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    Clinical Trial Results:
    A phase 3 randomised, partially double-blind and placebo-controlled study of BI 207127 in combination with faldaprevir and ribavirin in treatment naïve patients with chronic genotype 1 HCV infection.

    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
    2012-003533-41
    Trial protocol
    DE   PT   GB   ES   IE   IT   NL   HU   AT  
    Global end of trial date
    22 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
    1241.20
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01732796
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    QRPE Processes and Systems Coordination Clinical Trial Information Disclosure, Boehringer Ingelheim, 001 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
    03 Mar 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Feb 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    22 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 milligram (mg) of BID (twice daily) Deleobuvir (DBV) in combination with 120 mg QD (once daily) Faldaprevir (FDV) and Ribavirin (RBV) for 16 or 24 weeks in chronically infected hepatitis C virus (HCV) genotype (GT)1b treatment-naïve patients, including a separate group of patients with compensated cirrhosis who were treated open-label for 24 weeks. The primary objective was to determine if minimum historical target sustained virologic response at week 12 (SVR12) rates of 71% 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. Rescue medication was allowed for all patients as required.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    13 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
    Spain: 84
    Country: Number of subjects enrolled
    United Kingdom: 21
    Country: Number of subjects enrolled
    United States: 125
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Canada: 65
    Country: Number of subjects enrolled
    France: 68
    Country: Number of subjects enrolled
    Germany: 109
    Country: Number of subjects enrolled
    Hungary: 15
    Country: Number of subjects enrolled
    Ireland: 13
    Country: Number of subjects enrolled
    Italy: 104
    Country: Number of subjects enrolled
    Netherlands: 20
    Country: Number of subjects enrolled
    Portugal: 20
    Country: Number of subjects enrolled
    Romania: 38
    Country: Number of subjects enrolled
    Russian Federation: 8
    Worldwide total number of subjects
    691
    EEA total number of subjects
    493
    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)
    607
    From 65 to 84 years
    84
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    It was planned that approximately 800 patients would be screened in order to randomize and treat approximately 460 patients (195 in treatment Groups 1 and 2 each, 40-70 in group 3). Treatment-naïve patients with chronic hepatitis C infection of GT1b were included in the trial. Patients with compensated liver cirrhosis were assigned to Group 3.

    Pre-assignment
    Screening details
    All subjects were screened for eligibility to participate in the trial. Subjects attended specialist sites which would then ensure that the subject 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
    Treatment period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    16 wk NC FDV+DBV+RBV
    Arm description
    600 milligram (mg) of Deleobuvir (DBV) twice daily (BID) combined with 240 mg on the first day followed by 120mg of Faldaprevir (FDV) once daily (QD) and 1000-1200mg Ribavirin BID (RBV) for 16 weeks (wk) followed by DBV placebo, FDV placebo and RBV placebo for 8 weeks. All were administered per os (orally). This group included non-cirrhotic patients (NC).
    Arm type
    Experimental

    Investigational medicinal product name
    Faldaprevir
    Investigational medicinal product code
    BI 201335
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    starting dose of 240 milligram (mg) Faldaprevir (FDV), thereafter 120mg FDV once daily for 16 weeks followed by 8 weeks FDV placebo

    Investigational medicinal product name
    Deleobuvir
    Investigational medicinal product code
    BI 207127
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    total daily dose of 1200mg Deleobuvir (DBV), administered twice daily (BID) 600mg for 16 weeks followed by 8 weeks of DBV placebo

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Copegus (R)
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    total daily dose of 1000-1200mg Ribavirin (RBV), administered BID 500-600mg for 16 weeks followed by 8 weeks RBV placebo

    Investigational medicinal product name
    Placebo FDV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo FDV once daily for 8 weeks after 16 weeks FDV treatment

    Investigational medicinal product name
    Placebo DBV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BID for 8 weeks after 16 weeks DBV treatment

    Investigational medicinal product name
    Placebo RBV
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    BID for 8 weeks after 16 weeks RBV treatment

    Arm title
    24 wk NC FDV+DBV+RBV
    Arm description
    600 milligram (mg) of Deleobuvir (DBV) twice daily (BID) combined with 240 mg on the first day followed by 120mg of Faldaprevir (FDV) once daily (QD) and 1000-1200mg Ribavirin (RBV) BID for 24 weeks (wk). All were administered per os (orally). This group included non-cirrhotic patients (NC).
    Arm type
    Experimental

    Investigational medicinal product name
    Faldaprevir
    Investigational medicinal product code
    BI 201335
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    starting dose of 240 milligram (mg) Faldaprevir (FDV), thereafter 120mg FDV once daily for 16 weeks followed by 8 weeks FDV placebo

    Investigational medicinal product name
    Deleobuvir
    Investigational medicinal product code
    BI 207127
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    total daily dose of 1200mg Deleobuvir (DBV), administered twice daily (BID) 600mg for 16 weeks followed by 8 weeks of DBV placebo

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Copegus (R)
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    total daily dose of 1000-1200mg Ribavirin (RBV), administered BID 500-600mg for 16 weeks followed by 8 weeks RBV placebo

    Arm title
    24 wk CR FDV+DBV+RBV
    Arm description
    600 milligram (mg) of Deleobuvir (DBV) twice daily (BID) combined with 240 mg on the first day followed by 120mg of Faldaprevir (FDV) once daily (QD) and 1000-1200mg Ribavirin (RBV) BID for 24 weeks (wk). All were administered per os (orally). This group comprised patients with compensated cirrhosis (CR) who received open label treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    Faldaprevir
    Investigational medicinal product code
    BI 201335
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    starting dose of 240 milligram (mg) Faldaprevir (FDV), thereafter 120mg FDV once daily for 16 weeks followed by 8 weeks FDV placebo

    Investigational medicinal product name
    Deleobuvir
    Investigational medicinal product code
    BI 207127
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    total daily dose of 1200mg Deleobuvir (DBV), administered twice daily (BID) 600mg for 16 weeks followed by 8 weeks of DBV placebo

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Copegus (R)
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    total daily dose of 1000-1200mg Ribavirin (RBV), administered BID 500-600mg for 16 weeks followed by 8 weeks RBV placebo

    Number of subjects in period 1 [1]
    16 wk NC FDV+DBV+RBV 24 wk NC FDV+DBV+RBV 24 wk CR FDV+DBV+RBV
    Started
    208
    211
    51
    Completed
    162
    169
    38
    Not completed
    46
    42
    13
         Lack of efficacy
    21
    18
    5
         Adverse event, non-fatal
    16
    16
    4
         other reason, not defined above
    1
    -
    2
         Consent withdrawn by subject
    6
    8
    2
         Lost to follow-up
    2
    -
    -
    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 patients who were randomised after successfully completing the screening period and received at least one of the trial medication.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    16 wk NC FDV+DBV+RBV
    Reporting group description
    600 milligram (mg) of Deleobuvir (DBV) twice daily (BID) combined with 240 mg on the first day followed by 120mg of Faldaprevir (FDV) once daily (QD) and 1000-1200mg Ribavirin BID (RBV) for 16 weeks (wk) followed by DBV placebo, FDV placebo and RBV placebo for 8 weeks. All were administered per os (orally). This group included non-cirrhotic patients (NC).

    Reporting group title
    24 wk NC FDV+DBV+RBV
    Reporting group description
    600 milligram (mg) of Deleobuvir (DBV) twice daily (BID) combined with 240 mg on the first day followed by 120mg of Faldaprevir (FDV) once daily (QD) and 1000-1200mg Ribavirin (RBV) BID for 24 weeks (wk). All were administered per os (orally). This group included non-cirrhotic patients (NC).

    Reporting group title
    24 wk CR FDV+DBV+RBV
    Reporting group description
    600 milligram (mg) of Deleobuvir (DBV) twice daily (BID) combined with 240 mg on the first day followed by 120mg of Faldaprevir (FDV) once daily (QD) and 1000-1200mg Ribavirin (RBV) BID for 24 weeks (wk). All were administered per os (orally). This group comprised patients with compensated cirrhosis (CR) who received open label treatment.

    Reporting group values
    16 wk NC FDV+DBV+RBV 24 wk NC FDV+DBV+RBV 24 wk CR FDV+DBV+RBV Total
    Number of subjects
    208 211 51 470
    Age categorical
    The baseline characteristics were carried out on an intent-to-treat basis including all randomized patients who were dispensed study medication and were documented to havetaken at least one dose of study medication (FAS).
    Units: Subjects
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    50.1 ± 12.7 51.1 ± 12.9 57.9 ± 8.8 -
    Gender, Male/Female
    FAS
    Units: Participants
        Female
    122 114 18 254
        Male
    86 97 33 216

    End points

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    End points reporting groups
    Reporting group title
    16 wk NC FDV+DBV+RBV
    Reporting group description
    600 milligram (mg) of Deleobuvir (DBV) twice daily (BID) combined with 240 mg on the first day followed by 120mg of Faldaprevir (FDV) once daily (QD) and 1000-1200mg Ribavirin BID (RBV) for 16 weeks (wk) followed by DBV placebo, FDV placebo and RBV placebo for 8 weeks. All were administered per os (orally). This group included non-cirrhotic patients (NC).

    Reporting group title
    24 wk NC FDV+DBV+RBV
    Reporting group description
    600 milligram (mg) of Deleobuvir (DBV) twice daily (BID) combined with 240 mg on the first day followed by 120mg of Faldaprevir (FDV) once daily (QD) and 1000-1200mg Ribavirin (RBV) BID for 24 weeks (wk). All were administered per os (orally). This group included non-cirrhotic patients (NC).

    Reporting group title
    24 wk CR FDV+DBV+RBV
    Reporting group description
    600 milligram (mg) of Deleobuvir (DBV) twice daily (BID) combined with 240 mg on the first day followed by 120mg of Faldaprevir (FDV) once daily (QD) and 1000-1200mg Ribavirin (RBV) BID for 24 weeks (wk). All were administered per os (orally). This group comprised patients with compensated cirrhosis (CR) who received open label treatment.

    Subject analysis set title
    24 wk FDV+DBV+RBV
    Subject analysis set type
    Full analysis
    Subject analysis set description
    600 mg DBV (BID) + 120mg FDV (QD) + 1000-1200mg RBV (BID) for 24wk (orally) in cirrhotic and non-cirrhotic patients.

    Subject analysis set title
    16 wk FDV+DBV+RBV
    Subject analysis set type
    Full analysis
    Subject analysis set description
    600 mg DBV (BID) + 120mg FDV (QD) + 1000-1200mg RBV (BID), orally. This is the combination of non-cirrhotic patients in the 16 week treatment group and cirrhosis patients in the 24-week treatment group.

    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 ribonucleic acid (HCV RNA) level <25 international units/millilitre (IU/mL) 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 primary analyses of efficacy were carried out on an intent-to-treat basis including all randomized patients who were dispensed study medication and were documented to have taken at least one dose of study medication (FAS).
    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 1241.20, however due to the platform limitations those could not be provided. Results can be found on CT.gov study number: NCT01732796.
    End point values
    24 wk FDV+DBV+RBV 16 wk FDV+DBV+RBV
    Number of subjects analysed
    262 [2]
    259 [3]
    Units: Percentage of participants
    number (not applicable)
        non-cirrhotic
    82.5
    71.6
        cirrhotic
    72.5
    72.5
    Notes
    [2] - FAS
    [3] - FAS
    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
    16 wk NC FDV+DBV+RBV 24 wk NC FDV+DBV+RBV 24 wk CR FDV+DBV+RBV
    Number of subjects analysed
    208 [4]
    211 [5]
    51 [6]
    Units: Percentage of participants
        number (not applicable)
    71.6
    82.5
    72.5
    Notes
    [4] - FAS
    [5] - FAS
    [6] - FAS
    Statistical analysis title
    16 wk NC FDV+DBV+RBV vs. 24 wk NC FDV+DBV+RBV
    Statistical analysis description
    Koch’s stratum-adjusted Mantel Haenszel methods were used to compare durations, adjusting for stratification factors.
    Comparison groups
    16 wk NC FDV+DBV+RBV v 24 wk NC FDV+DBV+RBV
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.004 [7]
    Method
    z-test
    Parameter type
    Koch's method with continuity correction
    Point estimate
    10.8
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.8
         upper limit
    18.8
    Notes
    [7] - based on two sample z-test with continuity correction for variance.

    Secondary: SVR4

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    End point title
    SVR4
    End point description
    Sustained Virologic Response rates across treatment arms at Week 4 post-treatment (SVR4). The prognostic value of SVR12 predicting SVR4 are the patients with an SVR4 (=YES) and the SVR12 was assessed.
    End point type
    Secondary
    End point timeframe
    4 Week (post-treatment)
    End point values
    16 wk NC FDV+DBV+RBV 24 wk NC FDV+DBV+RBV 24 wk CR FDV+DBV+RBV
    Number of subjects analysed
    208 [8]
    211 [9]
    51 [10]
    Units: Percentage of participants
    number (not applicable)
        Percentage of patients with response
    78.4
    84.4
    76.5
        Positive predictive Value
    94
    98
    95
    Notes
    [8] - FAS
    [9] - FAS
    [10] - FAS
    Statistical analysis title
    16 wk NC FDV+DBV+RBV vs. 24 wk NC FDV+DBV+RBV
    Statistical analysis description
    Koch’s stratum-adjusted Mantel Haenszel methods were used to compare durations, adjusting for stratification factors. Category: Percentage of patient with response
    Comparison groups
    16 wk NC FDV+DBV+RBV v 24 wk NC FDV+DBV+RBV
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0575 [11]
    Method
    z-test
    Parameter type
    Koch's method with continuity correction
    Point estimate
    6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.5
         upper limit
    13.5
    Notes
    [11] - based on two sample z-test with continuity correction for variance.

    Secondary: SVR24

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    End point title
    SVR24
    End point description
    Sustained Virologic Response rates across treatment arms at Week 24 post-treatment (SVR24). The prognostic 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
    16 wk NC FDV+DBV+RBV 24 wk NC FDV+DBV+RBV 24 wk CR FDV+DBV+RBV
    Number of subjects analysed
    208 [12]
    211 [13]
    51 [14]
    Units: Percentage of participants
    number (not applicable)
        Percentage of patients with response
    70.7
    80.6
    72.5
        Positive predicted value
    97
    99
    100
    Notes
    [12] - FAS
    [13] - FAS
    [14] - FAS
    Statistical analysis title
    16 wk NC FDV+DBV+RBV vs. 24 wk NC FDV+DBV+RBV
    Statistical analysis description
    Koch’s stratum-adjusted Mantel Haenszel methods were used to compare durations, adjusting for stratification factors.
    Comparison groups
    16 wk NC FDV+DBV+RBV v 24 wk NC FDV+DBV+RBV
    Number of subjects included in analysis
    419
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0089 [15]
    Method
    z-test
    Parameter type
    Koch's method with continuity correction
    Point estimate
    9.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.7
         upper limit
    18.1
    Notes
    [15] - based on two sample z-test with continuity correction for variance.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first administration of study medication to 4 weeks after last intake (up to 200 days). Adverse events with an onset date thereafter were to be reported only if serious up to 24 or 48 weeks after last study treatment (up to 340 or 508 days).
    Adverse event reporting additional description
    Safety analyses were based on the safety set that included all patients who were dispensed study medication and were documented to have taken at least 1 dose of investigational treatment, regardless of randomization.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    16 wk NC FDV+DBV+RBV
    Reporting group description
    600 mg DBV (BID) + 120mg FDV (QD) + 1000-1200mg RBV (BID) for 16wk followed by DBV placebo, FDV placebo and RBV placebo for 8wk. All were administered per os (orally). This group included non-cirrhotic patients (NC).

    Reporting group title
    24 wk NC FDV+DBV+RBV
    Reporting group description
    600 mg DBV (BID) + 120mg FDV (QD) + 1000-1200mg RBV (BID) for 24wk. All were administered per os (orally). This group included non-cirrhotic patients (NC).

    Reporting group title
    24 wk CR FDV+DBV+RBV
    Reporting group description
    600 mg DBV (BID) + 120mg FDV (QD) + 1000-1200mg RBV (BID) for 24wk. All were administered per os (orally). This group comprised patients with compensated cirrhosis (CR) who received open label treatment.

    Serious adverse events
    16 wk NC FDV+DBV+RBV 24 wk NC FDV+DBV+RBV 24 wk CR FDV+DBV+RBV
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 208 (3.37%)
    11 / 211 (5.21%)
    4 / 51 (7.84%)
         number of deaths (all causes)
    1
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 211 (0.47%)
    0 / 51 (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
    Thrombosis
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 211 (0.47%)
    0 / 51 (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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Non-Hodgkin's lymphoma
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 211 (0.00%)
    0 / 51 (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
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 211 (0.00%)
    0 / 51 (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
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 211 (0.00%)
    0 / 51 (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
    Pyrexia
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 211 (0.47%)
    0 / 51 (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
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 211 (0.47%)
    0 / 51 (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
    Drug abuse
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 211 (0.47%)
    0 / 51 (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
    Psychotic disorder
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 211 (0.47%)
    0 / 51 (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
    Injury, poisoning and procedural complications
    Dumping syndrome
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 211 (0.47%)
    0 / 51 (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
    Fall
         subjects affected / exposed
    1 / 208 (0.48%)
    1 / 211 (0.47%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Multiple injuries
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 211 (0.00%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardiac disorders
    Pericarditis
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 211 (0.00%)
    0 / 51 (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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 208 (0.48%)
    2 / 211 (0.95%)
    0 / 51 (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
    Agranulocytosis
         subjects affected / exposed
    1 / 208 (0.48%)
    1 / 211 (0.47%)
    0 / 51 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 211 (0.47%)
    0 / 51 (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
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 211 (0.00%)
    0 / 51 (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
    Loss of consciousness
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 211 (0.00%)
    0 / 51 (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
    Syncope
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 211 (0.47%)
    0 / 51 (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
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 208 (0.00%)
    0 / 211 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 211 (0.47%)
    0 / 51 (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
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 211 (0.47%)
    0 / 51 (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
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 208 (0.00%)
    0 / 211 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 208 (0.00%)
    0 / 211 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 208 (0.00%)
    0 / 211 (0.00%)
    1 / 51 (1.96%)
         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
    Prerenal failure
         subjects affected / exposed
    0 / 208 (0.00%)
    0 / 211 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 211 (0.47%)
    0 / 51 (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
    Urethral stenosis
         subjects affected / exposed
    0 / 208 (0.00%)
    0 / 211 (0.00%)
    1 / 51 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthritis
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 211 (0.47%)
    0 / 51 (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
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 211 (0.00%)
    0 / 51 (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
    Infections and infestations
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 211 (0.47%)
    0 / 51 (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
    Gingivitis
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 211 (0.47%)
    0 / 51 (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
    Gastritis bacterial
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 211 (0.47%)
    0 / 51 (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
    16 wk NC FDV+DBV+RBV 24 wk NC FDV+DBV+RBV 24 wk CR FDV+DBV+RBV
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    192 / 208 (92.31%)
    198 / 211 (93.84%)
    49 / 51 (96.08%)
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    5 / 208 (2.40%)
    3 / 211 (1.42%)
    3 / 51 (5.88%)
         occurrences all number
    5
    4
    3
    Asthenia
         subjects affected / exposed
    40 / 208 (19.23%)
    58 / 211 (27.49%)
    7 / 51 (13.73%)
         occurrences all number
    43
    59
    7
    Fatigue
         subjects affected / exposed
    53 / 208 (25.48%)
    50 / 211 (23.70%)
    13 / 51 (25.49%)
         occurrences all number
    57
    50
    14
    Chills
         subjects affected / exposed
    5 / 208 (2.40%)
    3 / 211 (1.42%)
    3 / 51 (5.88%)
         occurrences all number
    5
    3
    3
    Pyrexia
         subjects affected / exposed
    6 / 208 (2.88%)
    6 / 211 (2.84%)
    4 / 51 (7.84%)
         occurrences all number
    7
    7
    4
    Psychiatric disorders
    Depression
         subjects affected / exposed
    11 / 208 (5.29%)
    18 / 211 (8.53%)
    1 / 51 (1.96%)
         occurrences all number
    11
    18
    1
    Irritability
         subjects affected / exposed
    6 / 208 (2.88%)
    14 / 211 (6.64%)
    2 / 51 (3.92%)
         occurrences all number
    6
    14
    2
    Insomnia
         subjects affected / exposed
    17 / 208 (8.17%)
    29 / 211 (13.74%)
    10 / 51 (19.61%)
         occurrences all number
    17
    30
    10
    Injury, poisoning and procedural complications
    Sunburn
         subjects affected / exposed
    9 / 208 (4.33%)
    17 / 211 (8.06%)
    4 / 51 (7.84%)
         occurrences all number
    11
    19
    4
    Investigations
    Weight decreased
         subjects affected / exposed
    13 / 208 (6.25%)
    19 / 211 (9.00%)
    5 / 51 (9.80%)
         occurrences all number
    13
    21
    5
    Blood bilirubin increased
         subjects affected / exposed
    8 / 208 (3.85%)
    10 / 211 (4.74%)
    5 / 51 (9.80%)
         occurrences all number
    8
    11
    5
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    14 / 208 (6.73%)
    18 / 211 (8.53%)
    4 / 51 (7.84%)
         occurrences all number
    15
    19
    4
    Cough
         subjects affected / exposed
    13 / 208 (6.25%)
    17 / 211 (8.06%)
    7 / 51 (13.73%)
         occurrences all number
    13
    18
    8
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    40 / 208 (19.23%)
    53 / 211 (25.12%)
    19 / 51 (37.25%)
         occurrences all number
    43
    56
    20
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    13 / 208 (6.25%)
    18 / 211 (8.53%)
    5 / 51 (9.80%)
         occurrences all number
    14
    19
    5
    Headache
         subjects affected / exposed
    33 / 208 (15.87%)
    30 / 211 (14.22%)
    4 / 51 (7.84%)
         occurrences all number
    36
    41
    4
    Dysgeusia
         subjects affected / exposed
    11 / 208 (5.29%)
    8 / 211 (3.79%)
    4 / 51 (7.84%)
         occurrences all number
    11
    9
    4
    Paraesthesia
         subjects affected / exposed
    11 / 208 (5.29%)
    17 / 211 (8.06%)
    2 / 51 (3.92%)
         occurrences all number
    11
    18
    2
    Syncope
         subjects affected / exposed
    0 / 208 (0.00%)
    8 / 211 (3.79%)
    3 / 51 (5.88%)
         occurrences all number
    0
    9
    4
    Eye disorders
    Ocular icterus
         subjects affected / exposed
    20 / 208 (9.62%)
    15 / 211 (7.11%)
    3 / 51 (5.88%)
         occurrences all number
    20
    17
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    14 / 208 (6.73%)
    16 / 211 (7.58%)
    4 / 51 (7.84%)
         occurrences all number
    15
    19
    4
    Abdominal discomfort
         subjects affected / exposed
    14 / 208 (6.73%)
    10 / 211 (4.74%)
    3 / 51 (5.88%)
         occurrences all number
    14
    10
    3
    Diarrhoea
         subjects affected / exposed
    50 / 208 (24.04%)
    66 / 211 (31.28%)
    17 / 51 (33.33%)
         occurrences all number
    58
    88
    24
    Abdominal pain upper
         subjects affected / exposed
    25 / 208 (12.02%)
    27 / 211 (12.80%)
    2 / 51 (3.92%)
         occurrences all number
    26
    33
    2
    Constipation
         subjects affected / exposed
    12 / 208 (5.77%)
    14 / 211 (6.64%)
    3 / 51 (5.88%)
         occurrences all number
    13
    16
    3
    Nausea
         subjects affected / exposed
    96 / 208 (46.15%)
    112 / 211 (53.08%)
    27 / 51 (52.94%)
         occurrences all number
    111
    141
    33
    Dyspepsia
         subjects affected / exposed
    24 / 208 (11.54%)
    25 / 211 (11.85%)
    5 / 51 (9.80%)
         occurrences all number
    25
    26
    5
    Vomiting
         subjects affected / exposed
    64 / 208 (30.77%)
    62 / 211 (29.38%)
    18 / 51 (35.29%)
         occurrences all number
    87
    88
    30
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    17 / 208 (8.17%)
    17 / 211 (8.06%)
    5 / 51 (9.80%)
         occurrences all number
    18
    19
    6
    Jaundice
         subjects affected / exposed
    28 / 208 (13.46%)
    35 / 211 (16.59%)
    10 / 51 (19.61%)
         occurrences all number
    28
    36
    10
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    18 / 208 (8.65%)
    9 / 211 (4.27%)
    2 / 51 (3.92%)
         occurrences all number
    18
    9
    2
    Erythema
         subjects affected / exposed
    23 / 208 (11.06%)
    28 / 211 (13.27%)
    8 / 51 (15.69%)
         occurrences all number
    25
    31
    10
    Dry skin
         subjects affected / exposed
    18 / 208 (8.65%)
    13 / 211 (6.16%)
    2 / 51 (3.92%)
         occurrences all number
    19
    13
    2
    Photosensitivity reaction
         subjects affected / exposed
    29 / 208 (13.94%)
    30 / 211 (14.22%)
    10 / 51 (19.61%)
         occurrences all number
    33
    33
    11
    Rash
         subjects affected / exposed
    35 / 208 (16.83%)
    37 / 211 (17.54%)
    11 / 51 (21.57%)
         occurrences all number
    43
    40
    15
    Pruritus
         subjects affected / exposed
    38 / 208 (18.27%)
    53 / 211 (25.12%)
    20 / 51 (39.22%)
         occurrences all number
    43
    65
    23
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    13 / 208 (6.25%)
    11 / 211 (5.21%)
    1 / 51 (1.96%)
         occurrences all number
    15
    11
    1
    Back pain
         subjects affected / exposed
    13 / 208 (6.25%)
    6 / 211 (2.84%)
    1 / 51 (1.96%)
         occurrences all number
    13
    6
    1
    Metabolism and nutrition disorders
    Vitamin D deficiency
         subjects affected / exposed
    14 / 208 (6.73%)
    21 / 211 (9.95%)
    1 / 51 (1.96%)
         occurrences all number
    14
    21
    1
    Decreased appetite
         subjects affected / exposed
    20 / 208 (9.62%)
    33 / 211 (15.64%)
    6 / 51 (11.76%)
         occurrences all number
    20
    33
    6
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    12 / 208 (5.77%)
    13 / 211 (6.16%)
    4 / 51 (7.84%)
         occurrences all number
    15
    14
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Dec 2012
    Excluded patients with GT1a IL28b CC; Removed stratification by sub-GT and IL-28b; Extended safety data collection at rescue to 4 weeks after the end of rescue therapy; Removed protein electrophoresis at screening; Revised sample size to 195 patients for Group 1, 195 patients for Group 2 and 40-70 patients for Group 3, based on exclusion of GT1a patients.
    04 Jul 2013
    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) where 1/2 CI is approximately 6%; Added power calculations for comparison to the historical control; Added increased ECG monitoring based on preliminary results from 1241.25; Added monitoring for appearance of systemic symptoms of DRESS and criteria for treatment discontinuation in case of potentially lifethreatening skin reactions; Added PK trough samples for all patients in the trial; Added second confirmation in case of virologic breakthrough; clarified the confirmation process; Clarified procedures related to rescue medication; Added details on the assessment of liver progression assessment; Revised SAE reporting processes based on updated sponsor SOP; Added IgE assessment for mild rash events.
    30 Oct 2013
    Changed the order of primary and secondary objectives; Re-defined the minimum historical target SVR12 rates. Specified a hierarchical order for primary and secondary objective testing; Updated power calculation for the primaryanalysis based on the proposed sample size; 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; Added potential risk of agranulocytosis/neutropenia; Added discontinuation of patients with ANC≤500 cells/mm3; Clarified SAE reporting requirements.
    03 Apr 2014
    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 SVR12 nonresponders provided they had not started an alternative HCV treatment; Follow-up of rescue treatment was reduced to RFU1 at REOT+12 weeks; FU3 snapshot was removed.

    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.
    BI stopped further development of DBV, the Follow-up period was reduced. First outcome measure: statistical analysis for one group are defined and analysed, due to the platform limitations those could not be provided (results in ct.gov NCT01732796)
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