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    Clinical Trial Results:
    Phase 3 open label study evaluating the efficacy and safety of pegylated interferon lambda-1a, in combination with ribavirin and daclatasvir, for treatment of chronic HCV infection with treatment naïve genotypes 1, 2, 3 or 4 in subjects co-infected with HIV.

    Summary
    EudraCT number
    		 2012-003280-22
    Trial protocol
    		 GB   BE   IT   DE   ES   FR  
    Global end of trial date
    27 Aug 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Aug 2016
    First version publication date
    21 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AI452-032
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01866930
    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
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, clinical.trials@bms.com
    Scientific contact
    EU Study Start-Up Unit, Bristol-Myers Squibb International Corporation, clinical.trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Aug 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Aug 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate Sustained Virologic Response at post treatment Week 12 (SVR12) following treatment with Lambda/RBV/DCV in chronic HCV GT-1, -2, -3 or -4 subjects co-infected with HIV-1.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization Good Clinical Practice Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 May 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 18
    Country: Number of subjects enrolled
    Spain: 93
    Country: Number of subjects enrolled
    United Kingdom: 25
    Country: Number of subjects enrolled
    Belgium: 18
    Country: Number of subjects enrolled
    France: 30
    Country: Number of subjects enrolled
    Germany: 16
    Country: Number of subjects enrolled
    Italy: 58
    Country: Number of subjects enrolled
    Argentina: 38
    Country: Number of subjects enrolled
    Canada: 43
    Country: Number of subjects enrolled
    Mexico: 13
    Country: Number of subjects enrolled
    Russian Federation: 54
    Country: Number of subjects enrolled
    United States: 47
    Worldwide total number of subjects
    453
    EEA total number of subjects
    258
    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)
    450
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were enrolled at 58 investigational sites in 13 countries.

    Pre-assignment
    Screening details
    		 A total of 453 subjects were enrolled in the study. 300 subjects were randomized and received treatment. 153 subjects were not randomized to a treatment group due to Adverse Event (3), withdrawal of consent (13), loss to follow-up (4), administrative reasons per sponsor (5), no longer met study criteria (105), or other reasons (23).

    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
    		 Cohort A: HCV GT-2 or GT-3
    Arm description
    		 Subjects with HCV (Genotype 2 or 3) and HIV co-infection were treated with Lambda/RBV/DCV for 12 weeks followed by Lambda/RBV for 12 weeks, for a total treatment duration of 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pegylated interferon Lambda-1a
    Investigational medicinal product code
    Other name
    Lambda, pegIFN-1a, BMS-914143
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects were administered 180μg of Lambda via subcutaneous injection, once weekly, for a planned duration of 24 weeks.

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    RBV, Ribasphere
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered 200 mg Ribavirin tablets , orally, twice daily, for a planned duration of 24 weeks. Subjects received a total dose of 800 mg/day in two divided doses (two 200 mg tablets in the morning with food and two 200 mg tablets in the evening with food).

    Investigational medicinal product name
    Daclatasvir
    Investigational medicinal product code
    Other name
    DCV, BMS-790052
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered 30 mg Daclatasvir tablets, orally, once daily, for a maximum of 12 weeks. The total daily dose was 30, 60 or 90 mg depending on the HIV concomitant regimen.

    Arm title
    		 Cohort B: HCV GT-1 or GT-4
    Arm description
    		 Subjects with HCV (Genotype 1 or 4) and HIV co-infection were treated with Lambda/RBV/DCV for 12 weeks followed by Lambda/RBV for either 12 or 36 weeks. Subjects who achieved an extended rapid virologic response (eRVR) during the initial 12 weeks of treatment with Lambda/RBV/DCV were then treated with Lambda/RBV for 12 weeks for a total of 24 weeks. Subjects who did not achieve eRVR during the initial 12 weeks of treatment with Lambda/RBV/DCV were then treated with Lambda/RBV for 36 weeks for a total of 48 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pegylated interferon Lambda-1a
    Investigational medicinal product code
    Other name
    Lambda, pegIFN-1a, BMS-914143
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects were administered 180μg of Lambda via subcutaneous injection, once weekly, for a maximum of 48 weeks.

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    RBV, Ribasphere
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered 200 mg Ribavirin tablets , orally, twice daily, for a maximum duration of 48 weeks. For subjects weighing < 75 kg, the total dose was 1000 mg/day in two divided doses (two 200 mg tablets in the morning with food and three 200 mg tablets in the evening with food). For subjects weighing >= 75 kg, the total dose was 1200 mg/day in two divided doses (three 200 mg tablets in morning with food and three 200 mg tablets in evening with food).

    Investigational medicinal product name
    Daclatasvir
    Investigational medicinal product code
    Other name
    DCV, BMS-790052
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered 30 mg Daclatasvir tablets, orally, once daily, for a maximum of 12 weeks. The total daily dose was 30, 60 or 90 mg depending on the HIV concomitant regimen.

    Number of subjects in period 1 [1]
    		Cohort A: HCV GT-2 or GT-3 Cohort B: HCV GT-1 or GT-4
    Started
    104
    196
    Completed
    95
    161
    Not completed
    9
    35
         Consent withdrawn by subject
    -
    3
         Adverse event, non-fatal
    4
    12
         Subject request to discontinue study treatment
    2
    5
         Death
    -
    2
         Lost to follow-up
    1
    1
         Poor/non-compliance
    -
    2
         Subject no longer meets study criteria
    -
    1
         unspecified
    1
    -
         Lack of efficacy
    1
    9
    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: Of the 453 subjects enrolled, 300 were randomized and received treatment.
    Period 2
    Period 2 title
    Follow-up Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort A: HCV GT-2 or GT-3
    Arm description
    		 Subjects with HCV (Genotype 2 or 3) and HIV co-infection were to be followed up for a planned duration of 24 weeks after 24 weeks of treatment (Lambda/RBV/DCV for 12 weeks followed by Lambda/RBV for 12 weeks).
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Cohort B: HCV GT-1 or GT-4
    Arm description
    		 Subjects with HCV (Genotype 1 or 4) and HIV co-infection were to be followed up for a planned duration of 24 weeks after 24 or 48 weeks of treatment (Lambda/RBV/DCV for 12 weeks followed by Lambda/RBV for either 12 or 36 weeks).
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Cohort A: HCV GT-2 or GT-3 Cohort B: HCV GT-1 or GT-4
    Started
    95
    161
    Completed
    96
    176
    Not completed
    6
    9
         Consent withdrawn by subject
    3
    3
         Follow-up no longer required per protocol
    1
    -
         Lost to follow-up
    1
    1
         unspecified
    1
    5
    Joined
    7
    24
         Rejoined for follow-up
    7
    24

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort A: HCV GT-2 or GT-3
    Reporting group description
    		 Subjects with HCV (Genotype 2 or 3) and HIV co-infection were treated with Lambda/RBV/DCV for 12 weeks followed by Lambda/RBV for 12 weeks, for a total treatment duration of 24 weeks.

    Reporting group title
    Cohort B: HCV GT-1 or GT-4
    Reporting group description
    		 Subjects with HCV (Genotype 1 or 4) and HIV co-infection were treated with Lambda/RBV/DCV for 12 weeks followed by Lambda/RBV for either 12 or 36 weeks. Subjects who achieved an extended rapid virologic response (eRVR) during the initial 12 weeks of treatment with Lambda/RBV/DCV were then treated with Lambda/RBV for 12 weeks for a total of 24 weeks. Subjects who did not achieve eRVR during the initial 12 weeks of treatment with Lambda/RBV/DCV were then treated with Lambda/RBV for 36 weeks for a total of 48 weeks.

    Reporting group values
    		 Cohort A: HCV GT-2 or GT-3 Cohort B: HCV GT-1 or GT-4 Total
    Number of subjects
    		 104 196 300
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 104 195 299
        From 65-84 years
    		 0 1 1
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 28 40 68
        Male
    		 76 156 232
    HCV Genotype
    Units: Subjects
        HCV GT-1
    		 0 149 149
        HCV GT-2
    		 20 0 20
        HCV GT-3
    		 83 0 83
        HCV GT-4
    		 0 41 41
        Unknown
    		 1 6 7

    End points

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    End points reporting groups
    Reporting group title
    Cohort A: HCV GT-2 or GT-3
    Reporting group description
    		 Subjects with HCV (Genotype 2 or 3) and HIV co-infection were treated with Lambda/RBV/DCV for 12 weeks followed by Lambda/RBV for 12 weeks, for a total treatment duration of 24 weeks.

    Reporting group title
    Cohort B: HCV GT-1 or GT-4
    Reporting group description
    		 Subjects with HCV (Genotype 1 or 4) and HIV co-infection were treated with Lambda/RBV/DCV for 12 weeks followed by Lambda/RBV for either 12 or 36 weeks. Subjects who achieved an extended rapid virologic response (eRVR) during the initial 12 weeks of treatment with Lambda/RBV/DCV were then treated with Lambda/RBV for 12 weeks for a total of 24 weeks. Subjects who did not achieve eRVR during the initial 12 weeks of treatment with Lambda/RBV/DCV were then treated with Lambda/RBV for 36 weeks for a total of 48 weeks.
    Reporting group title
    Cohort A: HCV GT-2 or GT-3
    Reporting group description
    		 Subjects with HCV (Genotype 2 or 3) and HIV co-infection were to be followed up for a planned duration of 24 weeks after 24 weeks of treatment (Lambda/RBV/DCV for 12 weeks followed by Lambda/RBV for 12 weeks).

    Reporting group title
    Cohort B: HCV GT-1 or GT-4
    Reporting group description
    		 Subjects with HCV (Genotype 1 or 4) and HIV co-infection were to be followed up for a planned duration of 24 weeks after 24 or 48 weeks of treatment (Lambda/RBV/DCV for 12 weeks followed by Lambda/RBV for either 12 or 36 weeks).

    Primary: Number of subjects with Sustained Virologic Response at post-treatment week 12 (SVR12)

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    End point title
    		 Number of subjects with Sustained Virologic Response at post-treatment week 12 (SVR12) [1]
    End point description
    SVR12 was defined as HCV RNA less than lower limit of quantification (< LLOQ) (25 IU/mL; target detected or not detected) at follow-up week 12. The analysis was performed in all treated subjects using modified intent-to-treat algorithm, where the numerator is based on subjects meeting the response criteria and the denominator is based on all treated subjects (Non-completer = Failure).
    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
    		 Cohort A: HCV GT-2 or GT-3 Cohort B: HCV GT-1 or GT-4
    Number of subjects analysed
    104
    196
    Units: subjects
    88
    149
    No statistical analyses for this end point

    Secondary: Number of subjects with rapid virologic response (RVR) and extended rapid virologic response (eRVR)

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    End point title
    		 Number of subjects with rapid virologic response (RVR) and extended rapid virologic response (eRVR)
    End point description
    RVR is defined as HCV RNA < LLOQ target not detected at Week 4 and eRVR defined as HCV RNA < LLOQ target not detected at Weeks 4 and 12. The analysis was performed in all treated subjects using modified intent-to-treat algorithm, where the numerator is based on subjects meeting the response criteria and the denominator is based on all treated subjects (Non-completer = Failure).
    End point type
    Secondary
    End point timeframe
    Treatment weeks 4 and 12
    End point values
    		 Cohort A: HCV GT-2 or GT-3 Cohort B: HCV GT-1 or GT-4
    Number of subjects analysed
    104
    196
    Units: subjects
        RVR
    82
    149
        eRVR
    80
    138
    No statistical analyses for this end point

    Secondary: Number of subjects with Sustained Virologic Response at post-treatment week 24 (SVR24)

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    End point title
    		 Number of subjects with Sustained Virologic Response at post-treatment week 24 (SVR24)
    End point description
    SVR24 was defined as HCV RNA < LLOQ (25 IU/mL; target detected or not detected) at 24 weeks post treatment. The analysis was performed in all treated subjects using modified intent-to-treat algorithm (numerator is based on subjects meeting the response criteria and the denominator is based on all treated subjects (Non-completer = Failure).
    End point type
    Secondary
    End point timeframe
    Follow-up week 24
    End point values
    		 Cohort A: HCV GT-2 or GT-3 Cohort B: HCV GT-1 or GT-4
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: subjects
    Notes
    [2] - The study was ended prematurely, giving few subjects an opportunity to reach follow-up week 24
    [3] - The study was ended prematurely, giving few subjects an opportunity to reach follow-up week 24
    No statistical analyses for this end point

    Secondary: Number of subjects with treatment emergent cytopenic abnormalities

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    End point title
    		 Number of subjects with treatment emergent cytopenic abnormalities
    End point description
    All treated subjects were monitored for treatment emergent cytopenic abnormalities (anemia as defined by hemoglobin (Hb) < 10 g/dL, and/or neutropenia as defined by absolute neutrophil count (ANC) < 750 mm3 and/or thrombocytopenia as defined by platelets < 50,000/mm3) during the treatment period (Weeks 1, 2, 4, 6, 8, 12, 20, and 24, and at Weeks 28, 32, 36, 40, 44, and 48 for subjects requiring those visits).
    End point type
    Secondary
    End point timeframe
    After Day 1 to end of treatment; up to Weeks 24 or 48.
    End point values
    		 Cohort A: HCV GT-2 or GT-3 Cohort B: HCV GT-1 or GT-4
    Number of subjects analysed
    104
    196
    Units: subjects
    4
    15
    No statistical analyses for this end point

    Secondary: Number of subjects with on-treatment IFN-associated Flu-like or Musculoskeletal symptoms

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    End point title
    		 Number of subjects with on-treatment IFN-associated Flu-like or Musculoskeletal symptoms
    End point description
    All treated subjects were monitored for IFN-associated Flu-like and Musculoskeletal symptoms. Flu-like symptoms were defined as pyrexia, chills, or pain. Musculoskeletal symptoms were defined as arthralgia, myalgia, or back pain. Subjects were monitored throughout the treatment period during the treatment period (After day 1 up to week 24, or After day 1 up to week 48 for subjects requiring those visits).
    End point type
    Secondary
    End point timeframe
    After day 1 until end of treatment; Up to weeks 24 or 48.
    End point values
    		 Cohort A: HCV GT-2 or GT-3 Cohort B: HCV GT-1 or GT-4
    Number of subjects analysed
    104
    196
    Units: subjects
        Musculoskeletal symptoms
    6
    21
        Flu-like symptoms
    6
    19
    No statistical analyses for this end point

    Secondary: Number of subjects who died or experienced Severe Adverse Events (SAEs), Dose reductions of Lambda or Discontinuation due to Adverse Events (AEs)

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    End point title
    		 Number of subjects who died or experienced Severe Adverse Events (SAEs), Dose reductions of Lambda or Discontinuation due to Adverse Events (AEs)
    End point description
    AE=any new unfavorable symptom, sign, or disease or worsening of a preexisting condition that may not have a causal relationship with treatment. SAE=a medical event that. at any dose, results in death, persistent or significant disability/incapacity, or drug dependency/abuse; is life-threatening, an important medical event, or a congenital anomaly/birth defect; or requires or prolongs hospitalization. Treatment-related=having certain, probable, possible, or missing relationship to study drug. The analysis included all treated subjects up to the end of the treatment period (Day 1 to week 24, or Day 1 to week 48 for subjects requiring those visits).
    End point type
    Secondary
    End point timeframe
    Day 1 to end of treatment; up to week 24 or week 48
    End point values
    		 Cohort A: HCV GT-2 or GT-3 Cohort B: HCV GT-1 or GT-4
    Number of subjects analysed
    104
    196
    Units: subjects
        Deaths
    0
    3
        SAEs
    6
    12
        Lambda Dose Reduction
    4
    19
        Discontinuation due to AEs
    4
    13
    No statistical analyses for this end point

    Secondary: Number of Subjects with Treatment-emergent Grade 3/4 Lab Abnormalities

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    End point title
    		 Number of Subjects with Treatment-emergent Grade 3/4 Lab Abnormalities
    End point description
    Grade 3/4 treatment-emergent lab abnormalities that occurred in >=5% of subjects in either cohort are reported. The analysis included all treated subjects up to the end of the treatment period (Day 1 to week 24, or Day 1 to week 48 for subjects requiring those visits). Grade (Gr) 1=Mild, Gr 2=Moderate, Gr 3=Severe, Gr 4= Potentially Life-threatening or disabling. AST = Aspartate aminotransferase, ALT = Alanine aminotransferase.
    End point type
    Secondary
    End point timeframe
    After day 1 to end of treatment; up to week 24 or week 48
    End point values
    		 Cohort A: HCV GT-2 or GT-3 Cohort B: HCV GT-1 or GT-4
    Number of subjects analysed
    104
    196
    Units: subjects
        Total Bilirubin
    26
    63
        AST
    10
    13
        ALT
    2
    10
    No statistical analyses for this end point

    Secondary: Mean Change in Absolute CD4 T Lymphocyte Count from Baseline to End of Treatment

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    End point title
    		 Mean Change in Absolute CD4 T Lymphocyte Count from Baseline to End of Treatment
    End point description
    All treated subjects were monitored for change in Absolute CD4 T Lymphocyte count from Baseline to the end of the treatment period. The mean change in each arm for all evaluable subjects is reported in Cells/µL.
    End point type
    Secondary
    End point timeframe
    Day 1 to end of treatment; up to week 24 or week 48
    End point values
    		 Cohort A: HCV GT-2 or GT-3 Cohort B: HCV GT-1 or GT-4
    Number of subjects analysed
    101
    192
    Units: Cells/µL
        arithmetic mean (standard deviation)
    -42.4 ± 99999
    -104.9 ± 99999
    No statistical analyses for this end point

    Secondary: Mean Percent Change in Absolute CD4 T Lymphocyte Count from Baseline to End of Treatment

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    End point title
    		 Mean Percent Change in Absolute CD4 T Lymphocyte Count from Baseline to End of Treatment
    End point description
    All treated subjects were monitored for percent change in Absolute CD4 T Lymphocyte count from Baseline to the end of the treatment period. The mean percent change in each arm is presented for all evaluable subjects.
    End point type
    Secondary
    End point timeframe
    Day 1 to end of treatment; up to week 24 or week 48
    End point values
    		 Cohort A: HCV GT-2 or GT-3 Cohort B: HCV GT-1 or GT-4
    Number of subjects analysed
    101
    192
    Units: Percent change from baseline
        arithmetic mean (standard deviation)
    -4 ± 99999
    -13.4 ± 99999
    No statistical analyses for this end point

    Secondary: Mean Change in Total Lymphocyte Count from Baseline to End of Treatment

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    End point title
    		 Mean Change in Total Lymphocyte Count from Baseline to End of Treatment
    End point description
    All treated subjects were monitored for change in Total Lymphocyte Count from Baseline to the end of the treatment period. The mean change in each arm for all evaluable subjects is reported in Cells/µL.
    End point type
    Secondary
    End point timeframe
    Day 1 to end of treatment; up to week 24 or week 48
    End point values
    		 Cohort A: HCV GT-2 or GT-3 Cohort B: HCV GT-1 or GT-4
    Number of subjects analysed
    104
    195
    Units: cells/µL
        arithmetic mean (standard deviation)
    -0.38 ± 99999
    -0.5 ± 99999
    No statistical analyses for this end point

    Secondary: Mean Percent Change in Total Lymphocyte Count from Baseline to End of Treatment

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    End point title
    		 Mean Percent Change in Total Lymphocyte Count from Baseline to End of Treatment
    End point description
    All treated subjects were monitored for percent change in Total Lymphocyte Count from Baseline to the end of the treatment period. The mean percent change in each arm is reported for all evaluable subjects.
    End point type
    Secondary
    End point timeframe
    Day 1 to end of treatment; up to week 24 or week 48
    End point values
    		 Cohort A: HCV GT-2 or GT-3 Cohort B: HCV GT-1 or GT-4
    Number of subjects analysed
    104
    195
    Units: percent change
        arithmetic mean (standard deviation)
    -15.33 ± 99999
    -22.95 ± 99999
    No statistical analyses for this end point

    Secondary: Mean change in Platelet Count from Baseline to End of Treatment

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    End point title
    		 Mean change in Platelet Count from Baseline to End of Treatment
    End point description
    All treated subjects were monitored for change in Platelet Count from Baseline to the end of the treatment period. The mean change in each arm is reported for all evaluable subjects (units of measurement = x10*9 cells/L)
    End point type
    Secondary
    End point timeframe
    Day 1 to end of treatment; up to week 24 or week 48
    End point values
    		 Cohort A: HCV GT-2 or GT-3 Cohort B: HCV GT-1 or GT-4
    Number of subjects analysed
    104
    195
    Units: 10^9 cells/L
        arithmetic mean (standard deviation)
    32.7 ± 99999
    33.3 ± 99999
    No statistical analyses for this end point

    Secondary: Mean percent change in Platelet Count from Baseline to End of Treatment

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    End point title
    		 Mean percent change in Platelet Count from Baseline to End of Treatment
    End point description
    All treated subjects were monitored for percent change in Platelet Count from Baseline to the end of the treatment period. The mean percent change in each arm is reported for all evaluable subjects.
    End point type
    Secondary
    End point timeframe
    Day 1 to end of treatment; up to week 24 or week 48
    End point values
    		 Cohort A: HCV GT-2 or GT-3 Cohort B: HCV GT-1 or GT-4
    Number of subjects analysed
    104
    195
    Units: percent change
        arithmetic mean (standard deviation)
    16.9 ± 99999
    20.1 ± 99999
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 to end of treatment; up to week 24 or week 48
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Cohort B: HCV GT-1 or GT-4
    Reporting group description
    		 Subjects with HCV (Genotype 1 or 4) and HIV co-infection were treated with Lambda/RBV/DCV for 12 weeks followed by Lambda/RBV for either 12 or 36 weeks. Subjects who achieved an extended rapid virologic response (eRVR) during the initial 12 weeks of treatment with Lambda/RBV/DCV were then treated with Lambda/RBV for 12 weeks for a total of 24 weeks. Subjects who did not achieve eRVR during the initial 12 weeks of treatment with Lambda/RBV/DCV were then treated with Lambda/RBV for 36 weeks for a total of 48 weeks.

    Reporting group title
    Cohort A: HCV GT-2 or GT-3
    Reporting group description
    		 Subjects with HCV (Genotype 2 or 3) and HIV co-infection were treated with Lambda/RBV/DCV for 12 weeks followed by Lambda/RBV for 12 weeks, for a total treatment duration of 24 weeks.

    Serious adverse events
    		 Cohort B: HCV GT-1 or GT-4 Cohort A: HCV GT-2 or GT-3
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 196 (6.12%)
    6 / 104 (5.77%)
         number of deaths (all causes)
    3
    0
         number of deaths resulting from adverse events
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multi-Organ failure
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Sudden death
         subjects affected / exposed
    2 / 196 (1.02%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    0 / 0
    Gastrointestinal disorders
    Small intestinal haemorrhage
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    2 / 196 (1.02%)
    2 / 104 (1.92%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Dysthymic disorder
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 104 (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
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Secondary syphilis
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 196 (0.00%)
    1 / 104 (0.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 196 (0.51%)
    0 / 104 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort B: HCV GT-1 or GT-4 Cohort A: HCV GT-2 or GT-3
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    159 / 196 (81.12%)
    70 / 104 (67.31%)
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 196 (2.04%)
    8 / 104 (7.69%)
         occurrences all number
    6
    10
    Weight decreased
         subjects affected / exposed
    11 / 196 (5.61%)
    4 / 104 (3.85%)
         occurrences all number
    11
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    32 / 196 (16.33%)
    10 / 104 (9.62%)
         occurrences all number
    39
    13
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    16 / 196 (8.16%)
    7 / 104 (6.73%)
         occurrences all number
    16
    7
    General disorders and administration site conditions
    Injection site erythema
         subjects affected / exposed
    12 / 196 (6.12%)
    0 / 104 (0.00%)
         occurrences all number
    12
    0
    Asthenia
         subjects affected / exposed
    32 / 196 (16.33%)
    22 / 104 (21.15%)
         occurrences all number
    34
    24
    Fatigue
         subjects affected / exposed
    47 / 196 (23.98%)
    9 / 104 (8.65%)
         occurrences all number
    53
    9
    Influenza like illness
         subjects affected / exposed
    5 / 196 (2.55%)
    8 / 104 (7.69%)
         occurrences all number
    6
    9
    Pyrexia
         subjects affected / exposed
    13 / 196 (6.63%)
    3 / 104 (2.88%)
         occurrences all number
    13
    4
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    30 / 196 (15.31%)
    7 / 104 (6.73%)
         occurrences all number
    43
    7
    Abdominal pain
         subjects affected / exposed
    15 / 196 (7.65%)
    4 / 104 (3.85%)
         occurrences all number
    15
    4
    Dyspepsia
         subjects affected / exposed
    12 / 196 (6.12%)
    4 / 104 (3.85%)
         occurrences all number
    12
    4
    Nausea
         subjects affected / exposed
    36 / 196 (18.37%)
    10 / 104 (9.62%)
         occurrences all number
    51
    11
    Vomiting
         subjects affected / exposed
    23 / 196 (11.73%)
    4 / 104 (3.85%)
         occurrences all number
    32
    4
    Hepatobiliary disorders
    Jaundice
         subjects affected / exposed
    10 / 196 (5.10%)
    6 / 104 (5.77%)
         occurrences all number
    11
    6
    Hyperbilirubinaemia
         subjects affected / exposed
    12 / 196 (6.12%)
    4 / 104 (3.85%)
         occurrences all number
    12
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    10 / 196 (5.10%)
    4 / 104 (3.85%)
         occurrences all number
    10
    4
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    33 / 196 (16.84%)
    15 / 104 (14.42%)
         occurrences all number
    35
    17
    Dry skin
         subjects affected / exposed
    27 / 196 (13.78%)
    9 / 104 (8.65%)
         occurrences all number
    27
    10
    Rash
         subjects affected / exposed
    26 / 196 (13.27%)
    8 / 104 (7.69%)
         occurrences all number
    28
    9
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    14 / 196 (7.14%)
    2 / 104 (1.92%)
         occurrences all number
    15
    2
    Anxiety
         subjects affected / exposed
    15 / 196 (7.65%)
    4 / 104 (3.85%)
         occurrences all number
    15
    4
    Depression
         subjects affected / exposed
    18 / 196 (9.18%)
    6 / 104 (5.77%)
         occurrences all number
    18
    7
    Insomnia
         subjects affected / exposed
    31 / 196 (15.82%)
    16 / 104 (15.38%)
         occurrences all number
    31
    19
    Irritability
         subjects affected / exposed
    23 / 196 (11.73%)
    15 / 104 (14.42%)
         occurrences all number
    24
    16
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    24 / 196 (12.24%)
    9 / 104 (8.65%)
         occurrences all number
    27
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Jul 2013
    -Add additional exclusion criteria specific to cirrhotic subjects, -Add Peripheral Blood Mononuclear Cell (PBMC) collection in a subset of 30 subjects who are receiving HAART at selected US sites at Baseline (Day 1), End of Treatment and Post Treatment Week 24 as an exploratory endpoint, -Add that of the total of 200 subjects with GT-1 or -4, there will be at least 10% (n = 20) subjects with GT-4, -Add GT-4 to the evaluation of SVR12 by genotype subtype, -Modify the futility criteria at Week 24 from HCV RNA detected after previously having HCV RNA not detected to HCV RNA ≥ LLOQ, -Remove HDV serology testing as a screening requirement, -Add the exclusion of subjects with psychotic disorder, such as bipolar disease, or history of hospitalization for suicidal ideation/attempt, -Add that Investigators should advise subjects to avoid excessive ultraviolet exposure since the potential for Lambda to induce photosensitivity has not been assessed, -Add that the assay being used for HIV-1 RNA quantification is the Abbott Real Time assay on the automated m2000 System with a linear range of 40 - 10,000,000 copies/mL, -Add that Quintiles will be the central laboratory used in the study, -Add that Monogram Biosciences/LabCorps will perform HIV-1 genotypic and phenotypic resistance assays.

    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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