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    Clinical Trial Results:
    Open-Label, Randomized Study of Daclatasvir, Sofosbuvir, and Ribavirin for 12 vs. 16 weeks in Treatment-Naïve and Treatment-Experienced Patients with Genotype 3 Chronic Hepatitis C Infection with Compensated Advanced Fibrosis/Cirrhosis (F3/F4)

    Summary
    EudraCT number
    		 2014-005310-28
    Trial protocol
    		 FR  
    Global end of trial date
    18 Dec 2015

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    AI444-326
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02319031
    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
    18 Dec 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to determine if the use of Daclatasvir, Sofosbuvir, and Ribavarin in combination for 12 or 16 weeks is safe and effective in the treatment of Genotype 3 Chronic Hepatitis C (HCV) in patients with HCV Genotype 3 infection and advanced fibrosis or compensated cirrhosis. Patients in this study may have already been treated prior for HCV or may have never received treatment for their HCV.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    16 Feb 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 22
    Country: Number of subjects enrolled
    Australia: 31
    Worldwide total number of subjects
    53
    EEA total number of subjects
    22
    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)
    52
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 10 sites in 2 countries.

    Pre-assignment
    Screening details
    		 A total of 53 subjects were enrolled and 50 were randomized and treated (24 to the 12 week arm, 26 to the 16 week arm). Reasons for non-randomized were 3 subjects no longer met study criteria.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Daclatasvir + Sofosbuvir + Ribavirin (12 Weeks)
    Arm description
    		 Treatment-naïve and treatment-experienced participants with HCV Genotype 3 infection and advanced fibrosis or compensated cirrhosis (F3 or F4) were treated for 12 weeks with oral dosing of Daclatasvir (DCV) 60 mg once daily (QD), Sofosbuvir (SOF) 400 mg QD, and Ribavirin (RBV) 1000-1200 mg (weight based dosing) split into AM and PM dosing. Participants received either 400 mg (2 tablets for participants < 75 kg) or 600 mg (3 tablets for participants ≥ 75 kg) of RBV in the morning with food and 600 mg (3 tablets) of RBV in the evening with food. After the completion of the 12 week treatment period, participants were followed off treatment for 24 weeks. mg=milligram; kg=kilogram
    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 (60 mg) QD. Daclatasvir was administered as 1 tablet in the AM.

    Investigational medicinal product name
    Sofosbuvir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Sofosbuvir orally (400 mg) QD. Sofosbuvir was administered as 1 tablet in the AM.

    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 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.

    Arm title
    		 Daclatasvir + Sofosbuvir + Ribavirin (16 Weeks)
    Arm description
    		 Treatment-naïve and treatment-experienced participants with HCV Genotype 3 infection and advanced fibrosis or compensated cirrhosis (F3 or F4) were treated for 16 weeks with oral dosing of Daclatasvir (DCV) 60 mg once daily (QD), Sofosbuvir (SOF) 400 mg QD, and Ribavirin (RBV) 1000-1200 mg (weight based dosing) split into AM and PM dosing. Participants received either 400 mg (2 tablets for participants < 75 kg) or 600 mg (3 tablets for participants ≥ 75 kg) of RBV in the morning with food and 600 mg (3 tablets) of RBV in the evening with food. After the completion of the 16 week treatment period, participants were followed off treatment for 24 weeks. mg=milligram; kg=kilogram
    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 (60 mg) QD. Daclatasvir was administered as 1 tablet in the AM.

    Investigational medicinal product name
    Sofosbuvir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Sofosbuvir orally (400 mg) QD. Sofosbuvir was administered as 1 tablet in the AM.

    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 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.

    Number of subjects in period 1 [1]
    		Daclatasvir + Sofosbuvir + Ribavirin (12 Weeks) Daclatasvir + Sofosbuvir + Ribavirin (16 Weeks)
    Started
    24
    26
    Completed
    23
    26
    Not completed
    1
    0
         Death
    1
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial as out of 53 subjects who were enrolled, 50 subjects were treated in the study.
    Period 2
    Period 2 title
    Follow-up Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Daclatasvir + Sofosbuvir + Ribavirin (12 Weeks)
    Arm description
    		 No treatment was received in the follow-up period. After the completion of the 12 week treatment period, participants were followed off treatment for 24 weeks. In the treatment period, treatment-naïve and treatment-experienced participants with HCV Genotype 3 infection and advanced fibrosis or compensated cirrhosis (F3 or F4) were treated for 12 weeks with oral dosing of Daclatasvir (DCV) 60 mg once daily (QD), Sofosbuvir (SOF) 400 mg QD, and Ribavirin (RBV) 1000-1200 mg (weight based dosing) split into AM and PM dosing. Participants received either 400 mg (2 tablets for participants < 75 kg) or 600 mg (3 tablets for participants ≥ 75 kg) of RBV in the morning with food and 600 mg (3 tablets) of RBV in the evening with food.
    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
    No treatment was received in the follow-up, however, subjects received a 60 mg Daclatasvir tablet orally QD in the treatment period.

    Investigational medicinal product name
    Sofosbuvir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    No treatment was received in the follow-up, however, subjects received a 400 mg Sofosbuvir tablet orally QD in the treatment period.

    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
    No treatment was received in the follow-up, however, subjects received a daily dose of 1,000 to 1,200 mg Ribavirin orally in the treatment period, which was administered as either 400 mg (2 tablets for subjects < 75 kg) or 600 mg (3 tablets for subjects ≥ 75 kg) of RBV in the morning with food and 600 mg (3 tablets) of RBV in the evening with food.

    Arm title
    		 Daclatasvir + Sofosbuvir + Ribavirin (16 Weeks)
    Arm description
    		 No treatment was received in the follow-up period. After the completion of the 16 week treatment period, participants were followed off treatment for 24 weeks. Treatment-naïve and treatment-experienced participants with HCV Genotype 3 infection and advanced fibrosis or compensated cirrhosis (F3 or F4) were treated for 16 weeks with oral dosing of Daclatasvir (DCV) 60 mg once daily (QD), Sofosbuvir (SOF) 400 mg QD, and Ribavirin (RBV) 1000-1200 mg (weight based dosing) split into AM and PM dosing. Participants received either 400 mg (2 tablets for participants < 75 kg) or 600 mg (3 tablets for participants ≥ 75 kg) of RBV in the morning with food and 600 mg (3 tablets) of RBV in the evening with food.
    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
    No treatment was received in the follow-up, however, subjects received a 60 mg Daclatasvir tablet orally QD in the treatment period.

    Investigational medicinal product name
    Sofosbuvir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    No treatment was received in the follow-up, however, subjects received a 400 mg Sofosbuvir tablet orally QD in the treatment period.

    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
    No treatment was received in the follow-up, however, subjects received a daily dose of 1,000 to 1,200 mg Ribavirin orally in the treatment period, which was administered as either 400 mg (2 tablets for subjects < 75 kg) or 600 mg (3 tablets for subjects ≥ 75 kg) of RBV in the morning with food and 600 mg (3 tablets) of RBV in the evening with food.

    Number of subjects in period 2
    		Daclatasvir + Sofosbuvir + Ribavirin (12 Weeks) Daclatasvir + Sofosbuvir + Ribavirin (16 Weeks)
    Started
    23
    26
    Completed
    23
    26

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Daclatasvir + Sofosbuvir + Ribavirin (12 Weeks)
    Reporting group description
    		 Treatment-naïve and treatment-experienced participants with HCV Genotype 3 infection and advanced fibrosis or compensated cirrhosis (F3 or F4) were treated for 12 weeks with oral dosing of Daclatasvir (DCV) 60 mg once daily (QD), Sofosbuvir (SOF) 400 mg QD, and Ribavirin (RBV) 1000-1200 mg (weight based dosing) split into AM and PM dosing. Participants received either 400 mg (2 tablets for participants < 75 kg) or 600 mg (3 tablets for participants ≥ 75 kg) of RBV in the morning with food and 600 mg (3 tablets) of RBV in the evening with food. After the completion of the 12 week treatment period, participants were followed off treatment for 24 weeks. mg=milligram; kg=kilogram

    Reporting group title
    Daclatasvir + Sofosbuvir + Ribavirin (16 Weeks)
    Reporting group description
    		 Treatment-naïve and treatment-experienced participants with HCV Genotype 3 infection and advanced fibrosis or compensated cirrhosis (F3 or F4) were treated for 16 weeks with oral dosing of Daclatasvir (DCV) 60 mg once daily (QD), Sofosbuvir (SOF) 400 mg QD, and Ribavirin (RBV) 1000-1200 mg (weight based dosing) split into AM and PM dosing. Participants received either 400 mg (2 tablets for participants < 75 kg) or 600 mg (3 tablets for participants ≥ 75 kg) of RBV in the morning with food and 600 mg (3 tablets) of RBV in the evening with food. After the completion of the 16 week treatment period, participants were followed off treatment for 24 weeks. mg=milligram; kg=kilogram

    Reporting group values
    		 Daclatasvir + Sofosbuvir + Ribavirin (12 Weeks) Daclatasvir + Sofosbuvir + Ribavirin (16 Weeks) Total
    Number of subjects
    		 24 26 50
    Age categorical
    Units: Subjects
        < 65 years
    		 23 26 49
        >= 65 years
    		 1 0 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 53 ( 7.77 ) 55 ( 5.75 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 4 10
        Male
    		 18 22 40

    End points

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    End points reporting groups
    Reporting group title
    Daclatasvir + Sofosbuvir + Ribavirin (12 Weeks)
    Reporting group description
    		 Treatment-naïve and treatment-experienced participants with HCV Genotype 3 infection and advanced fibrosis or compensated cirrhosis (F3 or F4) were treated for 12 weeks with oral dosing of Daclatasvir (DCV) 60 mg once daily (QD), Sofosbuvir (SOF) 400 mg QD, and Ribavirin (RBV) 1000-1200 mg (weight based dosing) split into AM and PM dosing. Participants received either 400 mg (2 tablets for participants < 75 kg) or 600 mg (3 tablets for participants ≥ 75 kg) of RBV in the morning with food and 600 mg (3 tablets) of RBV in the evening with food. After the completion of the 12 week treatment period, participants were followed off treatment for 24 weeks. mg=milligram; kg=kilogram

    Reporting group title
    Daclatasvir + Sofosbuvir + Ribavirin (16 Weeks)
    Reporting group description
    		 Treatment-naïve and treatment-experienced participants with HCV Genotype 3 infection and advanced fibrosis or compensated cirrhosis (F3 or F4) were treated for 16 weeks with oral dosing of Daclatasvir (DCV) 60 mg once daily (QD), Sofosbuvir (SOF) 400 mg QD, and Ribavirin (RBV) 1000-1200 mg (weight based dosing) split into AM and PM dosing. Participants received either 400 mg (2 tablets for participants < 75 kg) or 600 mg (3 tablets for participants ≥ 75 kg) of RBV in the morning with food and 600 mg (3 tablets) of RBV in the evening with food. After the completion of the 16 week treatment period, participants were followed off treatment for 24 weeks. mg=milligram; kg=kilogram
    Reporting group title
    Daclatasvir + Sofosbuvir + Ribavirin (12 Weeks)
    Reporting group description
    		 No treatment was received in the follow-up period. After the completion of the 12 week treatment period, participants were followed off treatment for 24 weeks. In the treatment period, treatment-naïve and treatment-experienced participants with HCV Genotype 3 infection and advanced fibrosis or compensated cirrhosis (F3 or F4) were treated for 12 weeks with oral dosing of Daclatasvir (DCV) 60 mg once daily (QD), Sofosbuvir (SOF) 400 mg QD, and Ribavirin (RBV) 1000-1200 mg (weight based dosing) split into AM and PM dosing. Participants received either 400 mg (2 tablets for participants < 75 kg) or 600 mg (3 tablets for participants ≥ 75 kg) of RBV in the morning with food and 600 mg (3 tablets) of RBV in the evening with food.

    Reporting group title
    Daclatasvir + Sofosbuvir + Ribavirin (16 Weeks)
    Reporting group description
    		 No treatment was received in the follow-up period. After the completion of the 16 week treatment period, participants were followed off treatment for 24 weeks. Treatment-naïve and treatment-experienced participants with HCV Genotype 3 infection and advanced fibrosis or compensated cirrhosis (F3 or F4) were treated for 16 weeks with oral dosing of Daclatasvir (DCV) 60 mg once daily (QD), Sofosbuvir (SOF) 400 mg QD, and Ribavirin (RBV) 1000-1200 mg (weight based dosing) split into AM and PM dosing. Participants received either 400 mg (2 tablets for participants < 75 kg) or 600 mg (3 tablets for participants ≥ 75 kg) of RBV in the morning with food and 600 mg (3 tablets) of RBV in the evening with food.

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

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    End point title
    		 Percent of Subjects With a Sustained Virologic Response (SVR) at Follow-up Week 12 (SVR12) [1]
    End point description
    SVR12, defined as percentage of subjects with hepatitis C virus (HCV) ribonucleic acid (RNA) < lower limit of quantitation (LLOQ), target detected (TD) or target not detected (TND) at follow-up Week 12. SVR12 imputation was based on Next Value Carried Backwards (NVCB) approach. HCV RNA measurements were excluded after the start of non-study anti-HCV medication on treatment or during follow-up. The analysis was performed with all treated subjects; enrolled subjects who received at least 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Follow-up Week 12
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive summary statistics were planned for this outcome measure.
    End point values
    		 Daclatasvir + Sofosbuvir + Ribavirin (12 Weeks) Daclatasvir + Sofosbuvir + Ribavirin (16 Weeks)
    Number of subjects analysed
    24
    26
    Units: percentage of subjects
        number (confidence interval 95%)
    87.5 (67.6 to 97.3)
    92.3 (74.9 to 99.1)
    No statistical analyses for this end point

    Secondary: Percent of Participants With a Sustained Virologic Response (SVR) at Follow-up Week 4 (SVR4) and Follow-up Week 24 (SVR24)

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    End point title
    		 Percent of Participants With a Sustained Virologic Response (SVR) at Follow-up Week 4 (SVR4) and Follow-up Week 24 (SVR24)
    End point description
    SVR4, defined as percentage of subjects with hepatitis C virus (HCV) ribonucleic acid (RNA) < lower limit of quantitation (LLOQ), target detected (TD) or target not detected (TND) at follow-up Week 4. SVR24, defined as percentage of subjects with hepatitis C virus (HCV) ribonucleic acid (RNA) < lower limit of quantitation (LLOQ), target detected (TD) or target not detected (TND) at follow-up Week 24. SVR4 imputation was based on Next Value Carried Backwards (NVCB) approach. SVR24 imputation was based on missing being treated as non-responder. HCV RNA measurements were excluded after the start of non-study anti-HCV medication on treatment or during follow-up. The analysis was performed with all treated subjects; enrolled subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Follow-up Weeks 4 and 24
    End point values
    		 Daclatasvir + Sofosbuvir + Ribavirin (12 Weeks) Daclatasvir + Sofosbuvir + Ribavirin (16 Weeks)
    Number of subjects analysed
    24
    26
    Units: percentage of subjects
    number (confidence interval 95%)
        Follow-up Week 4 (SVR4)
    87.5 (67.6 to 97.3)
    96.2 (80.4 to 99.9)
        Follow-up Week 24 (SVR 24)
    87.5 (67.6 to 97.3)
    92.3 (74.9 to 99.1)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Death, Serious Adverse Events (SAEs), Discontinuation Due to Adverse Events (AEs), Grade 3 or Grade 4 (Grade3/4) AEs, and Grade3/4 Laboratory Abnormalities

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    End point title
    		 Number of Subjects With Death, Serious Adverse Events (SAEs), Discontinuation Due to Adverse Events (AEs), Grade 3 or Grade 4 (Grade3/4) AEs, and Grade3/4 Laboratory Abnormalities
    End point description
    Serious adverse event (SAE) defined: a medical event that at any dose results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Adverse event (AE) defined: any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. The degree of the adverse event or laboratory abnormality are evaluated by grades: Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4=Life-threatening or disabling, Gr 5=Death. Grading as per using National Cancer Institute Common Terminology Criteria (NCI CTC) Version 3.0 criteria. The analysis was performed with all treated subjects; enrolled subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    Date of First Dose of Study Drug to 7 Days post last dose of study drug (up to 13 weeks or 17 weeks depending on the randomized treatment group)
    End point values
    		 Daclatasvir + Sofosbuvir + Ribavirin (12 Weeks) Daclatasvir + Sofosbuvir + Ribavirin (16 Weeks)
    Number of subjects analysed
    24
    26
    Units: subjects
        Death
    1
    0
        SAEs
    2
    3
        Discontinuation due to AEs
    0
    0
        Grade 3/4 AEs
    2
    2
        Grade 3/4 Laboratory Abnormalities
    1
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs were reported from date of first dose of study drug to 30 days post discontinuation of the last dose. Non-serious AEs were reported from date of first dose of study drug to 7 days post discontinuation of the last dose.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Daclatasvir + Sofosbuvir + Ribavirin (12 Weeks)
    Reporting group description
    		 Treatment-naïve and treatment-experienced participants with HCV Genotype 3 infection and advanced fibrosis or compensated cirrhosis (F3 or F4) were treated for 12 weeks with oral dosing of Daclatasvir (DCV) 60 mg once daily (QD), Sofosbuvir (SOF) 400 mg QD, and Ribavirin (RBV) 1000-1200 mg (weight based dosing) split into AM and PM dosing. Participants received either 400 mg (2 tablets for participants < 75 kg) or 600 mg (3 tablets for participants ≥ 75 kg) of RBV in the morning with food and 600 mg (3 tablets) of RBV in the evening with food. After the completion of the 12 week treatment period, participants were followed off treatment for 24 weeks. mg=milligram; kg=kilogram

    Reporting group title
    Daclatasvir + Sofosbuvir + Ribavirin (16 Weeks)
    Reporting group description
    		 Treatment-naïve and treatment-experienced participants with HCV Genotype 3 infection and advanced fibrosis or compensated cirrhosis (F3 or F4) were treated for 16 weeks with oral dosing of Daclatasvir (DCV) 60 mg once daily (QD), Sofosbuvir (SOF) 400 mg QD, and Ribavirin (RBV) 1000-1200 mg (weight based dosing) split into AM and PM dosing. Participants received either 400 mg (2 tablets for participants < 75 kg) or 600 mg (3 tablets for participants ≥ 75 kg) of RBV in the morning with food and 600 mg (3 tablets) of RBV in the evening with food. After the completion of the 16 week treatment period, participants were followed off treatment for 24 weeks. mg=milligram; kg=kilogram

    Serious adverse events
    		 Daclatasvir + Sofosbuvir + Ribavirin (12 Weeks) Daclatasvir + Sofosbuvir + Ribavirin (16 Weeks)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 24 (8.33%)
    3 / 26 (11.54%)
         number of deaths (all causes)
    1
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Arteriosclerosis
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Congestive cardiomyopathy
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Somnolence
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Daclatasvir + Sofosbuvir + Ribavirin (12 Weeks) Daclatasvir + Sofosbuvir + Ribavirin (16 Weeks)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 24 (87.50%)
    22 / 26 (84.62%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 24 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 24 (29.17%)
    5 / 26 (19.23%)
         occurrences all number
    7
    6
    Lethargy
         subjects affected / exposed
    2 / 24 (8.33%)
    2 / 26 (7.69%)
         occurrences all number
    2
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    5
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 24 (8.33%)
    5 / 26 (19.23%)
         occurrences all number
    2
    9
    Fatigue
         subjects affected / exposed
    6 / 24 (25.00%)
    7 / 26 (26.92%)
         occurrences all number
    7
    7
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    2
    Abdominal discomfort
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    2
    Abdominal pain upper
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    3
    0
    Diarrhoea
         subjects affected / exposed
    1 / 24 (4.17%)
    4 / 26 (15.38%)
         occurrences all number
    1
    4
    Mouth ulceration
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    2
    Nausea
         subjects affected / exposed
    3 / 24 (12.50%)
    1 / 26 (3.85%)
         occurrences all number
    3
    1
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 24 (8.33%)
    3 / 26 (11.54%)
         occurrences all number
    2
    5
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 24 (4.17%)
    2 / 26 (7.69%)
         occurrences all number
    1
    2
    Photosensitivity reaction
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Hyperhidrosis
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Dry skin
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    8 / 24 (33.33%)
    7 / 26 (26.92%)
         occurrences all number
    8
    7
    Depression
         subjects affected / exposed
    1 / 24 (4.17%)
    2 / 26 (7.69%)
         occurrences all number
    1
    2
    Depressed mood
         subjects affected / exposed
    1 / 24 (4.17%)
    2 / 26 (7.69%)
         occurrences all number
    2
    2
    Irritability
         subjects affected / exposed
    5 / 24 (20.83%)
    2 / 26 (7.69%)
         occurrences all number
    5
    3
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 24 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Feb 2015
    This amendment addressed the following items: • Clarify the inclusion requirements for liver biopsies for those patients who are considered F3 • Provide information included in EU approved Daklinza® (daclatasvir) Product Information related to treatment indication for patients with Genotype 3 and advanced liver disease (cirrhosis) • Contraception requirements and pregnancy testing for ribavirin (RBV) added • Updated safety information regarding patients receiving DCV+SOF when also administered with amiodarone • Amiodarone added to prohibited medications • Minor editorial and format changes.
    07 May 2015
    This amendment addressed the following item: • Revision to safety information regarding patients receiving DCV+SOF when also administered with amiodarone.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/26822022
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