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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Controlled Study Evaluating the Efficacy and Safety of Peginterferon Lambda-1a, with and without Daclatasvir, Compared to Peginterferon Alfa-2a, Each in Combination with Ribavirin, in the Treatment of Naïve Genotype 2 and 3 Chronic Hepatitis C Subjects.

    Summary
    EudraCT number
    		 2011-004885-14
    Trial protocol
    		 GB   BE   FI   NL   IT   GR  
    Global end of trial date
    24 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
    AI452-017
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01616524
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol-Myers Squibb
    Sponsor organisation address
    Chaussee de la Hulpe 185, Brussels, Belgium, 1170
    Public contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, clinical.trials@bms.com
    Scientific contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, clinical.trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 Sep 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate in treatment naive subjects with chronic hepatitis c virus (HCV) genotype (GT)-2 or -3 infection: 1) Sustained virologic response rate at post-treatment week 12 (SVR12) following 24 weeks of treatment with pegylated interferon lambda-1a/ribavirin and the SVR12 following 24 weeks of treatment with pegylated interferon alfa-2a/ribavirin (alfa-2a/RBV). 2) SVR12 following 12 weeks of treatment with pegylated interferon lambda-1a/ribavirin/daclatasvir and the SVR12 following 24 weeks of treatment with alfa-2a/RBV.
    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
    20 Jul 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 79
    Country: Number of subjects enrolled
    Australia: 143
    Country: Number of subjects enrolled
    Belgium: 19
    Country: Number of subjects enrolled
    Finland: 16
    Country: Number of subjects enrolled
    France: 55
    Country: Number of subjects enrolled
    United Kingdom: 38
    Country: Number of subjects enrolled
    Greece: 17
    Country: Number of subjects enrolled
    Hong Kong: 10
    Country: Number of subjects enrolled
    Italy: 62
    Country: Number of subjects enrolled
    Japan: 103
    Country: Number of subjects enrolled
    Korea, Republic of: 169
    Country: Number of subjects enrolled
    Mexico: 59
    Country: Number of subjects enrolled
    Netherlands: 10
    Country: Number of subjects enrolled
    New Zealand: 6
    Country: Number of subjects enrolled
    Russian Federation: 191
    Country: Number of subjects enrolled
    Singapore: 17
    Country: Number of subjects enrolled
    Taiwan: 59
    Country: Number of subjects enrolled
    United States: 190
    Worldwide total number of subjects
    1243
    EEA total number of subjects
    217
    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)
    1148
    From 65 to 84 years
    95
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study was conducted at 124 centers in 18 countries.

    Pre-assignment
    Screening details
    		 1243 subjects were enrolled, of which 880 subjects were randomized and 874 received study treatment (353: peginterferon lambda-1a+ribavirin+placebo, 349: peginterferon lambda-1a+ribavirin+ daclatasvir, 172: peginterferon alfa-2a+ribavirin+placebo, remaining 6 subjects either no longer met study criteria, or withdrew consent or lost to follow-up).

    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, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PegIFN Lambda-1a+Ribavirin+Placebo
    Arm description
    		 Subjects received pegIFN lambda-1a solution for injection 180 µg subcutaneously, once weekly, with placebo matched with daclatasvir tablets orally, once daily and ribavirin tablets 400 mg orally, twice daily, for up to 12 weeks. Subjects continued to receive pegIFN lambda-1a with ribavirin for an additional 12 weeks and followed-up for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Peginterferon Lambda-1a
    Investigational medicinal product code
    BMS-914143
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Self-administration of peginterferon lambda -1a 180 µg subcutaneous injection once in a week.

    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
    Ribavirin 400 mg was administered twice daily (2 tablets of 200 mg in the morning with food and 2 tablets of 200 mg in the evening with food).

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to daclatasvir was administered once daily with or without a meal.

    Arm title
    		 PegIFNλ-1a+Ribavirin+Daclatasvir
    Arm description
    		 Subjects received pegIFN lambda-1a solution for injection 180 µg subcutaneously, once weekly, with daclatasvir tablets 60 mg orally, once daily and ribavirin tablets 400 mg orally, twice daily, for up to 12 weeks and followed-up for 48 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Peginterferon Lambda -1a
    Investigational medicinal product code
    BMS-914143
    Other name
    Lambda
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Self-administration of peginterferon lamda-1a 180 µg subcutaneous injection once in a week.

    Investigational medicinal product name
    Daclatasvir
    Investigational medicinal product code
    BMS-790052
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Daclatasvir 60 mg was administered orally once daily with or without a meal.

    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
    Ribavirin 400 mg was administered twice daily (2 tablets of 200 mg in the morning with food and 2 tablets of 200 mg in the evening with food).

    Arm title
    		 PegIFN alfa-2a+Ribavirin+Placebo
    Arm description
    		 Subjects received pegIFN alfa-2a solution for injection 180 µg subcutaneously, once weekly, with placebo matched with daclatasvir tablets orally, once daily and ribavirin tablets 400 mg orally, twice daily, for up to 12 weeks. Subjects continued to receive pegIFN alfa-2a with ribavirin for an additional 12 weeks and followed-up for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Peginterferon Alfa-2a
    Investigational medicinal product code
    Other name
    Pegasys
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Self-administration of peginterferon Alfa-2a 180 µg subcutaneous injection once in a week.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to daclatasvir was administered once daily with or without a meal.

    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
    Ribavirin 400 mg was administered twice daily (2 tablets of 200 mg in the morning with food and 2 tablets of 200 mg in the evening with food).

    Number of subjects in period 1 [1]
    		PegIFN Lambda-1a+Ribavirin+Placebo PegIFNλ-1a+Ribavirin+Daclatasvir PegIFN alfa-2a+Ribavirin+Placebo
    Started
    353
    349
    172
    Completed
    311
    331
    153
    Not completed
    42
    18
    19
         Consent withdrawn by subject
    2
    2
    2
         Adverse event, non-fatal
    26
    10
    15
         Subject request
    3
    -
    -
         No longer meets study criteria
    3
    1
    -
         Unspecified
    1
    -
    -
         Lost to follow-up
    2
    -
    -
         Poor/non-compliance
    1
    1
    -
         Lack of efficacy
    4
    4
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Out of 1243 subjects enrolled, 880 subjects were randomised and 874 received study treatment.
    Period 2
    Period 2 title
    Follow-up period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PegIFN Lambda-1a+Ribavirin+Placebo
    Arm description
    		 Subjects received pegIFN lambda-1a solution for injection 180 µg subcutaneously, once weekly, with placebo matched with daclatasvir tablets orally, once daily and ribavirin tablets 400 mg orally, twice daily, for up to 12 weeks. Subjects continued to receive pegIFN lambda-1a with ribavirin for an additional 12 weeks and followed-up for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Peginterferon Lambda-1a
    Investigational medicinal product code
    BMS-914143
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Self-administration of peginterferon lambda -1a 180 µg subcutaneous injection once in a week.

    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
    Ribavirin 400 mg was administered twice daily (2 tablets of 200 mg in the morning with food and 2 tablets of 200 mg in the evening with food).

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to daclatasvir was administered once daily with or without a meal.

    Arm title
    		 PegIFNλ-1a+Ribavirin+Daclatasvir
    Arm description
    		 Subjects received pegIFN lambda-1a solution for injection 180 µg subcutaneously, once weekly, with daclatasvir tablets 60 mg orally, once daily and ribavirin tablets 400 mg orally, twice daily, for up to 12 weeks and followed-up for 48 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Peginterferon Lambda -1a
    Investigational medicinal product code
    BMS-914143
    Other name
    Lambda
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Self-administration of peginterferon lamda-1a 180 µg subcutaneous injection once in a week.

    Investigational medicinal product name
    Daclatasvir
    Investigational medicinal product code
    BMS-790052
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Daclatasvir 60 mg was administered orally once daily with or without a meal.

    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
    Ribavirin 400 mg was administered twice daily (2 tablets of 200 mg in the morning with food and 2 tablets of 200 mg in the evening with food).

    Arm title
    		 PegIFN alfa-2a+Ribavirin+Placebo
    Arm description
    		 Subjects received pegIFN alfa-2a solution for injection 180 µg subcutaneously, once weekly, with placebo matched with daclatasvir tablets orally, once daily and ribavirin tablets 400 mg orally, twice daily, for up to 12 weeks. Subjects continued to receive pegIFN alfa-2a with ribavirin for an additional 12 weeks and followed-up for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Peginterferon Alfa-2a
    Investigational medicinal product code
    Other name
    Pegasys
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Self-administration of peginterferon Alfa-2a 180 µg subcutaneous injection once in a week.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to daclatasvir was administered once daily with or without a meal.

    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
    Ribavirin 400 mg was administered twice daily (2 tablets of 200 mg in the morning with food and 2 tablets of 200 mg in the evening with food).

    Number of subjects in period 2
    		PegIFN Lambda-1a+Ribavirin+Placebo PegIFNλ-1a+Ribavirin+Daclatasvir PegIFN alfa-2a+Ribavirin+Placebo
    Started
    311
    331
    153
    Completed
    313
    324
    159
    Not completed
    30
    18
    9
         Consent withdrawn by subject
    6
    1
    2
         Death
    -
    1
    -
         Follow-up no longer required per protocol
    6
    7
    1
         Unspecified
    6
    4
    1
         Lost to follow-up
    12
    5
    5
    Joined
    32
    11
    15
         Rejoined for follow-up
    32
    11
    15

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PegIFN Lambda-1a+Ribavirin+Placebo
    Reporting group description
    		 Subjects received pegIFN lambda-1a solution for injection 180 µg subcutaneously, once weekly, with placebo matched with daclatasvir tablets orally, once daily and ribavirin tablets 400 mg orally, twice daily, for up to 12 weeks. Subjects continued to receive pegIFN lambda-1a with ribavirin for an additional 12 weeks and followed-up for 24 weeks.

    Reporting group title
    PegIFNλ-1a+Ribavirin+Daclatasvir
    Reporting group description
    		 Subjects received pegIFN lambda-1a solution for injection 180 µg subcutaneously, once weekly, with daclatasvir tablets 60 mg orally, once daily and ribavirin tablets 400 mg orally, twice daily, for up to 12 weeks and followed-up for 48 weeks.

    Reporting group title
    PegIFN alfa-2a+Ribavirin+Placebo
    Reporting group description
    		 Subjects received pegIFN alfa-2a solution for injection 180 µg subcutaneously, once weekly, with placebo matched with daclatasvir tablets orally, once daily and ribavirin tablets 400 mg orally, twice daily, for up to 12 weeks. Subjects continued to receive pegIFN alfa-2a with ribavirin for an additional 12 weeks and followed-up for 24 weeks.

    Reporting group values
    		 PegIFN Lambda-1a+Ribavirin+Placebo PegIFNλ-1a+Ribavirin+Daclatasvir PegIFN alfa-2a+Ribavirin+Placebo Total
    Number of subjects
    		 353 349 172 874
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 331 321 166 818
        From 65-84 years
    		 22 28 6 56
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 47.8 ( 11.28 ) 47.4 ( 11.96 ) 46.2 ( 11.45 ) -
    Gender categorical
    Units: Subjects
        Female
    		 143 154 79 376
        Male
    		 210 195 93 498

    End points

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    End points reporting groups
    Reporting group title
    PegIFN Lambda-1a+Ribavirin+Placebo
    Reporting group description
    		 Subjects received pegIFN lambda-1a solution for injection 180 µg subcutaneously, once weekly, with placebo matched with daclatasvir tablets orally, once daily and ribavirin tablets 400 mg orally, twice daily, for up to 12 weeks. Subjects continued to receive pegIFN lambda-1a with ribavirin for an additional 12 weeks and followed-up for 24 weeks.

    Reporting group title
    PegIFNλ-1a+Ribavirin+Daclatasvir
    Reporting group description
    		 Subjects received pegIFN lambda-1a solution for injection 180 µg subcutaneously, once weekly, with daclatasvir tablets 60 mg orally, once daily and ribavirin tablets 400 mg orally, twice daily, for up to 12 weeks and followed-up for 48 weeks.

    Reporting group title
    PegIFN alfa-2a+Ribavirin+Placebo
    Reporting group description
    		 Subjects received pegIFN alfa-2a solution for injection 180 µg subcutaneously, once weekly, with placebo matched with daclatasvir tablets orally, once daily and ribavirin tablets 400 mg orally, twice daily, for up to 12 weeks. Subjects continued to receive pegIFN alfa-2a with ribavirin for an additional 12 weeks and followed-up for 24 weeks.
    Reporting group title
    PegIFN Lambda-1a+Ribavirin+Placebo
    Reporting group description
    		 Subjects received pegIFN lambda-1a solution for injection 180 µg subcutaneously, once weekly, with placebo matched with daclatasvir tablets orally, once daily and ribavirin tablets 400 mg orally, twice daily, for up to 12 weeks. Subjects continued to receive pegIFN lambda-1a with ribavirin for an additional 12 weeks and followed-up for 24 weeks.

    Reporting group title
    PegIFNλ-1a+Ribavirin+Daclatasvir
    Reporting group description
    		 Subjects received pegIFN lambda-1a solution for injection 180 µg subcutaneously, once weekly, with daclatasvir tablets 60 mg orally, once daily and ribavirin tablets 400 mg orally, twice daily, for up to 12 weeks and followed-up for 48 weeks.

    Reporting group title
    PegIFN alfa-2a+Ribavirin+Placebo
    Reporting group description
    		 Subjects received pegIFN alfa-2a solution for injection 180 µg subcutaneously, once weekly, with placebo matched with daclatasvir tablets orally, once daily and ribavirin tablets 400 mg orally, twice daily, for up to 12 weeks. Subjects continued to receive pegIFN alfa-2a with ribavirin for an additional 12 weeks and followed-up for 24 weeks.

    Primary: Percentage of Chronically Infected Genotype 2 and 3 Subjects With Sustained Virologic Response at Follow-up Week 12 (SVR12)

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    End point title
    		 Percentage of Chronically Infected Genotype 2 and 3 Subjects With Sustained Virologic Response at Follow-up Week 12 (SVR12)
    End point description
    SVR12 was defined as Hepatitis C virus (HCV) RNA <lower limit of quantitation (LLOQ), target detected (TD) or target not detected (TND) at follow-up Week 12. The LLOQ was 25 international units per milliliter (IU/mL). HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. The analysis was performed in modified intent-to-treat (ITT) population, the numerator was based on subjects meeting the response criteria and denominator based on all treated subjects.
    End point type
    Primary
    End point timeframe
    Follow-up Week 12
    End point values
    		 PegIFN Lambda-1a+Ribavirin+Placebo PegIFNλ-1a+Ribavirin+Daclatasvir PegIFN alfa-2a+Ribavirin+Placebo
    Number of subjects analysed
    353
    349
    172
    Units: Percentage of subjects
        number (confidence interval 95%)
    68 (63.1 to 72.9)
    82.5 (78.5 to 86.5)
    73.3 (66.6 to 79.9)
    Statistical analysis title
    		 Treatment difference in SVR12
    Statistical analysis description
    The treatment difference in SVR12 response rates and its two-sided 97.5% CI were estimated using a stratum-adjusted Mantel-Haenszel (MH) approach stratified by HCV GT-2 or -3, baseline HCV RNA (< 800,000 or ≥ 800,000 IU/mL), cirrhosis status and region (Japan/ROW) using modified ITT.
    Comparison groups
    PegIFN Lambda-1a+Ribavirin+Placebo v PegIFN alfa-2a+Ribavirin+Placebo
    Number of subjects included in analysis
    525
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Percentage difference
    Point estimate
    -5.8
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -14.9
         upper limit
    		 3.4
    Notes
    [1] - Non-inferiority of PegIFN Lambda-1a+Ribavirin+Placebo to PegIFN alfa-2a+Ribavirin+Placebo was not demonstrated because the 97.5% CI lower limit was <=10%. Therefore, the second stage test for superiority was not conducted. No further hierarchical testing of secondary endpoints was conducted.
    Statistical analysis title
    		 Treatment difference in SVR12
    Statistical analysis description
    The treatment difference in SVR12 response rates and its two-sided 97.5% CI were estimated using a stratum-adjusted MH approach stratified by HCV GT-2 or -3, baseline HCV RNA, cirrhosis status and region using modified ITT.
    Comparison groups
    PegIFNλ-1a+Ribavirin+Daclatasvir v PegIFN alfa-2a+Ribavirin+Placebo
    Number of subjects included in analysis
    521
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Percentage difference
    Point estimate
    9
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 17.6
    Notes
    [2] - Both non-inferiority and superiority of PegIFNλ-1a+Ribavirin+Daclatasvir to PegIFN alfa-2a+Ribavirin+Placebo were demonstrated because the 97.5% CI lower limit was >0.

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

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    End point title
    		 Percentage of Subjects With Rapid Virologic Response (RVR)
    End point description
    RVR was defined as undetectable HCV RNA <LLOQ, TND at Week 4. The LLOQ was 25 IU/mL. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. The analysis was performed in modified ITT population, the numerator was based on subjects meeting the response criteria and denominator based on all treated subjects.
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    		 PegIFN Lambda-1a+Ribavirin+Placebo PegIFNλ-1a+Ribavirin+Daclatasvir PegIFN alfa-2a+Ribavirin+Placebo
    Number of subjects analysed
    353
    349
    172
    Units: Percentage of subjects
        number (confidence interval 95%)
    64.3 (59.3 to 69.3)
    85.7 (82 to 89.3)
    57.6 (50.2 to 64.9)
    Statistical analysis title
    		 Treatment difference in RVR
    Statistical analysis description
    The treatment difference in RVR response rates and its two-sided 97.5% CI were estimated using a stratum-adjusted MH approach stratified by HCV GT-2 or -3, baseline HCV RNA, cirrhosis status and region using modified ITT.
    Comparison groups
    PegIFN alfa-2a+Ribavirin+Placebo v PegIFNλ-1a+Ribavirin+Daclatasvir
    Number of subjects included in analysis
    521
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Percentage difference
    Point estimate
    27.9
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 18.7
         upper limit
    		 37.1
    Notes
    [3] - Both non-inferiority and superiority of PegIFNλ-1a+Ribavirin+Daclatasvir to PegIFN alfa-2a+Ribavirin+Placebo were demonstrated because the 97.5% CI lower limit was >0.

    Secondary: Percentage of Subjects With Treatment Emergent Cytopenic Abnormalities

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    End point title
    		 Percentage of Subjects With Treatment Emergent Cytopenic Abnormalities
    End point description
    Cytopenic abnormalities included anemia as defined by haemoglobin (Hb) <10 g/dL, neutropenia as defined by absolute neutrophil count (ANC) <750 mm3 or thrombocytopenia as defined by platelets <50,000 mm3. The analysis was performed in modified ITT population, the numerator was based on subjects having cytopenic abnormalities and denominator based on all treated subjects.
    End point type
    Secondary
    End point timeframe
    Up to End of Treatment (Week 12 or 24)
    End point values
    		 PegIFN Lambda-1a+Ribavirin+Placebo PegIFNλ-1a+Ribavirin+Daclatasvir PegIFN alfa-2a+Ribavirin+Placebo
    Number of subjects analysed
    353
    349
    172
    Units: Percentage of subjects
        number (confidence interval 95%)
    2.8 (1.1 to 4.6)
    2 (0.5 to 3.5)
    36.6 (29.4 to 43.8)
    Statistical analysis title
    		 Treatment difference in cytopenic abnormalities
    Statistical analysis description
    The treatment difference in cytopenic abnormality rates and its two-sided 97.5% CI were estimated using a stratum-adjusted Mantel-Haenszel (MH) approach stratified by HCV GT-2 or -3, baseline HCV RNA, cirrhosis status and region using modified ITT.
    Comparison groups
    PegIFNλ-1a+Ribavirin+Daclatasvir v PegIFN alfa-2a+Ribavirin+Placebo
    Number of subjects included in analysis
    521
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Percentage difference
    Point estimate
    -34.4
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -42.4
         upper limit
    		 -26.4
    Notes
    [4] - Superiority of PegIFNλ-1a+Ribavirin+Daclatasvir to PegIFN alfa-2a+Ribavirin+Placebo was demonstrated because the 97.5% CI upper limit was <0.

    Secondary: Percentage of Subjects With Sustained Virologic Response Rate at Follow-up Week 12 (SVR12) For Genotype 3 Chronic Hepatitis C Virus (HCV) Infection

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    End point title
    		 Percentage of Subjects With Sustained Virologic Response Rate at Follow-up Week 12 (SVR12) For Genotype 3 Chronic Hepatitis C Virus (HCV) Infection
    End point description
    SVR12 rate was defined HCV RNA <LLOQ TD or TND at follow-up Week 12. The LLOQ was 25 IU/mL. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. The analysis was performed in modified ITT population, the numerator was based on subjects meeting the response criteria and denominator based on all treated subjects with HCV genotype 3. Missing values were imputed using backward imputation technique
    End point type
    Secondary
    End point timeframe
    Follow-up Week 12
    End point values
    		 PegIFN Lambda-1a+Ribavirin+Placebo PegIFNλ-1a+Ribavirin+Daclatasvir PegIFN alfa-2a+Ribavirin+Placebo
    Number of subjects analysed
    170
    165
    81
    Units: Percentage of subjects
        number (confidence interval 95%)
    64.1 (56.9 to 71.3)
    74.5 (67.9 to 81.2)
    72.8 (63.2 to 82.5)
    Statistical analysis title
    		 Treatment difference in SVR12
    Statistical analysis description
    The treatment difference in SVR12 response rates and its two-sided 97.5% CI were estimated using a stratum-adjusted Mantel-Haenszel (MH) approach stratified by HCV GT-2 or -3, baseline HCV RNA, cirrhosis status and region using modified ITT.
    Comparison groups
    PegIFNλ-1a+Ribavirin+Daclatasvir v PegIFN alfa-2a+Ribavirin+Placebo
    Number of subjects included in analysis
    246
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Percentage difference
    Point estimate
    1.4
    Confidence interval
         level
    		 97.5%
         sides
    2-sided
         lower limit
    		 -11.5
         upper limit
    		 14.3
    Notes
    [5] - Non-inferiority of PegIFN Lambda-1a+Ribavirin+Daclatasvir to PegIFN alfa-2a+Ribavirin+Placebo was not demonstrated because the 97.5% CI lower limit was <=10%. Therefore, the second stage test for superiority was not conducted. No further hierarchical testing of secondary endpoints was conducted.

    Secondary: Percentage of Subjects With On-treatment Interferon-Associated Flu-Like Symptoms

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    End point title
    		 Percentage of Subjects With On-treatment Interferon-Associated Flu-Like Symptoms
    End point description
    Interferon-associated flu-like symptoms were defined by pyrexia or chills or pain. The analysis was performed on modified intent-to-treat (ITT) population, the numerator was based on subjects having interferon-associated flu-like symptoms and denominator based on all treated subjects.
    End point type
    Secondary
    End point timeframe
    Baseline up to End of Treatment (Week 12 or 24)
    End point values
    		 PegIFN Lambda-1a+Ribavirin+Placebo PegIFNλ-1a+Ribavirin+Daclatasvir PegIFN alfa-2a+Ribavirin+Placebo
    Number of subjects analysed
    353
    349
    172
    Units: Percentage of subjects
        number (confidence interval 95%)
    11.6 (8.3 to 15)
    9.2 (6.1 to 12.2)
    36.6 (29.4 to 43.8)
    No statistical analyses for this end point

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

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    End point title
    		 Percentage of Subjects With On-treatment Interferon-Associated Musculoskeletal Symptoms
    End point description
    Musculoskeletal symptoms was defined by arthralgia or myalgia or back pain. The analysis was performed in modified intent-to-treat (ITT) population, the numerator was based on subjects having interferon-associated musculoskeletal symptoms and denominator based on all treated subjects.
    End point type
    Secondary
    End point timeframe
    Baseline up to End of Treatment (Week 12 or 24)
    End point values
    		 PegIFN Lambda-1a+Ribavirin+Placebo PegIFNλ-1a+Ribavirin+Daclatasvir PegIFN alfa-2a+Ribavirin+Placebo
    Number of subjects analysed
    353
    349
    172
    Units: Percentage of subjects
        number (confidence interval 95%)
    25.5 (20.9 to 30)
    20.6 (16.4 to 24.9)
    49.4 (41.9 to 56.9)
    No statistical analyses for this end point

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

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    End point title
    		 Percentage of Subjects With Sustained Virologic Response at Post-treatment Follow-up Week 24 (SVR24)
    End point description
    SVR24 rate was defined HCV RNA <LLOQ TD or TND at follow-up Week 24. The LLOQ was 25 IU/mL. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. The analysis was performed in modified ITT population, the numerator was based on subjects meeting the response criteria and denominator based on all treated subjects.
    End point type
    Secondary
    End point timeframe
    Follow-up Week 24
    End point values
    		 PegIFN Lambda-1a+Ribavirin+Placebo PegIFNλ-1a+Ribavirin+Daclatasvir PegIFN alfa-2a+Ribavirin+Placebo
    Number of subjects analysed
    353
    349
    172
    Units: Percentage of subjects
        number (confidence interval 95%)
    65.7 (60.8 to 70.7)
    81.7 (77.6 to 85.7)
    71.5 (64.8 to 78.3)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With On-Treatment Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs)

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    End point title
    		 Percentage of Subjects With On-Treatment Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs)
    End point description
    AE was defined as any new unfavorable symptom, sign, or disease or worsening of a pre-existing condition that does not has a causal relationship with treatment. SAE was defined as a medical event that at any dose resulted in death, persistent or significant disability/incapacity, or drug dependency/abuse; was life-threatening, an important medical event, or a congenital anomaly/birth defect; or required or prolonged hospitalization. The analysis was performed on all treated subjects who received at least 1 dose of study therapy.
    End point type
    Secondary
    End point timeframe
    Baseline up to end of treatment (Week 12 or 24)
    End point values
    		 PegIFN Lambda-1a+Ribavirin+Placebo PegIFNλ-1a+Ribavirin+Daclatasvir PegIFN alfa-2a+Ribavirin+Placebo
    Number of subjects analysed
    353
    349
    172
    Units: Percentage of subjects
    number (not applicable)
        SAEs
    6.2
    2.9
    2.3
        AEs leading to discontinuation
    7.4
    2.9
    8.7
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With On-treatment Interferon- Associated Constitutional Symptoms

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    End point title
    		 Percentage of Subjects With On-treatment Interferon- Associated Constitutional Symptoms
    End point description
    Constitutional symptoms include fatigue and asthenia. The analysis was performed on all treated subjects who received at least 1 dose of study therapy.
    End point type
    Secondary
    End point timeframe
    Baseline up to End of Treatment (Week 12 or 24)
    End point values
    		 PegIFN Lambda-1a+Ribavirin+Placebo PegIFNλ-1a+Ribavirin+Daclatasvir PegIFN alfa-2a+Ribavirin+Placebo
    Number of subjects analysed
    353
    349
    172
    Units: Percentage of subjects
    number (not applicable)
        Fatigue
    31.2
    24.9
    43
        Asthenia
    12.2
    10
    13.4
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Dose Reductions

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    End point title
    		 Percentage of Subjects With Dose Reductions
    End point description
    Dose reductions were mainly due to adverse events or elevated liver function tests. The analysis was performed on all treated subjects who received at least 1 dose of study therapy.
    End point type
    Secondary
    End point timeframe
    Baseline up to End of Treatment (Week 12 or 24)
    End point values
    		 PegIFN Lambda-1a+Ribavirin+Placebo PegIFNλ-1a+Ribavirin+Daclatasvir PegIFN alfa-2a+Ribavirin+Placebo
    Number of subjects analysed
    353
    349
    172
    Units: Percentage of subjects
    number (not applicable)
        pegIFNλ dose reduction
    7.08
    2.87
    0
        Ribavirin dose reduction
    5.95
    3.44
    19.19
        pegIFNalfa-2a dose reduction
    0
    0
    29.07
    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 (Week 12 or 24) (On-treatment Period)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    PegIFN Lambda-1a+Ribavirin+Placebo
    Reporting group description
    		 Subjects received pegIFN lambda-1a solution for injection 180 µg subcutaneously, once weekly, with placebo matched with daclatasvir tablets orally, once daily and ribavirin tablets 400 mg orally, twice daily, for up to 12 weeks. Subjects continued to receive pegIFN lambda-1a with ribavirin for an additional 12 weeks and followed-up for 24 weeks.

    Reporting group title
    PegIFNλ-1a+Ribavirin+Daclatasvir
    Reporting group description
    		 Subjects received pegIFN lambda-1a solution for injection 180 µg subcutaneously, once weekly, with daclatasvir tablets 60 mg orally, once daily and ribavirin tablets 400 mg orally, twice daily, for up to 12 weeks and followed-up for 48 weeks.

    Reporting group title
    PegIFN alfa-2a+Ribavirin+Placebo
    Reporting group description
    		 Subjects received pegIFN alfa-2a solution for injection 180 µg subcutaneously, once weekly, with placebo matched with daclatasvir tablets orally, once daily and ribavirin tablets 400 mg orally, twice daily, for up to 12 weeks. Subjects continued to receive pegIFN alfa-2a with ribavirin for an additional 12 weeks and followed-up for 24 weeks.

    Serious adverse events
    		 PegIFN Lambda-1a+Ribavirin+Placebo PegIFNλ-1a+Ribavirin+Daclatasvir PegIFN alfa-2a+Ribavirin+Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    22 / 353 (6.23%)
    10 / 349 (2.87%)
    4 / 172 (2.33%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Liver function test abnormal
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 349 (0.29%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood potassium decreased
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 349 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 349 (0.29%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 349 (0.29%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Anosmia
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebellar Syndrome
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 349 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 349 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 349 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst ruptured
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Jaundice
         subjects affected / exposed
    7 / 353 (1.98%)
    1 / 349 (0.29%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    7 / 7
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinemia
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 349 (0.29%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 353 (0.00%)
    2 / 349 (0.57%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Substance abuse
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal tubular necrosis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc generation
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 353 (0.00%)
    1 / 349 (0.29%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Stoma site abscess
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 353 (0.28%)
    0 / 349 (0.00%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 349 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 349 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 353 (0.00%)
    0 / 349 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 PegIFN Lambda-1a+Ribavirin+Placebo PegIFNλ-1a+Ribavirin+Daclatasvir PegIFN alfa-2a+Ribavirin+Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    295 / 353 (83.57%)
    279 / 349 (79.94%)
    163 / 172 (94.77%)
    Investigations
    Alanine Aminotransferase increased
         subjects affected / exposed
    32 / 353 (9.07%)
    24 / 349 (6.88%)
    7 / 172 (4.07%)
         occurrences all number
    35
    28
    7
    Aspartate Aminotransferase increased
         subjects affected / exposed
    27 / 353 (7.65%)
    19 / 349 (5.44%)
    6 / 172 (3.49%)
         occurrences all number
    28
    22
    6
    Weight decreased
         subjects affected / exposed
    9 / 353 (2.55%)
    4 / 349 (1.15%)
    12 / 172 (6.98%)
         occurrences all number
    9
    4
    12
    Nervous system disorders
    Headache
         subjects affected / exposed
    64 / 353 (18.13%)
    47 / 349 (13.47%)
    44 / 172 (25.58%)
         occurrences all number
    87
    56
    57
    Dizziness
         subjects affected / exposed
    34 / 353 (9.63%)
    46 / 349 (13.18%)
    38 / 172 (22.09%)
         occurrences all number
    39
    51
    43
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    110 / 353 (31.16%)
    87 / 349 (24.93%)
    74 / 172 (43.02%)
         occurrences all number
    122
    100
    79
    Asthenia
         subjects affected / exposed
    43 / 353 (12.18%)
    35 / 349 (10.03%)
    23 / 172 (13.37%)
         occurrences all number
    48
    35
    25
    Influenza like illness
         subjects affected / exposed
    26 / 353 (7.37%)
    18 / 349 (5.16%)
    36 / 172 (20.93%)
         occurrences all number
    26
    18
    39
    Chills
         subjects affected / exposed
    26 / 353 (7.37%)
    16 / 349 (4.58%)
    25 / 172 (14.53%)
         occurrences all number
    31
    19
    27
    Pyrexia
         subjects affected / exposed
    20 / 353 (5.67%)
    23 / 349 (6.59%)
    41 / 172 (23.84%)
         occurrences all number
    24
    27
    48
    Injection site erythema
         subjects affected / exposed
    13 / 353 (3.68%)
    17 / 349 (4.87%)
    10 / 172 (5.81%)
         occurrences all number
    14
    18
    11
    Malaise
         subjects affected / exposed
    11 / 353 (3.12%)
    9 / 349 (2.58%)
    12 / 172 (6.98%)
         occurrences all number
    11
    9
    14
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    14 / 353 (3.97%)
    14 / 349 (4.01%)
    35 / 172 (20.35%)
         occurrences all number
    15
    14
    37
    Thrombocytopenia
         subjects affected / exposed
    2 / 353 (0.57%)
    2 / 349 (0.57%)
    21 / 172 (12.21%)
         occurrences all number
    3
    2
    24
    Neutropenia
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 349 (0.29%)
    53 / 172 (30.81%)
         occurrences all number
    1
    1
    74
    Leukopenia
         subjects affected / exposed
    1 / 353 (0.28%)
    1 / 349 (0.29%)
    16 / 172 (9.30%)
         occurrences all number
    1
    1
    18
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    88 / 353 (24.93%)
    71 / 349 (20.34%)
    51 / 172 (29.65%)
         occurrences all number
    119
    88
    52
    Diarrhoea
         subjects affected / exposed
    44 / 353 (12.46%)
    25 / 349 (7.16%)
    18 / 172 (10.47%)
         occurrences all number
    47
    33
    20
    Vomiting
         subjects affected / exposed
    36 / 353 (10.20%)
    26 / 349 (7.45%)
    17 / 172 (9.88%)
         occurrences all number
    45
    33
    24
    Dyspepsia
         subjects affected / exposed
    21 / 353 (5.95%)
    19 / 349 (5.44%)
    11 / 172 (6.40%)
         occurrences all number
    24
    19
    12
    Abdominal pain upper
         subjects affected / exposed
    21 / 353 (5.95%)
    16 / 349 (4.58%)
    13 / 172 (7.56%)
         occurrences all number
    27
    22
    15
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    32 / 353 (9.07%)
    15 / 349 (4.30%)
    24 / 172 (13.95%)
         occurrences all number
    36
    16
    26
    Cough
         subjects affected / exposed
    15 / 353 (4.25%)
    9 / 349 (2.58%)
    10 / 172 (5.81%)
         occurrences all number
    17
    9
    12
    Oropharyngeal pain
         subjects affected / exposed
    12 / 353 (3.40%)
    9 / 349 (2.58%)
    9 / 172 (5.23%)
         occurrences all number
    12
    9
    9
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    109 / 353 (30.88%)
    82 / 349 (23.50%)
    50 / 172 (29.07%)
         occurrences all number
    120
    92
    58
    Rash
         subjects affected / exposed
    46 / 353 (13.03%)
    45 / 349 (12.89%)
    33 / 172 (19.19%)
         occurrences all number
    53
    54
    34
    Dry skin
         subjects affected / exposed
    44 / 353 (12.46%)
    37 / 349 (10.60%)
    27 / 172 (15.70%)
         occurrences all number
    47
    41
    28
    Alopecia
         subjects affected / exposed
    12 / 353 (3.40%)
    4 / 349 (1.15%)
    30 / 172 (17.44%)
         occurrences all number
    13
    4
    30
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    110 / 353 (31.16%)
    74 / 349 (21.20%)
    50 / 172 (29.07%)
         occurrences all number
    121
    79
    54
    Irritability
         subjects affected / exposed
    41 / 353 (11.61%)
    30 / 349 (8.60%)
    20 / 172 (11.63%)
         occurrences all number
    46
    30
    20
    Depression
         subjects affected / exposed
    29 / 353 (8.22%)
    16 / 349 (4.58%)
    14 / 172 (8.14%)
         occurrences all number
    29
    16
    14
    Sleep Disorder
         subjects affected / exposed
    23 / 353 (6.52%)
    18 / 349 (5.16%)
    10 / 172 (5.81%)
         occurrences all number
    25
    21
    11
    Anxiety
         subjects affected / exposed
    20 / 353 (5.67%)
    17 / 349 (4.87%)
    14 / 172 (8.14%)
         occurrences all number
    21
    17
    14
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    49 / 353 (13.88%)
    45 / 349 (12.89%)
    60 / 172 (34.88%)
         occurrences all number
    55
    57
    69
    Arthralgia
         subjects affected / exposed
    48 / 353 (13.60%)
    44 / 349 (12.61%)
    49 / 172 (28.49%)
         occurrences all number
    56
    51
    54
    Back pain
         subjects affected / exposed
    20 / 353 (5.67%)
    11 / 349 (3.15%)
    15 / 172 (8.72%)
         occurrences all number
    21
    11
    16
    Muscle spasms
         subjects affected / exposed
    11 / 353 (3.12%)
    18 / 349 (5.16%)
    4 / 172 (2.33%)
         occurrences all number
    14
    19
    4
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    13 / 353 (3.68%)
    9 / 349 (2.58%)
    9 / 172 (5.23%)
         occurrences all number
    16
    9
    12
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    68 / 353 (19.26%)
    51 / 349 (14.61%)
    55 / 172 (31.98%)
         occurrences all number
    78
    64
    57

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Nov 2012
    Incorporated recommendations from the food and drug administration (daclatasvir dosing and prohibited medications clarified), added clarification text for dosing, inclusion/exclusion criteria and study procedures.
    19 Mar 2013
    Incorporated cardiac safety monitoring laboratory tests, updated and clarified text for dose modifications and study procedures.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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