    10 / 47 (21.28%)
    5 / 24 (20.83%)
         occurrences all number
    3
    8
    10
    5
    Hyperhidrosis
         subjects affected / exposed
    2 / 44 (4.55%)
    1 / 49 (2.04%)
    3 / 47 (6.38%)
    1 / 24 (4.17%)
         occurrences all number
    2
    1
    4
    1
    Rash
         subjects affected / exposed
    4 / 44 (9.09%)
    8 / 49 (16.33%)
    9 / 47 (19.15%)
    1 / 24 (4.17%)
         occurrences all number
    5
    8
    9
    1
    Alopecia
         subjects affected / exposed
    2 / 44 (4.55%)
    2 / 49 (4.08%)
    9 / 47 (19.15%)
    0 / 24 (0.00%)
         occurrences all number
    2
    2
    9
    0
    Eczema
         subjects affected / exposed
    1 / 44 (2.27%)
    3 / 49 (6.12%)
    3 / 47 (6.38%)
    0 / 24 (0.00%)
         occurrences all number
    1
    3
    3
    0
    Erythema
         subjects affected / exposed
    4 / 44 (9.09%)
    1 / 49 (2.04%)
    1 / 47 (2.13%)
    0 / 24 (0.00%)
         occurrences all number
    4
    2
    1
    0
    Rash maculo-papular
         subjects affected / exposed
    2 / 44 (4.55%)
    1 / 49 (2.04%)
    4 / 47 (8.51%)
    0 / 24 (0.00%)
         occurrences all number
    2
    1
    4
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 44 (11.36%)
    6 / 49 (12.24%)
    14 / 47 (29.79%)
    3 / 24 (12.50%)
         occurrences all number
    5
    7
    15
    3
    Myalgia
         subjects affected / exposed
    4 / 44 (9.09%)
    9 / 49 (18.37%)
    12 / 47 (25.53%)
    3 / 24 (12.50%)
         occurrences all number
    4
    11
    12
    3
    Back pain
         subjects affected / exposed
    3 / 44 (6.82%)
    4 / 49 (8.16%)
    3 / 47 (6.38%)
    0 / 24 (0.00%)
         occurrences all number
    3
    4
    4
    0
    Muscle spasms
         subjects affected / exposed
    0 / 44 (0.00%)
    3 / 49 (6.12%)
    4 / 47 (8.51%)
    0 / 24 (0.00%)
         occurrences all number
    0
    4
    4
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 44 (2.27%)
    2 / 49 (4.08%)
    3 / 47 (6.38%)
    0 / 24 (0.00%)
         occurrences all number
    1
    2
    3
    0
    Pain in extremity
         subjects affected / exposed
    1 / 44 (2.27%)
    2 / 49 (4.08%)
    3 / 47 (6.38%)
    0 / 24 (0.00%)
         occurrences all number
    1
    2
    3
    0
    Infections and infestations
    Influenza
         subjects affected / exposed
    0 / 44 (0.00%)
    0 / 49 (0.00%)
    3 / 47 (6.38%)
    0 / 24 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Nasopharyngitis
         subjects affected / exposed
    4 / 44 (9.09%)
    4 / 49 (8.16%)
    2 / 47 (4.26%)
    0 / 24 (0.00%)
         occurrences all number
    4
    7
    4
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    6 / 44 (13.64%)
    7 / 49 (14.29%)
    11 / 47 (23.40%)
    2 / 24 (8.33%)
         occurrences all number
    6
    7
    11
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Dec 2010
    Permitted the collection and storage of blood samples for use in future exploratory pharmacogenetics research.
    14 Feb 2011
    Randomised 21 additional Japanese subjects in Part A only of this study.
    17 May 2011
    The purpose of this amendment was to require blood samples for Hepatitis C virus (HCV) RNA and HCV resistance testing at treatment Weeks 16 and 20 for study subjects treated with direct antiviral agents (DAAs) for >16 weeks duration; Require a blood sample for pegylated interferon (pegIFN) lambda or pegIFN Alfa­2a at 168 hours post­dosing Week 4 in the Part A and B pharmacokinetic sub­studies; Include criteria for the Definition and reporting of potential drug­induced liver injury; Modify Part A futility criteria to allow subjects randomised to the reference regimen (Pegylated interferon Alfa ­2a + ribavirin) who exhibit Week 12 treatment futility criteria to be discontinued from treatment at Week 16 and provided the option to participate in a future open­label roll­over study with a DAA based regimen; Modify the definition for relapse to undetectable Hepatitis C virus (HCV) RNA at end of treatment followed by detectable HCV RNA in any follow­up visit window; Modify the efficacy criteria to proceed from Part A to Part B based on achieving a Part A protocol defined response rate of no less than 50% instead of 65% for each experimental cohort; Modify the requirement for pregnancy testing in women of childbearing potential from weekly to monthly during treatment; Remove the requirement for a second set of local laboratory assessments to be performed at the site’s local laboratory after Week 12; Restrict the use of sensitive CYP2D6 substrates such as desipramine, dextromethorphan, and atomoxetine with BMS­650032.
    25 Jul 2011
    Allowed systemic antibiotics and antivirals without anti­Hepatitis C virus activity to be used with caution instead of prohibited in Japanese subjects during the study.
    12 Mar 2012
    Added interim analyses with unblinded data after all subjects (including Japanese sub­study subjects) in Part A on arms containing Pegylated Interferon Lambda that achieve Part A PDR complete 4 and 12 weeks of follow­up to evaluate early sustained virologic response (SVR). SVR4 and SVR12 have a good correlation with SVR24 success.

    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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