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    Clinical Trial Results:
    A phase III randomised, partially double-blind and placebo controlled study of BI 207127 in combination with faldaprevir and ribavirin for chronic genotype 1 hepatitis C infection in an extended population of treatment naïve patients that includes those ineligible to receive peginterferon. This trial was prematurely discontinued due to discontinuation of the deleobuvir (DBV) drug development program.

    Due to the EudraCT – Results system being out of service between 31 July 2015 and 12 January 2016, these results have been published in compliance with revised timelines.
    Summary
    EudraCT number
    2012-003535-27
    Trial protocol
    BE   DE   PT   GB   ES   GR   IT  
    Global end of trial date
    15 Jan 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    05 May 2016
    First version publication date
    05 May 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    1241.36
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01728324
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    173 Binger Strasse, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, +1 8002430127, clintriage.rdg@boehringer-ingelheim.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 Feb 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Feb 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Jan 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The aim of the study was to confirm efficacy and safety of treatment with 600 mg of BID (twice daily) deleobuvir (DBV) in combination with 120 mg (milligram) QD (once a day) faldaprevir (FDV) and ribavirin (RBV) for 16 or 24 weeks in chronically infected hepatitis C virus (HCV) GT1b treatment-naïve patients, including patients with compensated cirrhosis. The primary objective was to determine if a minimum historical target SVR12 rate of 71% for pegylated interferon-alfa (PegIFN)-eligible patients and 50% for PegIFN-ineligible patients could be achieved by the combination treatments of DBV, FDV and RBV in GT1b patients, including patients with compensated cirrhosis. The comparison with historical control was framed as a statistical superiority test.
    Protection of trial subjects
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    03 Dec 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 53
    Country: Number of subjects enrolled
    Belgium: 61
    Country: Number of subjects enrolled
    Canada: 64
    Country: Number of subjects enrolled
    France: 55
    Country: Number of subjects enrolled
    Germany: 58
    Country: Number of subjects enrolled
    Greece: 29
    Country: Number of subjects enrolled
    Italy: 132
    Country: Number of subjects enrolled
    New Zealand: 6
    Country: Number of subjects enrolled
    Portugal: 24
    Country: Number of subjects enrolled
    Spain: 73
    Country: Number of subjects enrolled
    United Kingdom: 33
    Country: Number of subjects enrolled
    United States: 167
    Worldwide total number of subjects
    755
    EEA total number of subjects
    465
    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)
    650
    From 65 to 84 years
    105
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    All subjects were screened for eligibility to participate in the trial. Subjects attended specialist sites which would then ensure that they (the subjects) met all strictly implemented inclusion/exclusion criteria. Subjects were not to be randomised to trial treatment if any one of the specific entry criteria were violated.

    Period 1
    Period 1 title
    Termination of DBV
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Subject
    Blinding implementation details
    Groups 1 (24-wk NC) and Group 2 (16-wk NC) were double-blinded to treatment duration and Group 3 (24-wk CR) was open-label.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    24-wk non-cirrhotic (NC) treatment group 1
    Arm description
    24 weeks of treatment with 600mg BID deleobuvir (DBV) in combination with 120mg QD faldaprevir (FDV) plus ribavirin (RBV) in non-cirrhotic patients.
    Arm type
    Experimental

    Investigational medicinal product name
    deleobuvir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg deleobuvir (DBV) tablet was administered twice daily for a total daily dose of 1200 mg in non-cirrhotic patients for 24 weeks.

    Investigational medicinal product name
    ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500 mg or 600 mg ribavirin (RBV) tablet twice daily for a total daily dose of 1000 mg (<75 kg body weight) or 1200 mg (≥ 75 kg body weight) in non-cirrhotic patients for 24 weeks.

    Investigational medicinal product name
    faldaprevir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    120 mg faldaprevir (FDV) Soft gelatin capsule was administered once daily in non-cirrhotic patients for 24 weeks.

    Arm title
    16-wk non-cirrhotic (NC) treatment group 2
    Arm description
    Matching placebo to DBV, matching placebo to FDV and matching placebo to RBV for 8 weeks followed by 600mg BID DBV in combination with 120mg FDV plus RBV for 16 weeks in non-cirrhotic patients.
    Arm type
    Experimental

    Investigational medicinal product name
    deleobuvir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo to DBV for 8 weeks followed by 600 mg deleobuvir (DBV) tablet was administered twice daily for a total daily dose of 1200 mg in non-cirrhotic patients for 16 weeks.

    Investigational medicinal product name
    faldaprevir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo to FDV for 8 weeks followed by 120 mg faldaprevir (FDV) Soft gelatin capsule was administered once daily for 16 weeks.

    Investigational medicinal product name
    ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo to RBV for 8 weeks followed by 500 mg or 600 mg ribavirin (RBV) tablet twice daily for a total daily dose of 1000 mg (<75 kg body weight) or 1200 mg (≥ 75 kg body weight) in non-cirrhotic patients for 16 weeks.

    Arm title
    24-wk cirrhotic (CR) treatment group 3
    Arm description
    24 weeks of treatment with 600mg BID deleobuvir (DBV) in combination with 120mg QD faldaprevir (FDV) plus ribavirin (RBV) in cirrhotic patients.
    Arm type
    Experimental

    Investigational medicinal product name
    deleobuvir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg deleobuvir (DBV) tablet was administered twice daily for a total daily dose of 1200 mg in cirrhotic patients for 24 weeks.

    Investigational medicinal product name
    faldaprevir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    120 mg faldaprevir (FDV) Soft gelatin capsule was administered once daily in cirrhotic patients for 24 weeks.

    Investigational medicinal product name
    ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500 mg or 600 mg ribavirin (RBV) tablet twice daily for a total daily dose of 1000 mg (<75 kg body weight) or 1200 mg (≥ 75 kg body weight) in cirrhotic patients for 24 weeks.

    Number of subjects in period 1 [1]
    24-wk non-cirrhotic (NC) treatment group 1 16-wk non-cirrhotic (NC) treatment group 2 24-wk cirrhotic (CR) treatment group 3
    Started
    211
    213
    72
    Completed
    173
    177
    58
    Not completed
    38
    36
    14
         Lack of efficacy
    14
    12
    8
         Protocol Violation (Placebo Period)
    -
    1
    -
         Adverse Event (Placebo Period)
    -
    1
    -
         Adverse event, non-fatal
    14
    13
    4
         Consent withdrawn by subject
    9
    6
    2
         Other than stated above
    1
    3
    -
    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: Baseline characteristics are based on the patients who were randomised after successfully completing the screening period and received at least one of the trial medication.
    Period 2
    Period 2 title
    Termination of FDV
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    Groups 1 (24-wk NC) and Group 2 (16-wk NC) were double-blinded to treatment duration and Group 3 (24-wk CR) was open-label.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    24-wk non-cirrhotic (NC) treatment group 1
    Arm description
    24 weeks of treatment with 600mg BID deleobuvir (DBV) in combination with 120mg QD faldaprevir (FDV) plus ribavirin (RBV) in non-cirrhotic patients.
    Arm type
    Experimental

    Investigational medicinal product name
    deleobuvir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg deleobuvir (DBV) tablet was administered twice daily for a total daily dose of 1200 mg in non-cirrhotic patients for 24 weeks.

    Investigational medicinal product name
    faldaprevir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    120 mg faldaprevir (FDV) Soft gelatin capsule was administered once daily mg in non-cirrhotic patients for 24 weeks.

    Investigational medicinal product name
    ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500 mg or 600 mg ribavirin (RBV) tablet twice daily for a total daily dose of 1000 mg (<75 kg body weight) or 1200 mg (≥ 75 kg body weight) in non-cirrhotic patients for 24 weeks.

    Arm title
    16-wk non-cirrhotic (NC) treatment group 2
    Arm description
    Matching placebo to DBV, matching placebo to FDV and Matching placebo to RBV for 8 weeks followed by 600mg BID DBV in combination with 120mg FDV plus RBV for 16 weeks in non-cirrhotic patients.
    Arm type
    Experimental

    Investigational medicinal product name
    deleobuvir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo to DBV for 8 weeks followed by 600 mg deleobuvir (DBV) tablet was administered twice daily for a total daily dose of 1200 mg in non-cirrhotic patients for 16 weeks.

    Investigational medicinal product name
    ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo to RBV for 8 weeks followed by 500 mg or 600 mg ribavirin (RBV) tablet twice daily for a total daily dose of 1000 mg (<75 kg body weight) or 1200 mg (≥ 75 kg body weight) in non-cirrhotic patients for 16 weeks.

    Investigational medicinal product name
    faldaprevir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo to FDV for 8 weeks followed by 120 mg faldaprevir (FDV) Soft gelatin capsule was administered once daily for 16 weeks.

    Arm title
    24-wk cirrhotic (CR) treatment group 3
    Arm description
    24 weeks of treatment with 600mg BID deleobuvir (DBV) in combination with 120mg QD faldaprevir (FDV) plus ribavirin (RBV) in cirrhotic patients.
    Arm type
    Experimental

    Investigational medicinal product name
    faldaprevir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    120 mg faldaprevir (FDV) Soft gelatin capsule was administered once daily mg in cirrhotic patients for 24 weeks.

    Investigational medicinal product name
    deleobuvir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg deleobuvir (DBV) tablet was administered twice daily for a total daily dose of 1200 mg in cirrhotic patients for 24 weeks.

    Investigational medicinal product name
    ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500 mg or 600 mg ribavirin (RBV) tablet twice daily for a total daily dose of 1000 mg (<75 kg body weight) or 1200 mg (≥ 75 kg body weight) in cirrhotic patients for 24 weeks.

    Number of subjects in period 2
    24-wk non-cirrhotic (NC) treatment group 1 16-wk non-cirrhotic (NC) treatment group 2 24-wk cirrhotic (CR) treatment group 3
    Started
    211
    213
    72
    Completed
    173
    177
    58
    Not completed
    38
    36
    14
         Lack of efficacy
    14
    12
    8
         Protocol Violation (Placebo Period)
    -
    1
    -
         Adverse Event (Placebo Period)
    -
    1
    -
         Adverse event, non-fatal
    14
    13
    4
         Consent withdrawn by subject
    9
    6
    2
         Other than stated above
    1
    3
    -
    Period 3
    Period 3 title
    Termination of RBV
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator
    Blinding implementation details
    Groups 1 (24-wk NC) and Group 2 (16-wk NC) were double-blinded to treatment duration and Group 3 (24-wk CR) was open-label.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    24-wk non-cirrhotic (NC) treatment group 1
    Arm description
    24 weeks of treatment with 600mg BID deleobuvir (DBV) in combination with 120mg QD faldaprevir (FDV) plus ribavirin (RBV) in non-cirrhotic patients.
    Arm type
    Experimental

    Investigational medicinal product name
    deleobuvir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg deleobuvir (DBV) tablet was administered twice daily for a total daily dose of 1200 mg in non-cirrhotic patients for 24 weeks.

    Investigational medicinal product name
    ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use, Oral use
    Dosage and administration details
    500 mg or 600 mg ribavirin (RBV) tablet twice daily for a total daily dose of 1000 mg (<75 kg body weight) or 1200 mg (≥ 75 kg body weight) in non-cirrhotic patients for 24 weeks.

    Investigational medicinal product name
    faldaprevir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    120 mg faldaprevir (FDV) Soft gelatin capsule was administered once daily mg in non-cirrhotic patients for 24 weeks.

    Arm title
    16-wk non-cirrhotic (NC) treatment group 2
    Arm description
    Matching placebo to DBV, Matching placebo to FDVand Matching placebo to RBV for 8 weeks followed by 600mg BID DBV in combination with 120mg FDV plus RBV for 16 weeks in non-cirrhotic patients.
    Arm type
    Experimental

    Investigational medicinal product name
    deleobuvir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo to DBV for 8 weeks followed by 600 mg deleobuvir (DBV) tablet was administered twice daily for a total daily dose of 1200 mg in non-cirrhotic patients for 16 weeks.

    Investigational medicinal product name
    ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo to RBV for 8 weeks followed by 500 mg or 600 mg ribavirin (RBV) tablet twice daily for a total daily dose of 1000 mg (<75 kg body weight) or 1200 mg (≥ 75 kg body weight) in non-cirrhotic patients for 16 weeks.

    Investigational medicinal product name
    faldaprevir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo to FDV for 8 weeks followed by 120 mg faldaprevir (FDV) Soft gelatin capsule was administered once daily for 16 weeks.

    Arm title
    24-wk cirrhotic (CR) treatment group 3
    Arm description
    24 weeks of treatment with 600mg BID deleobuvir (DBV) in combination with 120mg QD faldaprevir (FDV) plus ribavirin (RBV) in cirrhotic patients.
    Arm type
    Experimental

    Investigational medicinal product name
    deleobuvir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg deleobuvir (DBV) tablet was administered twice daily for a total daily dose of 1200 mg in cirrhotic patients for 24 weeks.

    Investigational medicinal product name
    faldaprevir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    120 mg faldaprevir (FDV) Soft gelatin capsule was administered once daily mg in cirrhotic patients for 24 weeks.

    Investigational medicinal product name
    ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500 mg or 600 mg ribavirin (RBV) tablet twice daily for a total daily dose of 1000 mg (<75 kg body weight) or 1200 mg (≥ 75 kg body weight) in cirrhotic patients for 24 weeks.

    Number of subjects in period 3
    24-wk non-cirrhotic (NC) treatment group 1 16-wk non-cirrhotic (NC) treatment group 2 24-wk cirrhotic (CR) treatment group 3
    Started
    211
    213
    72
    Completed
    172
    176
    57
    Not completed
    39
    37
    15
         Lack of efficacy
    14
    11
    7
         Protocol Violation (Placebo Period)
    -
    1
    -
         Adverse Event (Placebo Period)
    -
    1
    -
         Adverse event, non-fatal
    15
    16
    5
         Consent withdrawn by subject
    9
    5
    2
         Other than stated above
    1
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    24-wk non-cirrhotic (NC) treatment group 1
    Reporting group description
    24 weeks of treatment with 600mg BID deleobuvir (DBV) in combination with 120mg QD faldaprevir (FDV) plus ribavirin (RBV) in non-cirrhotic patients.

    Reporting group title
    16-wk non-cirrhotic (NC) treatment group 2
    Reporting group description
    Matching placebo to DBV, matching placebo to FDV and matching placebo to RBV for 8 weeks followed by 600mg BID DBV in combination with 120mg FDV plus RBV for 16 weeks in non-cirrhotic patients.

    Reporting group title
    24-wk cirrhotic (CR) treatment group 3
    Reporting group description
    24 weeks of treatment with 600mg BID deleobuvir (DBV) in combination with 120mg QD faldaprevir (FDV) plus ribavirin (RBV) in cirrhotic patients.

    Reporting group values
    24-wk non-cirrhotic (NC) treatment group 1 16-wk non-cirrhotic (NC) treatment group 2 24-wk cirrhotic (CR) treatment group 3 Total
    Number of subjects
    211 213 72
    Age categorical
    Units: Subjects
    Age Continuous |
    Full Analysis Set (FAS): This analysis set includes all randomized patients who were dispensed study medication and were documented to have taken at least one dose of any study medication, either active or placebo.
    Units: years
        arithmetic mean (standard deviation)
    50.3 ± 12.5 50.5 ± 12.3 58 ± 8.8 -
    Gender, Male/Female
    Units: Participants
        Female
    108 120 27 255
        Male
    103 93 45 241

    End points

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    End points reporting groups
    Reporting group title
    24-wk non-cirrhotic (NC) treatment group 1
    Reporting group description
    24 weeks of treatment with 600mg BID deleobuvir (DBV) in combination with 120mg QD faldaprevir (FDV) plus ribavirin (RBV) in non-cirrhotic patients.

    Reporting group title
    16-wk non-cirrhotic (NC) treatment group 2
    Reporting group description
    Matching placebo to DBV, matching placebo to FDV and matching placebo to RBV for 8 weeks followed by 600mg BID DBV in combination with 120mg FDV plus RBV for 16 weeks in non-cirrhotic patients.

    Reporting group title
    24-wk cirrhotic (CR) treatment group 3
    Reporting group description
    24 weeks of treatment with 600mg BID deleobuvir (DBV) in combination with 120mg QD faldaprevir (FDV) plus ribavirin (RBV) in cirrhotic patients.
    Reporting group title
    24-wk non-cirrhotic (NC) treatment group 1
    Reporting group description
    24 weeks of treatment with 600mg BID deleobuvir (DBV) in combination with 120mg QD faldaprevir (FDV) plus ribavirin (RBV) in non-cirrhotic patients.

    Reporting group title
    16-wk non-cirrhotic (NC) treatment group 2
    Reporting group description
    Matching placebo to DBV, matching placebo to FDV and Matching placebo to RBV for 8 weeks followed by 600mg BID DBV in combination with 120mg FDV plus RBV for 16 weeks in non-cirrhotic patients.

    Reporting group title
    24-wk cirrhotic (CR) treatment group 3
    Reporting group description
    24 weeks of treatment with 600mg BID deleobuvir (DBV) in combination with 120mg QD faldaprevir (FDV) plus ribavirin (RBV) in cirrhotic patients.
    Reporting group title
    24-wk non-cirrhotic (NC) treatment group 1
    Reporting group description
    24 weeks of treatment with 600mg BID deleobuvir (DBV) in combination with 120mg QD faldaprevir (FDV) plus ribavirin (RBV) in non-cirrhotic patients.

    Reporting group title
    16-wk non-cirrhotic (NC) treatment group 2
    Reporting group description
    Matching placebo to DBV, Matching placebo to FDVand Matching placebo to RBV for 8 weeks followed by 600mg BID DBV in combination with 120mg FDV plus RBV for 16 weeks in non-cirrhotic patients.

    Reporting group title
    24-wk cirrhotic (CR) treatment group 3
    Reporting group description
    24 weeks of treatment with 600mg BID deleobuvir (DBV) in combination with 120mg QD faldaprevir (FDV) plus ribavirin (RBV) in cirrhotic patients.

    Subject analysis set title
    24-wk non-cirrhotic (NC)+24-wk Cirrhotic (CR) treatment group
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The subject analysis type is infact Modified full analysis set (mFAS). 24 weeks of treatment with 600mg BID deleobuvir (DBV) in combination with 120mg QD faldaprevir (FDV) plus ribavirin (RBV) in non-cirrhotic and cirrhotic patients.

    Subject analysis set title
    16-wk non-cirrhotic (NC)+24-wk cirrhotic (CR) treatment group
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The subject analysis type is infact Modified full analysis set (mFAS). This is the combination of 16 weeks of treatment with 600mg BID deleobuvir (DBV) in combination with 120mg QD faldaprevir (FDV) plus ribavirin (RBV) in non-cirrhotic patients and for 24 weeks in cirrhotic patients

    Primary: SVR12 rates with historical control

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    End point title
    SVR12 rates with historical control [1]
    End point description
    Sustained Virologic Response at Week 12 post-treatment (SVR12): Plasma Hepatitis C virus (HCV) RNA (Ribonucleic acid) level <25 IU/mL (international Unit/ milliliter) at 12 weeks after end of treatment (EOT). SVR12, was assessed based on the observed HCV RNA result taken at least 10 weeks after treatment discontinuation. This definition was also applied to patients who discontinued treatment early: if the patient had HCV RNA undetected at least 10 weeks after stopping all treatment, they were considered a responder in the primary analysis. This is the primary analyses of the primary endpoint. The Number of Paticipants Analyzed are actually Adjusted Number of Paticipant Analyzed.Modified full analysis set (mFAS): included patients in the full analysis set (FAS) who received at least one dose of active treatment.
    End point type
    Primary
    End point timeframe
    12 Week (post-treatment)
    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: This Primary outcome measure reporting statistical analysis for one group are defined and analysed for trial 1241.36, however due to the platform limitations those could not be provided. Results can be found on CT.gov study number: NCT01728324.
    End point values
    24-wk non-cirrhotic (NC)+24-wk Cirrhotic (CR) treatment group 16-wk non-cirrhotic (NC)+24-wk cirrhotic (CR) treatment group
    Number of subjects analysed
    283 [2]
    283 [3]
    Units: percentage of participants
    number (not applicable)
        PegIFN eligible
    79.95
    76.68
        PegIFN ineligible
    88.28
    70.78
    Notes
    [2] - Modified full analysis set (mFAS)
    [3] - Modified full analysis set (mFAS
    No statistical analyses for this end point

    Primary: Comparisons of SVR12 rates across treatment arms

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    End point title
    Comparisons of SVR12 rates across treatment arms
    End point description
    Sustained Virologic Response rates across treatment arms at Week 12 post-treatment (SVR12). This is the secondary analyses of the primary endpoint.
    End point type
    Primary
    End point timeframe
    12 Week (post-treatment)
    End point values
    24-wk non-cirrhotic (NC) treatment group 1 16-wk non-cirrhotic (NC) treatment group 2 24-wk cirrhotic (CR) treatment group 3
    Number of subjects analysed
    211 [4]
    213 [5]
    72 [6]
    Units: Percentage of participants
        number (confidence interval 95%)
    82 (76.8 to 87.2)
    75.6 (69.8 to 81.4)
    73.6 (63.4 to 83.8)
    Notes
    [4] - FAS
    [5] - FAS
    [6] - FAS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Koch’s stratum-adjusted Mantel Haenszel methods were used to compare durations, adjusting for stratification factors.
    Comparison groups
    16-wk non-cirrhotic (NC) treatment group 2 v 24-wk non-cirrhotic (NC) treatment group 1
    Number of subjects included in analysis
    424
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.0532 [7]
    Method
    Koch’s method
    Parameter type
    SVR12 Rates difference
    Point estimate
    6.4
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.4
         upper limit
    14.2
    Notes
    [7] - Adjusted for PegIFN eligibility using Koch’s method, with continuity correction.

    Secondary: SVR4: Plasma HCV RNA level <25 IU/mL at 4 weeks after EOT.

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    End point title
    SVR4: Plasma HCV RNA level <25 IU/mL at 4 weeks after EOT.
    End point description
    SVR4: Plasma HCV RNA level <25 IU/mL at 4 weeks after EOT.
    End point type
    Secondary
    End point timeframe
    4 weeks (after End Of Treatment)
    End point values
    24-wk non-cirrhotic (NC) treatment group 1 16-wk non-cirrhotic (NC) treatment group 2 24-wk cirrhotic (CR) treatment group 3
    Number of subjects analysed
    211 [8]
    213 [9]
    72 [10]
    Units: percentage of participants
        number (confidence interval)
    83.9 (78.9 to 88.8)
    80.3 (74.9 to 85.6)
    77.8 (68.2 to 87.4)
    Notes
    [8] - FAS
    [9] - FAS
    [10] - FAS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Koch’s stratum-adjusted Mantel Haenszel methods were used to compare durations, adjusting for stratification factors.
    Comparison groups
    24-wk non-cirrhotic (NC) treatment group 1 v 16-wk non-cirrhotic (NC) treatment group 2
    Number of subjects included in analysis
    424
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.1671 [11]
    Method
    Koch´s method
    Parameter type
    SVR4 Rates difference
    Point estimate
    3.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.7
         upper limit
    10.9
    Notes
    [11] - Adjusted for PegIFN eligibility using Koch´s method, with continuity correction.

    Secondary: SVR24: Plasma HCV RNA level <25 IU/mL at 24 weeks after EOT.

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    End point title
    SVR24: Plasma HCV RNA level <25 IU/mL at 24 weeks after EOT.
    End point description
    SVR24: Plasma HCV RNA level <25 IU/mL at 24 weeks after EOT.
    End point type
    Secondary
    End point timeframe
    4 weeks (after End Of Treatment)
    End point values
    24-wk non-cirrhotic (NC) treatment group 1 16-wk non-cirrhotic (NC) treatment group 2 24-wk cirrhotic (CR) treatment group 3
    Number of subjects analysed
    211 [12]
    213 [13]
    72 [14]
    Units: percentage of participants
        number (confidence interval 95%)
    81 (75.8 to 86.3)
    74.2 (68.3 to 80.1)
    72.2 (61.9 to 82.6)
    Notes
    [12] - FAS
    [13] - FAS
    [14] - FAS
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Koch’s stratum-adjusted Mantel Haenszel methods were used to compare durations, adjusting for stratification factors.
    Comparison groups
    24-wk non-cirrhotic (NC) treatment group 1 v 16-wk non-cirrhotic (NC) treatment group 2
    Number of subjects included in analysis
    424
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.0447 [15]
    Method
    Koch´s method
    Parameter type
    SVR24 Rates difference
    Point estimate
    -6.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -14.8
         upper limit
    1.1
    Notes
    [15] - Adjusted for PegIFN eligibility using Koch´s method, with continuity correction.

    Secondary: Prognostic value of SVR12 predicting SVR24

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    End point title
    Prognostic value of SVR12 predicting SVR24
    End point description
    The positive predictive value of SVR12 predicting SVR24 are the patients with an SVR12 (=YES) and the SVR24 was assessed.
    End point type
    Secondary
    End point timeframe
    24 Week (post-treatment)
    End point values
    24-wk non-cirrhotic (NC) treatment group 1 16-wk non-cirrhotic (NC) treatment group 2 24-wk cirrhotic (CR) treatment group 3
    Number of subjects analysed
    211 [16]
    213 [17]
    72 [18]
    Units: Percentage of participants
        number (not applicable)
    99
    99
    98
    Notes
    [16] - FAS
    [17] - FAS
    [18] - FAS
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first drug administration until 28 days after the last drug administration.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    24-wk non-cirrhotic (NC) treatment group 1
    Reporting group description
    24 weeks of treatment with 600mg BID deleobuvir (DBV) in combination with 120mg QD faldaprevir (FDV) plus ribavirin (RBV) in non-cirrhotic patients.

    Reporting group title
    16-wk non-cirrhotic (NC) treatment group 2
    Reporting group description
    Matching placebo to DBV, matching placebo to FDV and matching placebo to RBV for 8 weeks followed by 600mg BID DBV in combination with 120mg FDV plus RBV for 16 weeks in non-cirrhotic patients.

    Reporting group title
    24-wk cirrhotic (CR) treatment group 3
    Reporting group description
    24 weeks of treatment with 600mg BID deleobuvir (DBV) in combination with 120mg QD faldaprevir (FDV) plus ribavirin (RBV) in cirrhotic patients.

    Serious adverse events
    24-wk non-cirrhotic (NC) treatment group 1 16-wk non-cirrhotic (NC) treatment group 2 24-wk cirrhotic (CR) treatment group 3
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 211 (3.32%)
    12 / 213 (5.63%)
    8 / 72 (11.11%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Hypertensive crisis
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 213 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 213 (0.00%)
    0 / 72 (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
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 213 (0.47%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 213 (0.47%)
    0 / 72 (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
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 213 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 213 (0.47%)
    0 / 72 (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
    Malaise
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 213 (0.00%)
    0 / 72 (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
    Psychiatric disorders
    Bipolar I disorder
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 213 (0.47%)
    0 / 72 (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
    Depression
         subjects affected / exposed
    1 / 211 (0.47%)
    2 / 213 (0.94%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Insomnia
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 213 (0.47%)
    0 / 72 (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
    Suicide attempt
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 213 (0.47%)
    0 / 72 (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
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 213 (0.00%)
    0 / 72 (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
    Jaw fracture
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 213 (0.00%)
    0 / 72 (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
    Cardiac disorders
    Pericarditis
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 213 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 211 (0.47%)
    2 / 213 (0.94%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 213 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytosis
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 213 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 213 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 213 (0.00%)
    0 / 72 (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
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 211 (0.00%)
    2 / 213 (0.94%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 213 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 213 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 213 (0.47%)
    0 / 72 (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
    Pancreatitis
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 213 (0.47%)
    0 / 72 (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
    Portal hypertensive gastropathy
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 213 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 211 (0.00%)
    2 / 213 (0.94%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 213 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute prerenal failure
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 213 (0.47%)
    0 / 72 (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
    Renal failure acute
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 213 (0.47%)
    0 / 72 (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
    Skin and subcutaneous tissue disorders
    Drug eruption
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 213 (0.00%)
    0 / 72 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Photosensitivity reaction
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 213 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 211 (0.00%)
    0 / 213 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 211 (0.47%)
    0 / 213 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    0 / 211 (0.00%)
    1 / 213 (0.47%)
    0 / 72 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    24-wk non-cirrhotic (NC) treatment group 1 16-wk non-cirrhotic (NC) treatment group 2 24-wk cirrhotic (CR) treatment group 3
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    198 / 211 (93.84%)
    202 / 213 (94.84%)
    66 / 72 (91.67%)
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    43 / 211 (20.38%)
    34 / 213 (15.96%)
    18 / 72 (25.00%)
         occurrences all number
    45
    34
    20
    Fatigue
         subjects affected / exposed
    74 / 211 (35.07%)
    73 / 213 (34.27%)
    26 / 72 (36.11%)
         occurrences all number
    79
    82
    26
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    8 / 211 (3.79%)
    21 / 213 (9.86%)
    6 / 72 (8.33%)
         occurrences all number
    8
    21
    6
    Depression
         subjects affected / exposed
    16 / 211 (7.58%)
    9 / 213 (4.23%)
    4 / 72 (5.56%)
         occurrences all number
    16
    9
    4
    Insomnia
         subjects affected / exposed
    35 / 211 (16.59%)
    25 / 213 (11.74%)
    10 / 72 (13.89%)
         occurrences all number
    37
    25
    10
    Irritability
         subjects affected / exposed
    8 / 211 (3.79%)
    8 / 213 (3.76%)
    4 / 72 (5.56%)
         occurrences all number
    8
    8
    4
    Injury, poisoning and procedural complications
    Sunburn
         subjects affected / exposed
    13 / 211 (6.16%)
    14 / 213 (6.57%)
    3 / 72 (4.17%)
         occurrences all number
    13
    14
    3
    Investigations
    Weight decreased
         subjects affected / exposed
    19 / 211 (9.00%)
    11 / 213 (5.16%)
    6 / 72 (8.33%)
         occurrences all number
    19
    11
    6
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    14 / 211 (6.64%)
    20 / 213 (9.39%)
    7 / 72 (9.72%)
         occurrences all number
    15
    22
    7
    Dyspnoea
         subjects affected / exposed
    18 / 211 (8.53%)
    11 / 213 (5.16%)
    6 / 72 (8.33%)
         occurrences all number
    19
    12
    6
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    26 / 211 (12.32%)
    22 / 213 (10.33%)
    13 / 72 (18.06%)
         occurrences all number
    26
    23
    15
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    19 / 211 (9.00%)
    21 / 213 (9.86%)
    6 / 72 (8.33%)
         occurrences all number
    22
    22
    6
    Dysgeusia
         subjects affected / exposed
    14 / 211 (6.64%)
    8 / 213 (3.76%)
    5 / 72 (6.94%)
         occurrences all number
    15
    8
    6
    Paraesthesia
         subjects affected / exposed
    15 / 211 (7.11%)
    17 / 213 (7.98%)
    3 / 72 (4.17%)
         occurrences all number
    17
    17
    3
    Headache
         subjects affected / exposed
    33 / 211 (15.64%)
    46 / 213 (21.60%)
    5 / 72 (6.94%)
         occurrences all number
    36
    52
    6
    Tremor
         subjects affected / exposed
    2 / 211 (0.95%)
    2 / 213 (0.94%)
    5 / 72 (6.94%)
         occurrences all number
    2
    2
    5
    Eye disorders
    Ocular icterus
         subjects affected / exposed
    27 / 211 (12.80%)
    16 / 213 (7.51%)
    2 / 72 (2.78%)
         occurrences all number
    30
    16
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    8 / 211 (3.79%)
    6 / 213 (2.82%)
    5 / 72 (6.94%)
         occurrences all number
    8
    6
    5
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    6 / 211 (2.84%)
    8 / 213 (3.76%)
    7 / 72 (9.72%)
         occurrences all number
    8
    9
    7
    Abdominal pain
         subjects affected / exposed
    16 / 211 (7.58%)
    16 / 213 (7.51%)
    4 / 72 (5.56%)
         occurrences all number
    17
    17
    4
    Abdominal pain upper
         subjects affected / exposed
    26 / 211 (12.32%)
    19 / 213 (8.92%)
    7 / 72 (9.72%)
         occurrences all number
    28
    20
    8
    Constipation
         subjects affected / exposed
    22 / 211 (10.43%)
    16 / 213 (7.51%)
    12 / 72 (16.67%)
         occurrences all number
    22
    17
    12
    Diarrhoea
         subjects affected / exposed
    59 / 211 (27.96%)
    54 / 213 (25.35%)
    24 / 72 (33.33%)
         occurrences all number
    73
    63
    28
    Dyspepsia
         subjects affected / exposed
    26 / 211 (12.32%)
    26 / 213 (12.21%)
    13 / 72 (18.06%)
         occurrences all number
    27
    29
    14
    Gastrooesophageal reflux disease
         subjects affected / exposed
    9 / 211 (4.27%)
    5 / 213 (2.35%)
    4 / 72 (5.56%)
         occurrences all number
    10
    5
    4
    Nausea
         subjects affected / exposed
    129 / 211 (61.14%)
    121 / 213 (56.81%)
    41 / 72 (56.94%)
         occurrences all number
    153
    139
    45
    Vomiting
         subjects affected / exposed
    69 / 211 (32.70%)
    64 / 213 (30.05%)
    25 / 72 (34.72%)
         occurrences all number
    91
    84
    40
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    8 / 211 (3.79%)
    6 / 213 (2.82%)
    7 / 72 (9.72%)
         occurrences all number
    8
    6
    7
    Jaundice
         subjects affected / exposed
    27 / 211 (12.80%)
    15 / 213 (7.04%)
    18 / 72 (25.00%)
         occurrences all number
    31
    16
    19
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    15 / 211 (7.11%)
    3 / 213 (1.41%)
    3 / 72 (4.17%)
         occurrences all number
    15
    3
    3
    Dry skin
         subjects affected / exposed
    18 / 211 (8.53%)
    12 / 213 (5.63%)
    5 / 72 (6.94%)
         occurrences all number
    18
    12
    5
    Erythema
         subjects affected / exposed
    33 / 211 (15.64%)
    39 / 213 (18.31%)
    10 / 72 (13.89%)
         occurrences all number
    36
    41
    13
    Photosensitivity reaction
         subjects affected / exposed
    38 / 211 (18.01%)
    26 / 213 (12.21%)
    6 / 72 (8.33%)
         occurrences all number
    42
    27
    6
    Pruritus
         subjects affected / exposed
    47 / 211 (22.27%)
    47 / 213 (22.07%)
    23 / 72 (31.94%)
         occurrences all number
    50
    52
    24
    Rash
         subjects affected / exposed
    43 / 211 (20.38%)
    39 / 213 (18.31%)
    10 / 72 (13.89%)
         occurrences all number
    63
    52
    11
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    10 / 211 (4.74%)
    6 / 213 (2.82%)
    6 / 72 (8.33%)
         occurrences all number
    10
    6
    6
    Muscle spasms
         subjects affected / exposed
    11 / 211 (5.21%)
    8 / 213 (3.76%)
    2 / 72 (2.78%)
         occurrences all number
    11
    8
    2
    Myalgia
         subjects affected / exposed
    7 / 211 (3.32%)
    11 / 213 (5.16%)
    1 / 72 (1.39%)
         occurrences all number
    7
    11
    1
    Metabolism and nutrition disorders
    Vitamin D deficiency
         subjects affected / exposed
    8 / 211 (3.79%)
    5 / 213 (2.35%)
    8 / 72 (11.11%)
         occurrences all number
    8
    5
    8
    Decreased appetite
         subjects affected / exposed
    34 / 211 (16.11%)
    27 / 213 (12.68%)
    14 / 72 (19.44%)
         occurrences all number
    34
    27
    14
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    11 / 211 (5.21%)
    9 / 213 (4.23%)
    2 / 72 (2.78%)
         occurrences all number
    11
    10
    2
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 211 (3.79%)
    4 / 213 (1.88%)
    5 / 72 (6.94%)
         occurrences all number
    8
    4
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Nov 2012
    1) Excluded patients with GT1a IL28b CC. 2) Removed stratification by sub-GT and IL-28b. 3) Extended safety data collection at rescue to 4 weeks. 4) Removed protein electrophoresis at screening. 5) Revised sample size to 210 patients for Group 1, 210 patients for Group 2 and 50-70 patients for Group 3, based on exclusion of GT1a patients.
    28 Jun 2013
    1) Redefined the minimum historical target SVR12 rates from a point estimate of 71% for the lower bound of the CI (original protocol) to a weighted average of 66% (PegIFN-eligible) and 50% (PegIFN-ineligible), where 1/2 CI is approximately 6%. 2) Specified a hierarchical order for the comparisons to the historical control. Clarified that one-sided tests with alpha=0.025 were to be performed. 3) Added power calculations for comparison to the historical control. 4) Added increased ECG monitoring based on preliminary results from 1241.25. 5) Added monitoring for appearance of systemic symptoms of DRESS and criteria for treatment discontinuation in case of potentially life threatening skin reactions. 6) Added second confirmation in case of virologic breakthrough; clarified the confirmation process. 7) Clarified procedures related to rescue medication. 8) Revised SAE reporting processes based on updated sponsor SOP.
    24 Sep 2013
    1) Changed the order of primary and secondary objectives. 2) Re-defined the minimum historical target SVR12 rates. Specified a hierarchical order for primary and secondary objective testing. 3) Updated power calculation for the primaryanalysis based on the proposed sample size. 4) Specified collection of all SAEs with onset date after 28 days post-EOT until EOO. Defined residual effect period. Extended safety reporting during follow-up period.
    31 Oct 2013
    1) Added potential risk of agranulocytosis/neutropenia. 2) Added discontinuation of patients with ANC≤500 cells/mm3. 3) Clarified SAE reporting requirements. 4) Treatment phase cut-off revised to 7 days after last treatment for laboratory values.
    08 Apr 2014
    1) Due to termination of the DBV program, the FU period was reduced to 24 weeks for patients who achieved SVR12 and to 48 weeks for non-responders provided they had not started an alternative HCV treatment. 2) Follow-up of rescue treatment was reduced to RFU1 at REOT+12 weeks. 3) FU3 snapshot was removed.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    08 Apr 2014
    Clinical development of the DBV was terminated, thus this trial was prematurely discontinued.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Primary outcome measure 1 reporting statistical analysis for one group are defined and analysed for trial 1241.36, however due to the platform limitations those could not be provided. Results can be found on CT.gov study number: NCT01728324.
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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