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    Clinical Trial Results:
    A Phase 2, Open-Label Study of Daclatasvir (BMS-790052) and TMC435 in Combination With or Without Ribavirin (RBV) For Treatment-Naive Subjects or Null Responders to Prior Peginterferon Alfa (PegIFN)/RBV Therapy with Genotype 1 Chronic Hepatitis C

    Summary
    EudraCT number
    		 2012-000070-28
    Trial protocol
    		 HU   DE   ES  
    Global end of trial date
    21 Nov 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Feb 2017
    First version publication date
    16 Feb 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    AI444-062
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01628692
    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 International Corporation, clinical.trials@bms.com
    Scientific contact
    Bristol-Myers Squibb Study Director, Bristol-Myers Squibb International Corporation, clinical.trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    21 Nov 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Nov 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess efficacy of daclatasvir and TMC435 with and without ribavirin, as determined by the proportion of subjects with sustained virologic response at post-treatment follow-up Week 12 (SVR12), defined as hepatitis C virus (HCV) ribonucleic acid (RNA) < lower limit of quantitation (LLOQ) at post-treatment Week 12.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Jun 2012
    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
    Argentina: 18
    Country: Number of subjects enrolled
    United States: 48
    Country: Number of subjects enrolled
    Spain: 29
    Country: Number of subjects enrolled
    France: 75
    Country: Number of subjects enrolled
    Germany: 35
    Country: Number of subjects enrolled
    Hungary: 25
    Worldwide total number of subjects
    230
    EEA total number of subjects
    164
    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)
    185
    From 65 to 84 years
    45
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study was conducted at 25 sites in 6 countries.

    Pre-assignment
    Screening details
    		 A total of 230 subjects were enrolled and 168 were treated. 62 subjects were enrolled, but did not enter the treatment period. Reasons for non-treatment include 54 subjects no longer met the study entry criteria, 6 subjects withdrew consent, and 2 subjects were lost to follow-up.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Genotype 1b: Daclatasvir + Simeprevir (Naive)
    Arm description
    		 Subjects with no prior treatment of hepatitis C virus genotype 1b. Received daclatasvir 30 mg with or without food and simeprevir 150 mg with a light to standard meal once daily (QD), for a period of 12 weeks or 24 weeks based on re-randomization and continued into a post-treatment follow-up period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Daclatasvir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Daclatasvir orally 30-mg tablets once daily (QD). Daclatasvir was administered as 1 tablet with or without food for the duration of assigned treatment. mg=milligram

    Investigational medicinal product name
    Simeprevir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Simeprevir orally 150-mg gelatin capsule once daily (QD). Simeprevir was administered as 1 gelatin capsule with a light to standard meal for the duration of assigned treatment. mg=milligram

    Arm title
    		 Genotype 1b: Daclatasvir + Simeprevir (Null)
    Arm description
    		 Subjects with hepatitis C virus genotype 1b, and who never attained ≥2 log10 decline in hepatitis C virus RNA levels after at least 12 weeks of prior therapy with peginterferon/ribavirin. Received daclatasvir 30 mg with or without food and simeprevir 150 mg with a light to standard meal QD, for a period of 12 or 24 weeks based on re-randomization and continued into post-treatment follow-up.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Daclatasvir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Daclatasvir orally 30-mg tablets once daily (QD). Daclatasvir was administered as 1 tablet with or without food for the duration of assigned treatment. mg=milligram

    Investigational medicinal product name
    Simeprevir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Simeprevir orally 150-mg gelatin capsule once daily (QD). Simeprevir was administered as 1 gelatin capsule with a light to standard meal for the duration of assigned treatment. mg=milligram

    Arm title
    		 Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Naive)
    Arm description
    		 Subjects with no prior treatment of hepatitis C virus genotype 1b. Received daclatasvir 30 mg with or without food, simeprevir 150 mg with a light to standard meal QD, and weight stratified (1000/1200 mg for participants weighing <75/>= 75 kg, respectively) ribavirin twice daily (BID) for a period of 12 or 24 weeks based on re-randomization and continued into post-treatment follow-up.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Daclatasvir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Daclatasvir orally 30-mg tablets once daily (QD). Daclatasvir was administered as 1 tablet with or without food for the duration of assigned treatment. mg=milligram

    Investigational medicinal product name
    Simeprevir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Simeprevir orally 150-mg gelatin capsule once daily (QD). Simeprevir was administered as 1 gelatin capsule with a light to standard meal for the duration of assigned treatment. mg=milligram

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Ribavirin administered at a daily weight stratified dose of 1,000 to 1,200 mg orally in 2 divided doses. Subjects received either 400 mg (2 tablets for subjects < 75 kg) or 600 mg (3 tablets for subjects ≥ 75 kg) of Ribavirin in the morning with food and 600 mg (3 tablets) of RBV in the evening with food. mg=milligram; kg=kilogram

    Arm title
    		 Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Null)
    Arm description
    		 Subjects with hepatitis C virus genotype 1b, who never attained ≥2 log10 decline in hepatitis C virus RNA level after at least 12 weeks of prior therapy with peginterferon/ribavirin. Received daclatasvir 30 mg with or without food, simeprevir 150 mg with a light to standard meal QD, and weight stratified (1000/1200 mg for participants weighing <75/>=75 kg, respectively) ribavirin BID were continued to receive treatment for a period of 12 or 24 weeks based on re-randomization and continued into post-treatment follow-up period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Daclatasvir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Daclatasvir orally 30-mg tablets once daily (QD). Daclatasvir was administered as 1 tablet with or without food for the duration of assigned treatment. mg=milligram

    Investigational medicinal product name
    Simeprevir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Simeprevir orally 150-mg gelatin capsule once daily (QD). Simeprevir was administered as 1 gelatin capsule with a light to standard meal for the duration of assigned treatment. mg=milligram

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Ribavirin administered at a daily weight stratified dose of 1,000 to 1,200 mg orally in 2 divided doses. Subjects received either 400 mg (2 tablets for subjects < 75 kg) or 600 mg (3 tablets for subjects ≥ 75 kg) of Ribavirin in the morning with food and 600 mg (3 tablets) of RBV in the evening with food. mg=milligram; kg=kilogram

    Arm title
    		 Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Naive)
    Arm description
    		 Subjects with no prior treatment of hepatitis C virus genotype 1a. Received daclatasvir 30 mg with or without food, simeprevir 150 mg with a light to standard meal QD, and weight stratified (1000/1200 mg for participants weighing <75/>=75 kg, respectively) ribavirin BID for a period of 24 weeks and continued into post-treatment follow-up period of 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Daclatasvir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Daclatasvir orally 30-mg tablets once daily (QD). Daclatasvir was administered as 1 tablet with or without food for the duration of assigned treatment. mg=milligram

    Investigational medicinal product name
    Simeprevir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Simeprevir orally 150-mg gelatin capsule once daily (QD). Simeprevir was administered as 1 gelatin capsule with a light to standard meal for the duration of assigned treatment. mg=milligram

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Ribavirin administered at a daily weight stratified dose of 1,000 to 1,200 mg orally in 2 divided doses. Subjects received either 400 mg (2 tablets for subjects < 75 kg) or 600 mg (3 tablets for subjects ≥ 75 kg) of Ribavirin in the morning with food and 600 mg (3 tablets) of RBV in the evening with food. mg=milligram; kg=kilogram

    Arm title
    		 Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Null)
    Arm description
    		 Subjects with hepatitis C virus genotype 1a, who never attained ≥2 log10 decline in hepatitis C virus RNA level after at least 12 weeks of prior therapy. Received daclatasvir 30 mg with or without food, simeprevir 150 mg with a light to standard meal QD, and weight stratified (1000/1200 mg for participants weighing <75/>=75 kg, respectively) ribavirin BID for a period of 24 weeks and continued into post-treatment follow-up period of 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Daclatasvir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Daclatasvir orally 30-mg tablets once daily (QD). Daclatasvir was administered as 1 tablet with or without food for the duration of assigned treatment. mg=milligram

    Investigational medicinal product name
    Simeprevir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Simeprevir orally 150-mg gelatin capsule once daily (QD). Simeprevir was administered as 1 gelatin capsule with a light to standard meal for the duration of assigned treatment. mg=milligram

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Ribavirin administered at a daily weight stratified dose of 1,000 to 1,200 mg orally in 2 divided doses. Subjects received either 400 mg (2 tablets for subjects < 75 kg) or 600 mg (3 tablets for subjects ≥ 75 kg) of Ribavirin in the morning with food and 600 mg (3 tablets) of RBV in the evening with food. mg=milligram; kg=kilogram

    Number of subjects in period 1 [1]
    		Genotype 1b: Daclatasvir + Simeprevir (Naive) Genotype 1b: Daclatasvir + Simeprevir (Null) Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Naive) Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Null) Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Naive) Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Null)
    Started
    53
    23
    51
    20
    12
    9
    Completed
    46
    17
    43
    19
    8
    0
    Not completed
    7
    6
    8
    1
    4
    9
         Withdrawl by Subject
    -
    1
    1
    -
    -
    -
         Adverse Event
    2
    -
    2
    -
    -
    -
         Poor compliance/noncompliance
    1
    -
    -
    -
    -
    -
         Death
    -
    1
    -
    -
    -
    -
         Administrative Reason by Sponsor
    -
    -
    -
    -
    -
    1
         Completed 12 Week only
    -
    -
    -
    -
    -
    1
         Lack of efficacy
    4
    4
    5
    1
    4
    7
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Out of 230 subjects who were enrolled, 168 subjects received at least 1 dose of study therapy.
    Period 2
    Period 2 title
    Follow-up Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Genotype 1b: Daclatasvir + Simeprevir (Naive)
    Arm description
    		 Post-treatment follow-up for either 24 or 36 weeks depending on the duration of treatment assigned for subjects with no prior treatment of hepatitis C virus genotype 1b. Received daclatasvir 30 mg with or without food and simeprevir 150 mg with a light to standard meal once daily (QD), for a period of 12 weeks or 24 weeks based on re-randomization and continued into a post-treatment follow-up period.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Genotype 1b: Daclatasvir + Simeprevir (Null)
    Arm description
    		 Post-treatment follow-up for either 24 or 36 weeks depending on the duration of treatment assigned for subjects with hepatitis C virus genotype 1b, and who never attained ≥2 log10 decline in hepatitis C virus RNA levels after at least 12 weeks of prior therapy with peginterferon/ribavirin. Received daclatasvir 30 mg with or without food and simeprevir 150 mg with a light to standard meal QD, for a period of 12 or 24 weeks based on re-randomization and continued into post-treatment follow-up.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Naive)
    Arm description
    		 Post-treatment follow-up for either 24 or 36 weeks depending on the duration of treatment assigned for subjects with no prior treatment of hepatitis C virus genotype 1b. Received daclatasvir 30 mg with or without food, simeprevir 150 mg with a light to standard meal QD, and weight stratified (1000/1200 mg for participants weighing <75/>= 75 kg, respectively) ribavirin twice daily (BID) for a period of 12 or 24 weeks based on re-randomization and continued into post-treatment follow-up.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Null)
    Arm description
    		 Post-treatment follow-up for either 24 or 36 weeks depending on the duration of treatment assigned for subjects with hepatitis C virus genotype 1b, who never attained ≥2 log10 decline in hepatitis C virus RNA level after at least 12 weeks of prior therapy with peginterferon/ribavirin. Received daclatasvir 30 mg with or without food, simeprevir 150 mg with a light to standard meal QD, and weight stratified (1000/1200 mg for participants weighing <75/>=75 kg, respectively) ribavirin BID were continued to receive treatment for a period of 12 or 24 weeks based on re-randomization and continued into post-treatment follow-up period.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Naive)
    Arm description
    		 Post-treatment follow-up for 24 weeks for subjects with no prior treatment of hepatitis C virus genotype 1a. Received daclatasvir 30 mg with or without food, simeprevir 150 mg with a light to standard meal QD, and weight stratified (1000/1200 mg for participants weighing <75/>=75 kg, respectively) ribavirin BID for a period of 24 weeks and continued into post-treatment follow-up period of 24 weeks.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Null)
    Arm description
    		 Post-treatment follow-up for 24 weeks for subjects with hepatitis C virus genotype 1a, who never attained ≥2 log10 decline in hepatitis C virus RNA level after at least 12 weeks of prior therapy. Received daclatasvir 30 mg with or without food, simeprevir 150 mg with a light to standard meal QD, and weight stratified (1000/1200 mg for participants weighing <75/>=75 kg, respectively) ribavirin BID for a period of 24 weeks and continued into post-treatment follow-up period of 24 weeks.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Genotype 1b: Daclatasvir + Simeprevir (Naive) Genotype 1b: Daclatasvir + Simeprevir (Null) Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Naive) Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Null) Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Naive) Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Null)
    Started
    46
    17
    43
    19
    8
    2
    Completed
    51
    21
    44
    20
    10
    2
    Not completed
    0
    0
    3
    0
    0
    0
         Consent withdrawn by subject
    -
    -
    1
    -
    -
    -
         Death
    -
    -
    1
    -
    -
    -
         Lost to follow-up
    -
    -
    1
    -
    -
    -
    Joined
    5
    4
    4
    1
    2
    0
         Did not complete treatment, but joined follow up
    5
    4
    4
    1
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Genotype 1b: Daclatasvir + Simeprevir (Naive)
    Reporting group description
    		 Subjects with no prior treatment of hepatitis C virus genotype 1b. Received daclatasvir 30 mg with or without food and simeprevir 150 mg with a light to standard meal once daily (QD), for a period of 12 weeks or 24 weeks based on re-randomization and continued into a post-treatment follow-up period.

    Reporting group title
    Genotype 1b: Daclatasvir + Simeprevir (Null)
    Reporting group description
    		 Subjects with hepatitis C virus genotype 1b, and who never attained ≥2 log10 decline in hepatitis C virus RNA levels after at least 12 weeks of prior therapy with peginterferon/ribavirin. Received daclatasvir 30 mg with or without food and simeprevir 150 mg with a light to standard meal QD, for a period of 12 or 24 weeks based on re-randomization and continued into post-treatment follow-up.

    Reporting group title
    Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Naive)
    Reporting group description
    		 Subjects with no prior treatment of hepatitis C virus genotype 1b. Received daclatasvir 30 mg with or without food, simeprevir 150 mg with a light to standard meal QD, and weight stratified (1000/1200 mg for participants weighing <75/>= 75 kg, respectively) ribavirin twice daily (BID) for a period of 12 or 24 weeks based on re-randomization and continued into post-treatment follow-up.

    Reporting group title
    Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Null)
    Reporting group description
    		 Subjects with hepatitis C virus genotype 1b, who never attained ≥2 log10 decline in hepatitis C virus RNA level after at least 12 weeks of prior therapy with peginterferon/ribavirin. Received daclatasvir 30 mg with or without food, simeprevir 150 mg with a light to standard meal QD, and weight stratified (1000/1200 mg for participants weighing <75/>=75 kg, respectively) ribavirin BID were continued to receive treatment for a period of 12 or 24 weeks based on re-randomization and continued into post-treatment follow-up period.

    Reporting group title
    Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Naive)
    Reporting group description
    		 Subjects with no prior treatment of hepatitis C virus genotype 1a. Received daclatasvir 30 mg with or without food, simeprevir 150 mg with a light to standard meal QD, and weight stratified (1000/1200 mg for participants weighing <75/>=75 kg, respectively) ribavirin BID for a period of 24 weeks and continued into post-treatment follow-up period of 24 weeks.

    Reporting group title
    Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Null)
    Reporting group description
    		 Subjects with hepatitis C virus genotype 1a, who never attained ≥2 log10 decline in hepatitis C virus RNA level after at least 12 weeks of prior therapy. Received daclatasvir 30 mg with or without food, simeprevir 150 mg with a light to standard meal QD, and weight stratified (1000/1200 mg for participants weighing <75/>=75 kg, respectively) ribavirin BID for a period of 24 weeks and continued into post-treatment follow-up period of 24 weeks.

    Reporting group values
    		 Genotype 1b: Daclatasvir + Simeprevir (Naive) Genotype 1b: Daclatasvir + Simeprevir (Null) Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Naive) Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Null) Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Naive) Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Null) Total
    Number of subjects
    		 53 23 51 20 12 9 168
    Age categorical
    Units: Subjects
        < 21 years
    		 0 0 0 1 1 0 2
        Between 21 and 64 years
    		 41 19 42 11 11 9 133
        >=65 years
    		 12 4 9 8 0 0 33
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53.6 ( 12.98 ) 53.8 ( 11.26 ) 53 ( 11.29 ) 57.2 ( 14.94 ) 50 ( 11.15 ) 48.1 ( 6.09 ) -
    Gender categorical
    Units: Subjects
        Female
    		 31 11 26 11 5 2 86
        Male
    		 22 12 25 9 7 7 82
    Hepatitis C Virus RNA Distribution
    Units: Subjects
        <800,000 IU/mL
    		 12 3 11 4 5 0 35
        ≥800,000 IU/mL
    		 41 20 40 16 7 9 133
    Randomization Stratum
    Units: Subjects
        Hepatitis C Virus Genotype 1b
    		 53 23 51 20 0 0 147
        Hepatitis C Virus Genotype 1a
    		 0 0 0 0 12 9 21

    End points

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    End points reporting groups
    Reporting group title
    Genotype 1b: Daclatasvir + Simeprevir (Naive)
    Reporting group description
    		 Subjects with no prior treatment of hepatitis C virus genotype 1b. Received daclatasvir 30 mg with or without food and simeprevir 150 mg with a light to standard meal once daily (QD), for a period of 12 weeks or 24 weeks based on re-randomization and continued into a post-treatment follow-up period.

    Reporting group title
    Genotype 1b: Daclatasvir + Simeprevir (Null)
    Reporting group description
    		 Subjects with hepatitis C virus genotype 1b, and who never attained ≥2 log10 decline in hepatitis C virus RNA levels after at least 12 weeks of prior therapy with peginterferon/ribavirin. Received daclatasvir 30 mg with or without food and simeprevir 150 mg with a light to standard meal QD, for a period of 12 or 24 weeks based on re-randomization and continued into post-treatment follow-up.

    Reporting group title
    Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Naive)
    Reporting group description
    		 Subjects with no prior treatment of hepatitis C virus genotype 1b. Received daclatasvir 30 mg with or without food, simeprevir 150 mg with a light to standard meal QD, and weight stratified (1000/1200 mg for participants weighing <75/>= 75 kg, respectively) ribavirin twice daily (BID) for a period of 12 or 24 weeks based on re-randomization and continued into post-treatment follow-up.

    Reporting group title
    Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Null)
    Reporting group description
    		 Subjects with hepatitis C virus genotype 1b, who never attained ≥2 log10 decline in hepatitis C virus RNA level after at least 12 weeks of prior therapy with peginterferon/ribavirin. Received daclatasvir 30 mg with or without food, simeprevir 150 mg with a light to standard meal QD, and weight stratified (1000/1200 mg for participants weighing <75/>=75 kg, respectively) ribavirin BID were continued to receive treatment for a period of 12 or 24 weeks based on re-randomization and continued into post-treatment follow-up period.

    Reporting group title
    Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Naive)
    Reporting group description
    		 Subjects with no prior treatment of hepatitis C virus genotype 1a. Received daclatasvir 30 mg with or without food, simeprevir 150 mg with a light to standard meal QD, and weight stratified (1000/1200 mg for participants weighing <75/>=75 kg, respectively) ribavirin BID for a period of 24 weeks and continued into post-treatment follow-up period of 24 weeks.

    Reporting group title
    Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Null)
    Reporting group description
    		 Subjects with hepatitis C virus genotype 1a, who never attained ≥2 log10 decline in hepatitis C virus RNA level after at least 12 weeks of prior therapy. Received daclatasvir 30 mg with or without food, simeprevir 150 mg with a light to standard meal QD, and weight stratified (1000/1200 mg for participants weighing <75/>=75 kg, respectively) ribavirin BID for a period of 24 weeks and continued into post-treatment follow-up period of 24 weeks.
    Reporting group title
    Genotype 1b: Daclatasvir + Simeprevir (Naive)
    Reporting group description
    		 Post-treatment follow-up for either 24 or 36 weeks depending on the duration of treatment assigned for subjects with no prior treatment of hepatitis C virus genotype 1b. Received daclatasvir 30 mg with or without food and simeprevir 150 mg with a light to standard meal once daily (QD), for a period of 12 weeks or 24 weeks based on re-randomization and continued into a post-treatment follow-up period.

    Reporting group title
    Genotype 1b: Daclatasvir + Simeprevir (Null)
    Reporting group description
    		 Post-treatment follow-up for either 24 or 36 weeks depending on the duration of treatment assigned for subjects with hepatitis C virus genotype 1b, and who never attained ≥2 log10 decline in hepatitis C virus RNA levels after at least 12 weeks of prior therapy with peginterferon/ribavirin. Received daclatasvir 30 mg with or without food and simeprevir 150 mg with a light to standard meal QD, for a period of 12 or 24 weeks based on re-randomization and continued into post-treatment follow-up.

    Reporting group title
    Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Naive)
    Reporting group description
    		 Post-treatment follow-up for either 24 or 36 weeks depending on the duration of treatment assigned for subjects with no prior treatment of hepatitis C virus genotype 1b. Received daclatasvir 30 mg with or without food, simeprevir 150 mg with a light to standard meal QD, and weight stratified (1000/1200 mg for participants weighing <75/>= 75 kg, respectively) ribavirin twice daily (BID) for a period of 12 or 24 weeks based on re-randomization and continued into post-treatment follow-up.

    Reporting group title
    Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Null)
    Reporting group description
    		 Post-treatment follow-up for either 24 or 36 weeks depending on the duration of treatment assigned for subjects with hepatitis C virus genotype 1b, who never attained ≥2 log10 decline in hepatitis C virus RNA level after at least 12 weeks of prior therapy with peginterferon/ribavirin. Received daclatasvir 30 mg with or without food, simeprevir 150 mg with a light to standard meal QD, and weight stratified (1000/1200 mg for participants weighing <75/>=75 kg, respectively) ribavirin BID were continued to receive treatment for a period of 12 or 24 weeks based on re-randomization and continued into post-treatment follow-up period.

    Reporting group title
    Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Naive)
    Reporting group description
    		 Post-treatment follow-up for 24 weeks for subjects with no prior treatment of hepatitis C virus genotype 1a. Received daclatasvir 30 mg with or without food, simeprevir 150 mg with a light to standard meal QD, and weight stratified (1000/1200 mg for participants weighing <75/>=75 kg, respectively) ribavirin BID for a period of 24 weeks and continued into post-treatment follow-up period of 24 weeks.

    Reporting group title
    Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Null)
    Reporting group description
    		 Post-treatment follow-up for 24 weeks for subjects with hepatitis C virus genotype 1a, who never attained ≥2 log10 decline in hepatitis C virus RNA level after at least 12 weeks of prior therapy. Received daclatasvir 30 mg with or without food, simeprevir 150 mg with a light to standard meal QD, and weight stratified (1000/1200 mg for participants weighing <75/>=75 kg, respectively) ribavirin BID for a period of 24 weeks and continued into post-treatment follow-up period of 24 weeks.

    Subject analysis set title
    Genotype 1b: Daclatasvir + Simeprevir (Naive + Null)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects with hepatitis C virus genotype 1b and who either had no prior treatment or had never attained ≥2 log10 decline in hepatitis C virus RNA levels after at least 12 weeks of prior therapy with peginterferon/ribavirin. Received daclatasvir 30 mg with or without food and simeprevir 150 mg with a light to standard meal once daily (QD), for a period of 12 weeks or 24 weeks based on re-randomization and continued into a post-treatment follow-up period.

    Subject analysis set title
    Genotype1b: Daclatasvir +Simeprevir + Ribavirin (Naive + Null)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects with hepatitis C virus genotype 1b and who either had no prior treatment or had never attained ≥2 log10 decline in hepatitis C virus RNA levels after at least 12 weeks of prior therapy with peginterferon/ribavirin. Received daclatasvir 30 mg with or without food, simeprevir 150 mg with a light to standard meal QD, and weight stratified (1000/1200 mg for subjects weighing <75/>= 75 kg, respectively) ribavirin twice daily (BID) for a period of 12 or 24 weeks based on re-randomization and continued into post-treatment follow-up.

    Subject analysis set title
    Genotype1a: Daclatasvir +Simeprevir + Ribavirin(Naive + Null)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Subjects with hepatitis C virus genotype 1a and who either had no prior treatment or had never attained ≥2 log10 decline in hepatitis C virus RNA levels after at least 12 weeks of prior therapy with peginterferon/ribavirin. Received daclatasvir 30 mg with or without food, simeprevir 150 mg with a light to standard meal QD, and weight stratified (1000/1200 mg for subjects weighing <75/>=75 kg, respectively) ribavirin BID for a period of 24 weeks and continued into post-treatment follow-up period of 24 weeks.

    Primary: Percentage of Subjects With Sustained Virologic Response Rate at Post-treatment Week 12 (SVR12)

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    End point title
    		 Percentage of Subjects With Sustained Virologic Response Rate at Post-treatment Week 12 (SVR12) [1]
    End point description
    SVR12 rate was defined as hepatitis C virus (HCV) RNA levels to be <lower limit of quantitation, target detected or target not detected, at post-treatment Week 12. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. All participants who were randomized and received at least 1 dose of active study therapy (daclatasvir, simeprevir, ribavirin).
    End point type
    Primary
    End point timeframe
    Post Treatment Week 12 (Follow-up period)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive summary statistics were planned for this outcome measure.
    End point values
    		 Genotype 1b: Daclatasvir + Simeprevir (Naive) Genotype 1b: Daclatasvir + Simeprevir (Null) Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Naive) Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Null) Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Naive) Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Null)
    Number of subjects analysed
    53
    23
    51
    20
    12
    9 [2]
    Units: Percentage of subjects
        number (confidence interval 80%)
    84.9 (78.6 to 91.2)
    69.6 (57.3 to 81.9)
    74.5 (66.7 to 82.3)
    95 (88.8 to 100)
    66.7 (49.2 to 84.1)
    0 (-99999 to 99999)
    Notes
    [2] - As no subjects achieved SVR12, 80% confidence interval value is not available.
    No statistical analyses for this end point

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

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    End point title
    		 Percentage of Subjects With Rapid Virologic Response (RVR)
    End point description
    RVR was defined as hepatitis C virus (HCV) RNA levels to be <lower limit of quantitation, target not detected at Week 4. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. All treated subjects.
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    		 Genotype 1b: Daclatasvir + Simeprevir (Naive) Genotype 1b: Daclatasvir + Simeprevir (Null) Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Naive) Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Null) Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Naive) Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Null)
    Number of subjects analysed
    53
    23
    51
    20
    12
    9
    Units: Percentage of Subjects
        number (confidence interval 80%)
    79.2 (72.1 to 86.4)
    69.6 (57.3 to 81.9)
    68.6 (60.3 to 77)
    85 (74.8 to 95.2)
    75 (59 to 91)
    33.3 (13.2 to 53.5)
    No statistical analyses for this end point

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

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    End point title
    		 Percentage of Subjects With Complete Early Virologic Response (cEVR)
    End point description
    cEVR was defined as hepatitis C virus (HCV) RNA levels to be <lower limit of quantitation, target not detected at Week 12. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. All treated subejcts.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Genotype 1b: Daclatasvir + Simeprevir (Naive) Genotype 1b: Daclatasvir + Simeprevir (Null) Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Naive) Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Null) Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Naive) Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Null)
    Number of subjects analysed
    53
    23
    51
    20
    12
    9
    Units: Percentage of Subjects
        number (confidence interval 80%)
    84.9 (78.6 to 91.2)
    73.9 (62.2 to 85.6)
    82.4 (75.5 to 89.2)
    90 (81.4 to 98.6)
    66.7 (49.2 to 84.1)
    11.1 (0 to 24.5)
    No statistical analyses for this end point

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

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    End point title
    		 Percentage of Subjects With Extended Rapid Virologic Response (eRVR)
    End point description
    eRVR were defined as hepatitis C virus (HCV) RNA levels to be <lower limit of quantitation, target not detected at both Week 4 and Week 12. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. All treated subjects.
    End point type
    Secondary
    End point timeframe
    Week 4 and Week 12
    End point values
    		 Genotype 1b: Daclatasvir + Simeprevir (Naive) Genotype 1b: Daclatasvir + Simeprevir (Null) Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Naive) Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Null) Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Naive) Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Null)
    Number of subjects analysed
    53
    23
    51
    20
    12
    9
    Units: Percentage of Subject
        number (confidence interval 80%)
    71.7 (63.8 to 79.6)
    60.9 (47.8 to 73.9)
    62.7 (54.1 to 71.4)
    75 (62.6 to 87.4)
    58.3 (40.1 to 76.6)
    11.1 (0 to 24.5)
    No statistical analyses for this end point

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

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    End point title
    		 Percentage of Subjects With End of Treatment Response (EOTR)
    End point description
    EOTR were defined as hepatitis C virus (HCV) RNA levels <lower limit of quantitation, target not detected at end of treatment. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. All treated subjects.
    End point type
    Secondary
    End point timeframe
    End of treatment (Week 24)
    End point values
    		 Genotype 1b: Daclatasvir + Simeprevir (Naive) Genotype 1b: Daclatasvir + Simeprevir (Null) Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Naive) Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Null) Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Naive) Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Null)
    Number of subjects analysed
    53
    23
    51
    20
    12
    9
    Units: Percentage of Subjects
        number (confidence interval 80%)
    88.7 (83.1 to 94.3)
    78.3 (67.2 to 89.3)
    78.4 (71.1 to 85.8)
    95 (88.8 to 100)
    66.7 (49.2 to 84.1)
    0 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Sustained Virologic Response at Follow-up Week 12 (SVR12) by rs12979860 Single Nucleotide Polymorphisms in the IL-28B Gene Categories

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    End point title
    		 Percentage of Subjects With Sustained Virologic Response at Follow-up Week 12 (SVR12) by rs12979860 Single Nucleotide Polymorphisms in the IL-28B Gene Categories
    End point description
    Subjects were categorized into 3 genotypes based on single nucleotide polymorphisms in the IL28B gene. SVR12 was defined as hepatitis C virus (HCV) RNA levels below lower limit of quantitation, target detected or target not detected at follow-up Week 12. HCV RNA levels were measured by the Roche COBAS® TaqMan® HCV Test version 2.0 from the central laboratory. All treated subjects. Here ‘n’ signifies those subjects evaluable for this measure at specified time points for each group, respectively.
    End point type
    Secondary
    End point timeframe
    Post-treatment Week 12 (Follow-up period)
    End point values
    		 Genotype 1b: Daclatasvir + Simeprevir (Naive) Genotype 1b: Daclatasvir + Simeprevir (Null) Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Naive) Genotype 1b: Daclatasvir + Simeprevir + Ribavirin (Null) Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Naive) Genotype 1a: Daclatasvir + Simeprevir + Ribavirin (Null)
    Number of subjects analysed
    53
    23
    51
    20
    12
    9
    Units: Percentage of Subjects
    number (not applicable)
        IL28B Genotype CC type (n= 16,1,13,1,3,0)
    87.5
    100
    84.6
    100
    66.7
    99999
        IL28B Genotype CT type (n= 22,15, 28,10,9,8)
    95.5
    60
    82.1
    90
    66.7
    0
        IL28B Genotype TT type (n= 12,6,10,7,0,1)
    66.7
    83.3
    40
    100
    99999
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) and Who Died

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    End point title
    		 Number of Subjects With Serious Adverse Events (SAEs) and Discontinuations Due to Adverse Events (AEs) and Who Died
    End point description
    AE was defined as any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that does not necessarily have 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. Based on the severity, AEs were categorized as Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4=Life-threatening or disabling, Gr 5=Death. All treated subjects.
    End point type
    Secondary
    End point timeframe
    From start of treatment (Day 1) up to 7 days post last dose of study treatment (Week 24)
    End point values
    		 Genotype 1b: Daclatasvir + Simeprevir (Naive + Null) Genotype1b: Daclatasvir +Simeprevir + Ribavirin (Naive + Null) Genotype1a: Daclatasvir +Simeprevir + Ribavirin(Naive + Null)
    Number of subjects analysed
    76
    71
    21
    Units: Subjects
        SAEs
    7
    3
    1
        AEs Leading to Discontinuation
    2
    2
    0
        Death
    1
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of treatment (Day 1) up to 7 days post last dose of study treatment (24 Weeks)
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Genotype 1b: Daclatasvir + Simeprevir (Naive + Null)
    Reporting group description
    		 Subjects with hepatitis C virus genotype 1b and who either had no prior treatment or had never attained ≥2 log10 decline in hepatitis C virus RNA levels after at least 12 weeks of prior therapy with peginterferon/ribavirin. Received daclatasvir 30 mg with or without food and simeprevir 150 mg with a light to standard meal once daily (QD), for a period of 12 weeks or 24 weeks based on re-randomization and continued into a post-treatment follow-up period.

    Reporting group title
    Genotype1b: Daclatasvir +Simeprevir + Ribavirin (Naive + Null)
    Reporting group description
    		 Subjects with hepatitis C virus genotype 1b and who either had no prior treatment or had never attained ≥2 log10 decline in hepatitis C virus RNA levels after at least 12 weeks of prior therapy with peginterferon/ribavirin. Received daclatasvir 30 mg with or without food, simeprevir 150 mg with a light to standard meal QD, and weight stratified (1000/1200 mg for subjects weighing <75/>= 75 kg, respectively) ribavirin twice daily (BID) for a period of 12 or 24 weeks based on re-randomization and continued into post-treatment follow-up.

    Reporting group title
    Genotype1a: Daclatasvir +Simeprevir + Ribavirin(Naive + Null)
    Reporting group description
    		 Subjects with hepatitis C virus genotype 1a and who either had no prior treatment or had never attained ≥2 log10 decline in hepatitis C virus RNA levels after at least 12 weeks of prior therapy with peginterferon/ribavirin. Received daclatasvir 30 mg with or without food, simeprevir 150 mg with a light to standard meal QD, and weight stratified (1000/1200 mg for subjects weighing <75/>=75 kg, respectively) ribavirin BID for a period of 24 weeks and continued into post-treatment follow-up period of 24 weeks.

    Serious adverse events
    		 Genotype 1b: Daclatasvir + Simeprevir (Naive + Null) Genotype1b: Daclatasvir +Simeprevir + Ribavirin (Naive + Null) Genotype1a: Daclatasvir +Simeprevir + Ribavirin(Naive + Null)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 76 (9.21%)
    3 / 71 (4.23%)
    1 / 21 (4.76%)
         number of deaths (all causes)
    1
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatic cancer
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 71 (0.00%)
    1 / 21 (4.76%)
         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
    Post lumbar puncture syndrome
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 71 (0.00%)
    0 / 21 (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
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 71 (1.41%)
    0 / 21 (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
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 71 (1.41%)
    0 / 21 (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
    Nervous system disorders
    Hypoaesthesia
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 71 (0.00%)
    0 / 21 (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
    Intracranial haematoma
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 71 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 71 (0.00%)
    0 / 21 (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
    Neurotoxicity
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 71 (0.00%)
    0 / 21 (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
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 71 (0.00%)
    0 / 21 (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
    Cholelithiasis
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 71 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 71 (1.41%)
    0 / 21 (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
    Depression
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 71 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 71 (1.41%)
    0 / 21 (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
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 71 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 71 (1.41%)
    0 / 21 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Genotype 1b: Daclatasvir + Simeprevir (Naive + Null) Genotype1b: Daclatasvir +Simeprevir + Ribavirin (Naive + Null) Genotype1a: Daclatasvir +Simeprevir + Ribavirin(Naive + Null)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    49 / 76 (64.47%)
    63 / 71 (88.73%)
    21 / 21 (100.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 71 (1.41%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    2
    Hypertension
         subjects affected / exposed
    5 / 76 (6.58%)
    2 / 71 (2.82%)
    1 / 21 (4.76%)
         occurrences all number
    5
    2
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    15 / 76 (19.74%)
    16 / 71 (22.54%)
    5 / 21 (23.81%)
         occurrences all number
    17
    19
    9
    Chills
         subjects affected / exposed
    1 / 76 (1.32%)
    2 / 71 (2.82%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2
    3
    Fatigue
         subjects affected / exposed
    6 / 76 (7.89%)
    11 / 71 (15.49%)
    7 / 21 (33.33%)
         occurrences all number
    6
    12
    10
    Influenza like illness
         subjects affected / exposed
    5 / 76 (6.58%)
    1 / 71 (1.41%)
    3 / 21 (14.29%)
         occurrences all number
    5
    1
    7
    Irritability
         subjects affected / exposed
    3 / 76 (3.95%)
    1 / 71 (1.41%)
    2 / 21 (9.52%)
         occurrences all number
    3
    1
    3
    Pain
         subjects affected / exposed
    3 / 76 (3.95%)
    1 / 71 (1.41%)
    2 / 21 (9.52%)
         occurrences all number
    3
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 76 (2.63%)
    7 / 71 (9.86%)
    4 / 21 (19.05%)
         occurrences all number
    3
    9
    4
    Dyspnoea
         subjects affected / exposed
    4 / 76 (5.26%)
    11 / 71 (15.49%)
    2 / 21 (9.52%)
         occurrences all number
    4
    11
    4
    Epistaxis
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 71 (2.82%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    2
    Rhinorrhoea
         subjects affected / exposed
    1 / 76 (1.32%)
    0 / 71 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    0
    2
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 71 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    5
    Depression
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 71 (2.82%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    2
    Insomnia
         subjects affected / exposed
    4 / 76 (5.26%)
    7 / 71 (9.86%)
    1 / 21 (4.76%)
         occurrences all number
    4
    7
    3
    Sleep disorder
         subjects affected / exposed
    5 / 76 (6.58%)
    5 / 71 (7.04%)
    3 / 21 (14.29%)
         occurrences all number
    7
    6
    5
    Nervous system disorders
    Disturbance in attention
         subjects affected / exposed
    2 / 76 (2.63%)
    0 / 71 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    2
    0
    2
    Headache
         subjects affected / exposed
    16 / 76 (21.05%)
    10 / 71 (14.08%)
    6 / 21 (28.57%)
         occurrences all number
    22
    10
    7
    Paraesthesia
         subjects affected / exposed
    2 / 76 (2.63%)
    2 / 71 (2.82%)
    3 / 21 (14.29%)
         occurrences all number
    2
    2
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 76 (1.32%)
    12 / 71 (16.90%)
    5 / 21 (23.81%)
         occurrences all number
    2
    13
    7
    Neutropenia
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 71 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    8
    Thrombocytopenia
         subjects affected / exposed
    0 / 76 (0.00%)
    1 / 71 (1.41%)
    2 / 21 (9.52%)
         occurrences all number
    0
    1
    4
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 76 (1.32%)
    1 / 71 (1.41%)
    2 / 21 (9.52%)
         occurrences all number
    1
    1
    2
    Visual acuity reduced
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 71 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    3
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    4 / 76 (5.26%)
    0 / 71 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    4
    0
    4
    Abdominal pain
         subjects affected / exposed
    4 / 76 (5.26%)
    2 / 71 (2.82%)
    5 / 21 (23.81%)
         occurrences all number
    4
    2
    6
    Abdominal pain upper
         subjects affected / exposed
    3 / 76 (3.95%)
    5 / 71 (7.04%)
    1 / 21 (4.76%)
         occurrences all number
    3
    5
    1
    Constipation
         subjects affected / exposed
    6 / 76 (7.89%)
    5 / 71 (7.04%)
    4 / 21 (19.05%)
         occurrences all number
    9
    5
    5
    Diarrhoea
         subjects affected / exposed
    5 / 76 (6.58%)
    2 / 71 (2.82%)
    2 / 21 (9.52%)
         occurrences all number
    5
    2
    3
    Dyspepsia
         subjects affected / exposed
    2 / 76 (2.63%)
    5 / 71 (7.04%)
    0 / 21 (0.00%)
         occurrences all number
    2
    5
    0
    Gastric disorder
         subjects affected / exposed
    0 / 76 (0.00%)
    0 / 71 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    3
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 76 (3.95%)
    4 / 71 (5.63%)
    0 / 21 (0.00%)
         occurrences all number
    4
    4
    0
    Nausea
         subjects affected / exposed
    14 / 76 (18.42%)
    11 / 71 (15.49%)
    4 / 21 (19.05%)
         occurrences all number
    18
    11
    5
    Vomiting
         subjects affected / exposed
    0 / 76 (0.00%)
    3 / 71 (4.23%)
    2 / 21 (9.52%)
         occurrences all number
    0
    3
    4
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 76 (1.32%)
    12 / 71 (16.90%)
    3 / 21 (14.29%)
         occurrences all number
    3
    19
    4
    Jaundice
         subjects affected / exposed
    1 / 76 (1.32%)
    4 / 71 (5.63%)
    0 / 21 (0.00%)
         occurrences all number
    1
    4
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    3 / 76 (3.95%)
    4 / 71 (5.63%)
    0 / 21 (0.00%)
         occurrences all number
    3
    4
    0
    Dry skin
         subjects affected / exposed
    5 / 76 (6.58%)
    5 / 71 (7.04%)
    4 / 21 (19.05%)
         occurrences all number
    5
    5
    5
    Eczema
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 71 (2.82%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    2
    Photosensitivity reaction
         subjects affected / exposed
    6 / 76 (7.89%)
    3 / 71 (4.23%)
    1 / 21 (4.76%)
         occurrences all number
    7
    5
    3
    Pruritus
         subjects affected / exposed
    5 / 76 (6.58%)
    15 / 71 (21.13%)
    5 / 21 (23.81%)
         occurrences all number
    5
    16
    8
    Rash
         subjects affected / exposed
    3 / 76 (3.95%)
    9 / 71 (12.68%)
    3 / 21 (14.29%)
         occurrences all number
    3
    10
    6
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 76 (5.26%)
    0 / 71 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    5
    0
    2
    Myalgia
         subjects affected / exposed
    3 / 76 (3.95%)
    1 / 71 (1.41%)
    2 / 21 (9.52%)
         occurrences all number
    3
    1
    3
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 76 (2.63%)
    3 / 71 (4.23%)
    2 / 21 (9.52%)
         occurrences all number
    3
    3
    2
    Influenza
         subjects affected / exposed
    0 / 76 (0.00%)
    2 / 71 (2.82%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    2
    Nasopharyngitis
         subjects affected / exposed
    10 / 76 (13.16%)
    9 / 71 (12.68%)
    2 / 21 (9.52%)
         occurrences all number
    12
    11
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 76 (3.95%)
    1 / 71 (1.41%)
    4 / 21 (19.05%)
         occurrences all number
    3
    2
    6

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Dec 2012
    The primary purpose of this amendment was to clarify certain inclusion and exclusion criteria and maintain consistency with other direct-acting antiviral program Phase 2 studies. In addition there were other minor administrative changes. A summary, but not the full list of changes included in this amendment are bulleted below. • Changed the week for the interim analysis referring to treatment Week 12 to Week 16. Clarified that this would encompass subjects treated for at least 12 weeks of treatment and 4 weeks post treatment follow-up, (subtype 1b), or 16 weeks of treatment, (subtype 1a or 1b), or prematurely discontinued from the study • Changed from a minimum of 10% black/African-American to Approximately 10% black/Africian American • Additional information provided on how to define a Null responder • Additional criteria provided defining F3 cirrhosis. Reference to support this addition also added. • Further clarification on the types of psychiatric disorders and substance abuse that would be exclusionary in the study • Removed “confirmed” reference under the Laboratory exclusion criteria • Under prohibited and/or restricted treatments - included timeframe surrounding the stopping of such medications and starting study drug • Under prohibited and/or restricted treatments - Additional restricted medications added under CYP3A4 inducers • ECG added to Week 8 and End of Treatment study visits while in Treatment Phase and Week 8 and End of Treatment study visits if subject is in Rescue Treatment Phase • Added a timeframe for how long the post treatment follow-up period should be for 1b subjects that discontinue prior to re-randomization • Added the following sections; “Post Treatment Study Follow up”, “Withdrawal of Consent”, and “Lost to Follow up” • Additional language added regarding study drug disposal and return • Time window added for the Week 2 PK samples • Added a note regarding the definition of HCV RNA results

    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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