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    Clinical Trial Results:
    An Open-Label Re-treatment Study with Peg-Interferon Alfa-2a, Ribavirin and BMS-790052 With or Without BMS-650032 for Subjects With Chronic Hepatitis C.

    Summary
    EudraCT number
    		 2011-000836-27
    Trial protocol
    		 IE   GB   ES   SE   DK   IT   AT   NL   GR  
    Global end of trial date
    23 Sep 2014

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

    Trial information

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    Trial identification
    Sponsor protocol code
    AI444-026
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01428063
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bristol Myers Squibb
    Sponsor organisation address
    Chaussee de la Hulpe 185, Brussels, Belgium,
    Public contact
    Bristol Myers Squibb Study Director, Bristol Myers Squibb, clinical.trials@bms.com
    Scientific contact
    Bristol Myers Squibb Study Director, Bristol Myers Squibb, clinical.trials@bms.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Sep 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to assess the efficacy based on the percentage of subjects with sustained virologic response for 12 weeks (SVR12), in both the global and site-specific cohorts.
    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
    06 Oct 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 12
    Country: Number of subjects enrolled
    Australia: 13
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Canada: 20
    Country: Number of subjects enrolled
    Denmark: 1
    Country: Number of subjects enrolled
    France: 30
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Ireland: 2
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Korea, Republic of: 13
    Country: Number of subjects enrolled
    Mexico: 1
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    New Zealand: 1
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    Taiwan: 14
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    United States: 137
    Worldwide total number of subjects
    276
    EEA total number of subjects
    65
    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)
    248
    From 65 to 84 years
    28
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 92 centers in 20 countries.

    Pre-assignment
    Screening details
    		 A total of 228 subjects enrolled, of which 227 received treatment; 206 completed the study. The majority of subjects discontinued due to lack of efficacy and adverse events.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Daclatasvir + Asunaprevir
    Arm description
    		 Subjects received daclatasvir (DCV), 60 mg tablet, by mouth once daily + asunaprevir (ASV), 100 mg capsule, by mouth twice daily for 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 were administered with DCV 60 mg orally twice daily.

    Investigational medicinal product name
    Asunaprevir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered with ASV 100 mg orally twice daily.

    Arm title
    		 DCV + ASV + pegIFN-2a+ Ribavirin
    Arm description
    		 Subjects received DCV, 60 mg tablet, by mouth once daily + ASV,100 mg capsule or 200 mg tablet, by mouth twice daily + pegylated interferon alfa-2a (pegIFNα2a), 80 μg solution, subcutaneously weekly + ribavirin (RBV), weight based dosing (<75 kg = 1000 mg once daily; >=75 kg = 1200 mg once daily) for 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 were administered with DCV 60 mg orally twice daily.

    Investigational medicinal product name
    Asunaprevir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered with ASV 100 mg orally twice daily.

    Investigational medicinal product name
    Pegylated interferon alfa-2a (pegIFNα-2a)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects were administered with 80 μg pegIFNα-2a subcutaneously.

    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 were administered with ribavirin orally, based on weight <75 kg = 1000 mg once daily or >=75 kg = 1200 mg once daily.

    Arm title
    		 DCV + pegIFN-2a+ RBV
    Arm description
    		 Subjects received DCV, 60 mg tablet, by mouth once daily + pegIFNα2a, 80 μg solution, subcutaneously weekly + RBV, weight based dosing (<75 kg = 1000 mg once daily; >=75 kg = 1200 mg once daily) for 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 were administered with DCV 60 mg orally twice daily.

    Investigational medicinal product name
    Pegylated interferon alfa-2a (pegIFNα-2a)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Subjects were administered with 80 μg pegIFNα-2a subcutaneously.

    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 were administered with ribavirin orally, based on weight <75 kg = 1000 mg once daily or >=75 kg = 1200 mg once daily.

    Number of subjects in period 1 [1]
    		Daclatasvir + Asunaprevir DCV + ASV + pegIFN-2a+ Ribavirin DCV + pegIFN-2a+ RBV
    Started
    99
    122
    6
    Completed
    89
    112
    5
    Not completed
    10
    10
    1
         Adverse event, non-fatal
    2
    3
    -
         No longer meets study criteria
    -
    1
    -
         Lost to follow-up
    -
    2
    -
         Lack of efficacy
    8
    4
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The number of subjects reported in the baseline period are different from the worldwide number enrolled in the trial as 49 subjects discontinued from the study due to various reasons.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Daclatasvir + Asunaprevir
    Reporting group description
    		 Subjects received daclatasvir (DCV), 60 mg tablet, by mouth once daily + asunaprevir (ASV), 100 mg capsule, by mouth twice daily for 24 weeks.

    Reporting group title
    DCV + ASV + pegIFN-2a+ Ribavirin
    Reporting group description
    		 Subjects received DCV, 60 mg tablet, by mouth once daily + ASV,100 mg capsule or 200 mg tablet, by mouth twice daily + pegylated interferon alfa-2a (pegIFNα2a), 80 μg solution, subcutaneously weekly + ribavirin (RBV), weight based dosing (<75 kg = 1000 mg once daily; >=75 kg = 1200 mg once daily) for 24 weeks.

    Reporting group title
    DCV + pegIFN-2a+ RBV
    Reporting group description
    		 Subjects received DCV, 60 mg tablet, by mouth once daily + pegIFNα2a, 80 μg solution, subcutaneously weekly + RBV, weight based dosing (<75 kg = 1000 mg once daily; >=75 kg = 1200 mg once daily) for 24 weeks.

    Reporting group values
    		 Daclatasvir + Asunaprevir DCV + ASV + pegIFN-2a+ Ribavirin DCV + pegIFN-2a+ RBV Total
    Number of subjects
    		 99 122 6 227
    Age categorical
    Units: Subjects
        Younger than 65 years
    		 80 114 6 200
        65 years and older
    		 19 8 0 27
    Gender categorical
    Units: Subjects
        Female
    		 48 84 2 134
        Male
    		 51 38 4 93

    End points

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    End points reporting groups
    Reporting group title
    Daclatasvir + Asunaprevir
    Reporting group description
    		 Subjects received daclatasvir (DCV), 60 mg tablet, by mouth once daily + asunaprevir (ASV), 100 mg capsule, by mouth twice daily for 24 weeks.

    Reporting group title
    DCV + ASV + pegIFN-2a+ Ribavirin
    Reporting group description
    		 Subjects received DCV, 60 mg tablet, by mouth once daily + ASV,100 mg capsule or 200 mg tablet, by mouth twice daily + pegylated interferon alfa-2a (pegIFNα2a), 80 μg solution, subcutaneously weekly + ribavirin (RBV), weight based dosing (<75 kg = 1000 mg once daily; >=75 kg = 1200 mg once daily) for 24 weeks.

    Reporting group title
    DCV + pegIFN-2a+ RBV
    Reporting group description
    		 Subjects received DCV, 60 mg tablet, by mouth once daily + pegIFNα2a, 80 μg solution, subcutaneously weekly + RBV, weight based dosing (<75 kg = 1000 mg once daily; >=75 kg = 1200 mg once daily) for 24 weeks.

    Subject analysis set title
    DCV + ASV + pegIFN-2a+ Ribavirin (Genotype 1)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Genotype 1 subjects received DCV, 60 mg tablet, by mouth once daily + ASV,100 mg capsule or 200 mg tablet, by mouth twice daily + pegIFNα2a, 80 μg solution, subcutaneously weekly + ribavirin (RBV), weight based dosing (<75 kg=1000 mg once daily; >=75 kg=1200 mg once daily) for 24 weeks.

    Subject analysis set title
    DCV + ASV + pegIFN-2a+ Ribavirin (Genotype 4)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Genotype 4 subjects received DCV, 60 mg tablet, by mouth once daily + ASV,100 mg capsule or 200 mg tablet, by mouth twice daily + pegylated interferon alfa-2a(pegIFNα2a), 80 μg solution, subcutaneously weekly + ribavirin (RBV), weight based dosing (<75 kg=1000 mg once daily; >=75 kg=1200 mg once daily) for 24 weeks.

    Subject analysis set title
    DCV + ASV + pegIFN-2a+ RBV (Prior DCV Failures)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    subjects who were nor responders to earlier DCV/pegIFN/RBV therapy were administered with DCV, 60 mg tablet, by mouth once daily + ASV,100 mg capsule or 200 mg tablet, by mouth twice daily + pegIFNα2a, 80 μg solution, subcutaneously weekly + RBV, weight based dosing (<75 kg=1000 mg once daily; >=75 kg=1200 mg once daily) for 24 weeks.

    Subject analysis set title
    DCV + ASV + pegIFN-2a+ RBV (Prior ASV Failures)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    subjects who were nor responders to earlier ASV/pegIFN/RBV therapy were administered with DCV, 60 mg tablet, by mouth once daily + ASV,100 mg capsule or 200 mg tablet, by mouth twice daily + pegIFNα2a, 80 μg solution, subcutaneously weekly + RBV, weight based dosing (<75 kg=1000 mg once daily; >=75 kg=1200 mg once daily) for 24 weeks.

    Subject analysis set title
    DCV + ASV + pegIFN-2a+ RBV (Prior BOC Failures)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    subjects who were nor responders to earlier boceprevir(BOC) /pegIFN/RBV therapy were administered with DCV, 60 mg tablet, by mouth once daily + ASV,100 mg capsule or 200 mg tablet, by mouth twice daily + pegIFNα2a, 80 μg solution, subcutaneously weekly + RBV, weight based dosing (<75 kg=1000 mg once daily; >=75 kg=1200 mg once daily) for 24 weeks.

    Subject analysis set title
    DCV + ASV + pegIFN-2a+ RBV (Prior TVR Failures)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    subjects who were nor responders to earlier telaprevir (TVR) /pegIFN/RBV therapy were administered with DCV, 60 mg tablet, by mouth once daily + ASV,100 mg capsule or 200 mg tablet, by mouth twice daily + pegIFNα2a, 80 μg solution, subcutaneously weekly + RBV, weight based dosing (<75 kg=1000 mg once daily; >=75 kg=1200 mg once daily) for 24 weeks.

    Subject analysis set title
    DCV + ASV + pegIFN-2a+ RBV (Treatment Naive)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    HCV GT-1a infection treatment-naive subjects were administered with DCV, 60 mg tablet, by mouth once daily + ASV,100 mg capsule or 200 mg tablet, by mouth twice daily + pegIFNα2a, 80 μg solution, subcutaneously weekly + RBV, weight based dosing (<75 kg=1000 mg once daily; >=75 kg=1200 mg once daily) for 12 weeks.

    Subject analysis set title
    DCV + ASV + pegIFN-2a+ RBV (pegIFNα /RBV Relapsers)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    PegIFNα /RBV relapsers were administered with DCV, 60 mg tablet, by mouth once daily + ASV,100 mg capsule or 200 mg tablet, by mouth twice daily + pegIFNα2a, 80 μg solution, subcutaneously weekly + RBV, weight based dosing (<75 kg=1000 mg once daily; >=75 kg=1200 mg once daily) for 12 week.

    Primary: Percentage of Genotype 1 Subjects who Were Prior Non-Responders to pegIFNα-2a/RBV With Sustained Virologic Response at Follow-up Week 12 (SVR12)

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    End point title
    		 Percentage of Genotype 1 Subjects who Were Prior Non-Responders to pegIFNα-2a/RBV With Sustained Virologic Response at Follow-up Week 12 (SVR12) [1]
    End point description
    SVR12 was defined as hepatitis C virus RNA less than the lower limit of quantitation, target detected or target not detected at follow-up Week 12. Here, ‘Number of Subjects Analysed’ signifies subjects evaluable for SVR12 at week 12. The analysis was performed in Intent-to-Treat population defined as all treated subjects defined as subjects who received at least 1 dose of study therapy.
    End point type
    Primary
    End point timeframe
    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 was planned for this outcome measure
    End point values
    		 DCV + ASV + pegIFN-2a+ Ribavirin (Genotype 1)
    Number of subjects analysed
    37
    Units: Percentage of subjects
        number (confidence interval 95%)
    94.6 (81.8 to 99.3)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Sustained Virologic Response at Follow-up Week 12 (SVR12)

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    End point title
    		 Percentage of Subjects With Sustained Virologic Response at Follow-up Week 12 (SVR12) [2]
    End point description
    SVR12 was defined as hepatitis C virus (HCV) RNA less than the lower limit of quantitation, target detected or target not detected at follow-up Week 12. Here, ‘Number of subjects Analysed’ signifies subjects evaluable for this outcome measure. The analysis was performed in all treated subjects defined as subjects who received at least 1 dose of study therapy.
    End point type
    Secondary
    End point timeframe
    Week 12 (Follow-up period)
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be assessed for pre-specified reporting group.
    End point values
    		 Daclatasvir + Asunaprevir DCV + pegIFN-2a+ RBV DCV + ASV + pegIFN-2a+ Ribavirin (Genotype 4) DCV + ASV + pegIFN-2a+ RBV (Prior DCV Failures) DCV + ASV + pegIFN-2a+ RBV (Prior ASV Failures) DCV + ASV + pegIFN-2a+ RBV (Prior BOC Failures) DCV + ASV + pegIFN-2a+ RBV (Prior TVR Failures) DCV + ASV + pegIFN-2a+ RBV (Treatment Naive) DCV + ASV + pegIFN-2a+ RBV (pegIFNα /RBV Relapsers)
    Number of subjects analysed
    99
    6
    10
    10
    6
    11
    13
    25
    9
    Units: Percentage of subjects
        number (confidence interval 95%)
    85.9 (77.4 to 92)
    50 (11.8 to 88.2)
    90 (55.5 to 99.7)
    40 (12.2 to 73.8)
    100 (54.1 to 100)
    90.9 (58.7 to 99.8)
    76.9 (46.2 to 95)
    84 (63.9 to 95.5)
    88.9 (51.8 to 99.7)
    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 the status at which the proportion of subjects with hepatitis C virus (HCV) RNA less than the lower limit of quantitation, target not detected at Week 4. Here, ‘Number of subjects Analysed’ signifies subjects evaluable for this outcome measure. The analysis was performed in all treated subjects defined as subjects who received at least 1 dose of study therapy.
    End point type
    Secondary
    End point timeframe
    Week 4
    End point values
    		 Daclatasvir + Asunaprevir DCV + ASV + pegIFN-2a+ Ribavirin DCV + pegIFN-2a+ RBV DCV + ASV + pegIFN-2a+ RBV (Prior DCV Failures) DCV + ASV + pegIFN-2a+ RBV (Prior ASV Failures) DCV + ASV + pegIFN-2a+ RBV (Prior BOC Failures) DCV + ASV + pegIFN-2a+ RBV (Prior TVR Failures) DCV + ASV + pegIFN-2a+ RBV (Treatment Naive) DCV + ASV + pegIFN-2a+ RBV (pegIFNα /RBV Relapsers)
    Number of subjects analysed
    99
    48
    6
    10
    6
    11
    13
    25
    9
    Units: Percentage of subjects
        number (not applicable)
    72.7
    91.7
    83.3
    70
    83.3
    90.9
    76.9
    76
    88.9
    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 was defined as the status at which the proportion of subjects with hepatitis C virus (HCV) RNA less than the lower limit of quantitation, target not detected at both weeks 4 and 12. Here, ‘Number of subjects Analysed’ signifies subjects evaluable for this outcome measure. The analysis was performed in all treated subjects defined as subjects who received at least 1 dose of study therapy.
    End point type
    Secondary
    End point timeframe
    Week 4 and 12
    End point values
    		 Daclatasvir + Asunaprevir DCV + ASV + pegIFN-2a+ Ribavirin DCV + pegIFN-2a+ RBV DCV + ASV + pegIFN-2a+ RBV (Prior DCV Failures) DCV + ASV + pegIFN-2a+ RBV (Prior ASV Failures) DCV + ASV + pegIFN-2a+ RBV (Prior BOC Failures) DCV + ASV + pegIFN-2a+ RBV (Prior TVR Failures) DCV + ASV + pegIFN-2a+ RBV (Treatment Naive) DCV + ASV + pegIFN-2a+ RBV (pegIFNα /RBV Relapsers)
    Number of subjects analysed
    99
    48
    6
    10
    6
    11
    13
    25
    9
    Units: Percentage of subjects
        number (not applicable)
    67.7
    87.5
    83.3
    70
    83.3
    81.8
    76.9
    64
    88.9
    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 the status at which the proportion of subjects with hepatitis C virus (HCV) RNA less than the lower limit of quantitation, target not detected at week 12. Here, ‘Number of subjects Analysed’ signifies subjects evaluable for this outcome measure. The analysis was performed in all treated subjects defined as subjects who received at least 1 dose of study therapy.
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 Daclatasvir + Asunaprevir DCV + ASV + pegIFN-2a+ Ribavirin DCV + pegIFN-2a+ RBV DCV + ASV + pegIFN-2a+ RBV (Prior DCV Failures) DCV + ASV + pegIFN-2a+ RBV (Prior ASV Failures) DCV + ASV + pegIFN-2a+ RBV (Prior BOC Failures) DCV + ASV + pegIFN-2a+ RBV (Prior TVR Failures) DCV + ASV + pegIFN-2a+ RBV (Treatment Naive) DCV + ASV + pegIFN-2a+ RBV (pegIFNα /RBV Relapsers)
    Number of subjects analysed
    99
    48
    6
    10
    6
    11
    13
    25
    9
    Units: Percentage of subjects
        number (not applicable)
    87.9
    95.8
    83.3
    90
    100
    90.9
    92.3
    76
    88.9
    No statistical analyses for this end point

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

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    End point title
    		 Percentage of Subjects With End of the Treatment Response (EOTR)
    End point description
    EOTR was defined as the status at which the proportion of subjects with hepatitis C virus (HCV) RNA less than the lower limit of quantitation, target not detected at end of treatment. Here, ‘Number of subjects Analysed’ signifies subjects evaluable for this outcome measure. The analysis was performed in all treated subjects defined as subjects who received at least 1 dose of study therapy.
    End point type
    Secondary
    End point timeframe
    End of the study (Week 24)
    End point values
    		 Daclatasvir + Asunaprevir DCV + ASV + pegIFN-2a+ Ribavirin DCV + pegIFN-2a+ RBV DCV + ASV + pegIFN-2a+ RBV (Prior DCV Failures) DCV + ASV + pegIFN-2a+ RBV (Prior ASV Failures) DCV + ASV + pegIFN-2a+ RBV (Prior BOC Failures) DCV + ASV + pegIFN-2a+ RBV (Prior TVR Failures) DCV + ASV + pegIFN-2a+ RBV (Treatment Naive) DCV + ASV + pegIFN-2a+ RBV (pegIFNα /RBV Relapsers)
    Number of subjects analysed
    99
    48
    6
    10
    6
    11
    13
    25
    9
    Units: Percentage of subjects
        number (not applicable)
    85.9
    97.9
    83.3
    90
    100
    90.9
    92.3
    84
    88.9
    No statistical analyses for this end point

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

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    End point title
    		 Percentage of Subjects With Sustained Virologic Response at Follow-up Week 24 (SVR24)
    End point description
    SVR24 was defined as the status at which the proportion of subjects with hepatitis C virus (HCV) RNA less than the lower limit of quantitation, target detected or target not detected at follow-up week 24. Here, ‘Number of subjects Analysed’ signifies subjects evaluable for this outcome measure. The analysis was performed in all treated subjects defined as subjects who received at least 1 dose of study therapy.
    End point type
    Secondary
    End point timeframe
    Week 24 (Follow-up)
    End point values
    		 Daclatasvir + Asunaprevir DCV + ASV + pegIFN-2a+ Ribavirin DCV + pegIFN-2a+ RBV DCV + ASV + pegIFN-2a+ RBV (Prior DCV Failures) DCV + ASV + pegIFN-2a+ RBV (Prior ASV Failures) DCV + ASV + pegIFN-2a+ RBV (Prior BOC Failures) DCV + ASV + pegIFN-2a+ RBV (Prior TVR Failures) DCV + ASV + pegIFN-2a+ RBV (Treatment Naive) DCV + ASV + pegIFN-2a+ RBV (pegIFNα /RBV Relapsers)
    Number of subjects analysed
    99
    48
    6
    10
    6
    11
    13
    25
    9
    Units: Percentage of subjects
        number (not applicable)
    84.8
    95.8
    50
    40
    100
    90.9
    76.9
    84
    88.9
    No statistical analyses for this end point

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

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    End point title
    		 Number of Subjects With Serious Adverse Events (SAEs), Discontinuations Due to AEs, and Who Died During the Study
    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 hospitalisation. Here, ‘Number of subjects Analysed’ signifies subjects evaluable for this outcome measure. The analysis was performed in all treated subjects defined as subjects who received at least 1 dose of study therapy.
    End point type
    Secondary
    End point timeframe
    For AEs: From Day 1, first dose until subject's last scheduled visit. For SAEs: Date of subject's written consent until 30 days post discontinuation of dosing or participation in the study if last scheduled visit occurred at a later time (72 Week)
    End point values
    		 Daclatasvir + Asunaprevir DCV + ASV + pegIFN-2a+ Ribavirin DCV + pegIFN-2a+ RBV DCV + ASV + pegIFN-2a+ RBV (Prior DCV Failures) DCV + ASV + pegIFN-2a+ RBV (Prior ASV Failures) DCV + ASV + pegIFN-2a+ RBV (Prior BOC Failures) DCV + ASV + pegIFN-2a+ RBV (Prior TVR Failures) DCV + ASV + pegIFN-2a+ RBV (Treatment Naive) DCV + ASV + pegIFN-2a+ RBV (pegIFNα /RBV Relapsers)
    Number of subjects analysed
    99
    48
    6
    10
    6
    11
    13
    25
    9
    Units: Subjects
        SAEs
    4
    0
    0
    0
    0
    2
    0
    1
    0
        AEs leading to discontinuation of therapy
    2
    2
    0
    0
    1
    0
    0
    2
    0
        Death
    0
    0
    0
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    For AEs: From Day 1, first dose until subject’s last scheduled visit. For SAEs: Date of subject’s written consent until 30 days post discontinuation of dosing or participation in the study if the last scheduled visit occurred later (72 weeks).
    Adverse event reporting additional description
    On treatment period.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Daclatasvir + Asunaprevir
    Reporting group description
    		 Subjects received daclatasvir (DCV), 60 mg tablet, by mouth once daily + asunaprevir (ASV), 100 mg capsule, by mouth twice daily for 24 weeks.

    Reporting group title
    DCV + ASV + pegIFN-2a+ Ribavirin
    Reporting group description
    		 Subjects received DCV, 60 mg tablet, by mouth once daily + ASV,100 mg capsule or 200 mg tablet, by mouth twice daily + pegylated interferon alfa-2a(pegIFNα2a), 80 μg solution, subcutaneously weekly + ribavirin (RBV), weight based dosing (<75 kg = 1000 mg once daily; >=75 kg = 1200 mg once daily) for 24 weeks.

    Reporting group title
    DCV + pegIFN-2a+ RBV
    Reporting group description
    		 Subjects received DCV, 60 mg tablet, by mouth once daily + pegIFNα2a, 80 μg solution, subcutaneously weekly + RBV, weight based dosing (<75 kg = 1000 mg once daily; >=75 kg = 1200 mg once daily) for 24 weeks.

    Serious adverse events
    		 Daclatasvir + Asunaprevir DCV + ASV + pegIFN-2a+ Ribavirin DCV + pegIFN-2a+ RBV
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 99 (4.04%)
    3 / 122 (2.46%)
    0 / 6 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 122 (0.00%)
    0 / 6 (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
    Breast cancer
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 122 (0.00%)
    0 / 6 (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
    Neuroendocrine carcinoma of the skin
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 122 (0.00%)
    0 / 6 (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
    Uterine leiomyoma
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 122 (0.00%)
    0 / 6 (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
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 122 (0.82%)
    0 / 6 (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
    Radiculopathy
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 122 (0.82%)
    0 / 6 (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
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 122 (0.82%)
    0 / 6 (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
    Suicide attempt
         subjects affected / exposed
    1 / 99 (1.01%)
    0 / 122 (0.00%)
    0 / 6 (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
    Infections and infestations
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 122 (0.82%)
    0 / 6 (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
    		 Daclatasvir + Asunaprevir DCV + ASV + pegIFN-2a+ Ribavirin DCV + pegIFN-2a+ RBV
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    58 / 99 (58.59%)
    118 / 122 (96.72%)
    6 / 6 (100.00%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 99 (2.02%)
    15 / 122 (12.30%)
    0 / 6 (0.00%)
         occurrences all number
    2
    15
    0
    Chills
         subjects affected / exposed
    1 / 99 (1.01%)
    10 / 122 (8.20%)
    2 / 6 (33.33%)
         occurrences all number
    1
    11
    2
    Fatigue
         subjects affected / exposed
    15 / 99 (15.15%)
    65 / 122 (53.28%)
    3 / 6 (50.00%)
         occurrences all number
    15
    65
    3
    Influenza like illness
         subjects affected / exposed
    5 / 99 (5.05%)
    45 / 122 (36.89%)
    3 / 6 (50.00%)
         occurrences all number
    6
    47
    3
    Pyrexia
         subjects affected / exposed
    4 / 99 (4.04%)
    17 / 122 (13.93%)
    2 / 6 (33.33%)
         occurrences all number
    4
    18
    3
    Reproductive system and breast disorders
    Uterine polyp
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 122 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 122 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 99 (5.05%)
    14 / 122 (11.48%)
    2 / 6 (33.33%)
         occurrences all number
    7
    15
    2
    Dyspnoea
         subjects affected / exposed
    0 / 99 (0.00%)
    12 / 122 (9.84%)
    2 / 6 (33.33%)
         occurrences all number
    0
    12
    2
    Nasal dryness
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 122 (0.82%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 99 (0.00%)
    6 / 122 (4.92%)
    1 / 6 (16.67%)
         occurrences all number
    0
    6
    1
    Insomnia
         subjects affected / exposed
    3 / 99 (3.03%)
    25 / 122 (20.49%)
    2 / 6 (33.33%)
         occurrences all number
    3
    27
    2
    Irritability
         subjects affected / exposed
    1 / 99 (1.01%)
    11 / 122 (9.02%)
    1 / 6 (16.67%)
         occurrences all number
    1
    11
    1
    Investigations
    Transaminases increased
         subjects affected / exposed
    1 / 99 (1.01%)
    1 / 122 (0.82%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    1
    Weight decreased
         subjects affected / exposed
    1 / 99 (1.01%)
    4 / 122 (3.28%)
    1 / 6 (16.67%)
         occurrences all number
    1
    4
    1
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 122 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 122 (0.82%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Dysgeusia
         subjects affected / exposed
    0 / 99 (0.00%)
    8 / 122 (6.56%)
    1 / 6 (16.67%)
         occurrences all number
    0
    8
    1
    Headache
         subjects affected / exposed
    17 / 99 (17.17%)
    43 / 122 (35.25%)
    3 / 6 (50.00%)
         occurrences all number
    23
    50
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 99 (1.01%)
    23 / 122 (18.85%)
    0 / 6 (0.00%)
         occurrences all number
    1
    24
    0
    Lymphopenia
         subjects affected / exposed
    0 / 99 (0.00%)
    5 / 122 (4.10%)
    1 / 6 (16.67%)
         occurrences all number
    0
    5
    1
    Neutropenia
         subjects affected / exposed
    1 / 99 (1.01%)
    30 / 122 (24.59%)
    0 / 6 (0.00%)
         occurrences all number
    1
    36
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 99 (0.00%)
    9 / 122 (7.38%)
    1 / 6 (16.67%)
         occurrences all number
    0
    9
    1
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 99 (0.00%)
    3 / 122 (2.46%)
    1 / 6 (16.67%)
         occurrences all number
    0
    3
    1
    Ocular icterus
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 122 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Visual acuity reduced
         subjects affected / exposed
    0 / 99 (0.00%)
    1 / 122 (0.82%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 99 (5.05%)
    9 / 122 (7.38%)
    2 / 6 (33.33%)
         occurrences all number
    5
    9
    2
    Abdominal pain upper
         subjects affected / exposed
    6 / 99 (6.06%)
    8 / 122 (6.56%)
    0 / 6 (0.00%)
         occurrences all number
    7
    8
    0
    Constipation
         subjects affected / exposed
    5 / 99 (5.05%)
    4 / 122 (3.28%)
    0 / 6 (0.00%)
         occurrences all number
    5
    4
    0
    Diarrhoea
         subjects affected / exposed
    9 / 99 (9.09%)
    33 / 122 (27.05%)
    0 / 6 (0.00%)
         occurrences all number
    12
    37
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 99 (2.02%)
    2 / 122 (1.64%)
    1 / 6 (16.67%)
         occurrences all number
    2
    2
    1
    Nausea
         subjects affected / exposed
    14 / 99 (14.14%)
    31 / 122 (25.41%)
    1 / 6 (16.67%)
         occurrences all number
    15
    32
    1
    Vomiting
         subjects affected / exposed
    5 / 99 (5.05%)
    5 / 122 (4.10%)
    1 / 6 (16.67%)
         occurrences all number
    6
    6
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    3 / 99 (3.03%)
    13 / 122 (10.66%)
    2 / 6 (33.33%)
         occurrences all number
    3
    13
    2
    Dry skin
         subjects affected / exposed
    2 / 99 (2.02%)
    22 / 122 (18.03%)
    2 / 6 (33.33%)
         occurrences all number
    2
    22
    2
    Erythema
         subjects affected / exposed
    1 / 99 (1.01%)
    3 / 122 (2.46%)
    1 / 6 (16.67%)
         occurrences all number
    1
    3
    1
    Petechiae
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 122 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Pruritus
         subjects affected / exposed
    5 / 99 (5.05%)
    23 / 122 (18.85%)
    3 / 6 (50.00%)
         occurrences all number
    5
    24
    3
    Rash generalised
         subjects affected / exposed
    0 / 99 (0.00%)
    10 / 122 (8.20%)
    0 / 6 (0.00%)
         occurrences all number
    0
    10
    0
    Rash
         subjects affected / exposed
    3 / 99 (3.03%)
    15 / 122 (12.30%)
    0 / 6 (0.00%)
         occurrences all number
    3
    15
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 99 (6.06%)
    16 / 122 (13.11%)
    2 / 6 (33.33%)
         occurrences all number
    6
    17
    2
    Back pain
         subjects affected / exposed
    4 / 99 (4.04%)
    7 / 122 (5.74%)
    0 / 6 (0.00%)
         occurrences all number
    4
    10
    0
    Limb discomfort
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 122 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Muscle spasms
         subjects affected / exposed
    0 / 99 (0.00%)
    8 / 122 (6.56%)
    0 / 6 (0.00%)
         occurrences all number
    0
    8
    0
    Myalgia
         subjects affected / exposed
    5 / 99 (5.05%)
    14 / 122 (11.48%)
    2 / 6 (33.33%)
         occurrences all number
    5
    14
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 99 (7.07%)
    3 / 122 (2.46%)
    0 / 6 (0.00%)
         occurrences all number
    7
    3
    0
    Viral rhinitis
         subjects affected / exposed
    0 / 99 (0.00%)
    0 / 122 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 99 (9.09%)
    0 / 122 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    9
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 99 (1.01%)
    20 / 122 (16.39%)
    2 / 6 (33.33%)
         occurrences all number
    1
    20
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Jan 2012
    The 48-week post-treatment follow-up period was reduced to 24-weeks, revised treatment population, primary endpoint to additionally specify that they include subjects that are prior non-responders to pegINFalfa-2a/RBV, revised the on treatment futility rules from the Week 4 and Week 12 criteria to a Week 8 Futility only that includes any detectable Hepatitis C virus (HCV) RNA (>=lower limit of quantification) results after Week 8 (with no confirmation HCV RNA value required), revised the futility rule definitions, revised the definition of a relapse, revised the wording regarding the timing of the 1st interim analysis, reduced the safety endpoint measurements from the last dose of study drug therapy from 30-days to 7-days for treated subjects and wording modifications designed to clarify or correct inconsistencies in the protocol procedures.
    20 Mar 2012
    Removed Week 8 treatment futility rule of genotype-(GT)-2 and GT-3 subjects, updated futility rule to Week 8 for GT-1 and GT-4 subjects and added that confirmation of HCV RNA is required within 2 weeks of Week 8 result, updated definition of virologic breakthrough, updated study design to allow rollover of treatment naive GT-1b subjects assigned to the placebo arm in AI447028 who were treated with the combination of asunaprevir and daclatasvir therapy, these subjects met pre-defined rescue therapy criteria and could have been treated with daclatasvir/asunaprevir/pegIFNalfa/RBV therapy (daclatasvir and asunaprevir plus pegIFNalfa-2a/RBV) for 24 weeks at the discretion of the investigator, added new formulation of 60 mg tablets daclatasvir and 100 mg capsules of asunaprevir, updated reasons for discontinuation from treatment, updated rules for dose modifications and interruptions, revised timing of primary objective to SVR12, revised sample size of HCV GT-1 or -4 subjects who were prior non-responders to pegIFNalfa-2a/RBV, added sample size for HCV GT-1b treatment-naive subjects, updated interim and final analysis based on SVR12 rate instead of SVR24.
    25 May 2012
    Added new safety information as well as guidance regarding the management of subjects exposed to combination therapy with asunaprevir and daclatasvir who present with unexplained pyrexia.
    20 Nov 2012
    Clarified that women of child bearing potential (WOCBP) and men who were sexually active with WOCBP who rolled over from Study AI447028 and took daclatasvir/asunaprevir therapy were to use 1 method of contraception throughout the study and for a minimum of 12 weeks after discontinuation of ASV and DCV. Oral contraceptive pills were allowed but were not considered an effective form of contraception.
    13 Jun 2013
    Revised guidance for contraception for WOCBP and male subjects sexually active with WOCBP and added the option to treat subjects receiving rescue therapy for either 24 or 48 weeks.

    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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