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    Clinical Trial Results:
    A Randomized, Open-Label Study to Evaluate the Safety and Efficacy of Ombitasvir/ABT-450/Ritonavir Co-administered With Ribavirin (RBV) in Adults With Genotype 4 Chronic Hepatitis C Virus (HCV) Infection and Cirrhosis (AGATE-1)

    Summary
    EudraCT number
    		 2014-001496-31
    Trial protocol
    		 DE   BE   AT   ES   IT   GR   FR  
    Global end of trial date
    07 Apr 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Jan 2018
    First version publication date
    19 Jan 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    M11-665
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02265237
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AbbVie Deutschland GmbH & Co.KG
    Sponsor organisation address
    AbbVie House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6-4UB
    Public contact
    Global Medical Services, AbbVie, 001 800-633-9110,
    Scientific contact
    Negar Niki Alami, AbbVie, negarniki.alami@abbvie.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
    07 Apr 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study in HCV genotype 4-infected participants with compensated cirrhosis is to assess the safety and to compare the percentage of participants achieving a 12-week sustained virologic response (SVR12), [HCV ribonucleic acid (RNA) < lower limit of quantification (LLOQ) 12 weeks following treatment], to a clinically relevant threshold [based on SVR rates for HCV genotype 4-infected participants treated with pegylated interferon (pegIFN)/RBV].
    Protection of trial subjects
    Subject and/or legal guardian read and understood the information provided about the study and gave written permission.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Oct 2014
    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
    Austria: 19
    Country: Number of subjects enrolled
    Belgium: 21
    Country: Number of subjects enrolled
    Canada: 18
    Country: Number of subjects enrolled
    France: 47
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Greece: 23
    Country: Number of subjects enrolled
    Italy: 15
    Country: Number of subjects enrolled
    Spain: 23
    Country: Number of subjects enrolled
    United States: 13
    Worldwide total number of subjects
    184
    EEA total number of subjects
    153
    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)
    150
    From 65 to 84 years
    34
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was divided into 2 parts with 184 total participants. Part I (Arms A and B) included participants who received either 12 or 16 weeks of treatment and Part II (Arms C and D) included participants who received 24 weeks of treatment. Enrollment into Part II opened once randomization in Part I was completed.

    Pre-assignment
    Screening details
    		 Safety analysis population: all participants who received at least 1 dose of study drug. One participant randomized to the arm B (16 weeks arm) was erroneously administered study drug for 12 weeks (as in arm A). Therefore this participant is included in arm A for the safety population.

    Period 1
    Period 1 title
    As Enrolled (Overall Study) (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 Ombitasvir/paritaprevir/ritonavir (25/150/100 mg) and Ribavirin dosed for 12 weeks for genotype 4 treatment naïve or treatment-experienced with IFN/RBV.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ribavirin was administered based on subject's weight.

    Investigational medicinal product name
    ombitasvir/paritaprevir/ritonavir
    Investigational medicinal product code
    Other name
    norvir (ritonavir), paritaprevir (ABT-450), ombitasvir (ABT-267).
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ombitasvir/paritaprevir/ritonavir (25/150/100 mg)

    Arm title
    		 Arm B
    Arm description
    		 Ombitasvir/paritaprevir/ritonavir (25/150/100 mg) and Ribavirin dosed for 16 weeks for genotype 4 treatment naive or treatment-experienced with IFN/RBV.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ribavirin was administered based on subject's weight.

    Investigational medicinal product name
    ombitasvir/paritaprevir/ritonavir
    Investigational medicinal product code
    Other name
    norvir (ritonavir), paritaprevir (ABT-450), ombitasvir (ABT-267).
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ombitasvir/paritaprevir/ritonavir (25/150/100 mg)

    Arm title
    		 Arm C
    Arm description
    		 Ombitasvir/paritaprevir/ritonavir (25/150/100 mg) and Ribavirin dosed for 24 weeks for genotype 4 treatment naive and treatment-experienced with IFN/RBV.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ribavirin was administered based on subject's weight.

    Investigational medicinal product name
    ombitasvir/paritaprevir/ritonavir
    Investigational medicinal product code
    Other name
    norvir (ritonavir), paritaprevir (ABT-450), ombitasvir (ABT-267).
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ombitasvir/paritaprevir/ritonavir (25/150/100 mg)

    Arm title
    		 Arm D
    Arm description
    		 Ombitasvir/paritaprevir/ritonavir (25/150/100 mg) and Ribavirin dosed for 24 weeks for genotype 4 SOF/pegIFN/RBV or SOF/RBV treatment-experienced.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ombitasvir/paritaprevir/ritonavir
    Investigational medicinal product code
    Other name
    norvir (ritonavir), paritaprevir (ABT-450), ombitasvir (ABT-267).
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ombitasvir/paritaprevir/ritonavir (25/150/100 mg)

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ribavirin was administered based on subject's weight.

    Number of subjects in period 1
    		Arm A Arm B Arm C Arm D
    Started
    59
    61
    61
    3
    Completed
    54
    58
    51
    2
    Not completed
    5
    3
    10
    1
         Consent withdrawn by subject
    1
    -
    1
    -
         Adverse event, non-fatal
    1
    1
    -
    -
         Unknown
    2
    -
    3
    1
         Lost to follow-up
    1
    2
    6
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    As Enrolled (Overall Study)
    Reporting group description
    		 Safety analysis population: all participants who received at least 1 dose of study drug.

    Reporting group values
    		 As Enrolled (Overall Study) Total
    Number of subjects
    		 184 184
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.6 ( 8.80 ) -
    Gender categorical
    Units: Subjects
        Female
    		 54 54
        Male
    		 130 130

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Ombitasvir/paritaprevir/ritonavir (25/150/100 mg) and Ribavirin dosed for 12 weeks for genotype 4 treatment naïve or treatment-experienced with IFN/RBV.

    Reporting group title
    Arm B
    Reporting group description
    		 Ombitasvir/paritaprevir/ritonavir (25/150/100 mg) and Ribavirin dosed for 16 weeks for genotype 4 treatment naive or treatment-experienced with IFN/RBV.

    Reporting group title
    Arm C
    Reporting group description
    		 Ombitasvir/paritaprevir/ritonavir (25/150/100 mg) and Ribavirin dosed for 24 weeks for genotype 4 treatment naive and treatment-experienced with IFN/RBV.

    Reporting group title
    Arm D
    Reporting group description
    		 Ombitasvir/paritaprevir/ritonavir (25/150/100 mg) and Ribavirin dosed for 24 weeks for genotype 4 SOF/pegIFN/RBV or SOF/RBV treatment-experienced.

    Primary: Percentage of Participants in Arms A, B and C With Sustained Virologic Response 12 Weeks Post-treatment (SVR12)

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    End point title
    		 Percentage of Participants in Arms A, B and C With Sustained Virologic Response 12 Weeks Post-treatment (SVR12) [1] [2]
    End point description
    SVR12 was defined as plasma hepatitis C virus ribonucleic acid (HCV RNA) level less than the lower limit of quantification (<LLOQ) 12 weeks after the last dose of study drug.
    End point type
    Primary
    End point timeframe
    12 weeks after the last actual dose of study drug
    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: The lower confidence bound of the 2-sided 97.5% confidence interval for the percentage of participants with SVR12 in each arm (A, B and C) must exceed 67% to achieve superiority.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Given the small number of participants planned to be enrolled in Arm D, this arm was not include in the primary or secondary endpoints in the protocol but rather was considered exploratory.
    End point values
    		 Arm A Arm B Arm C
    Number of subjects analysed
    59 [3]
    61 [4]
    61 [5]
    Units: percentage of participants
        number (confidence interval 97.5%)
    96.6 (86.7 to 99.2)
    100.0 (92.4 to 100.0)
    93.4 (82.6 to 97.7)
    Notes
    [3] - All subjects who received at least 1 dose of study drug; with missing data imputed as nonresponders
    [4] - All subjects who received at least 1 dose of study drug; with missing data imputed as nonresponders
    [5] - All subjects who received at least 1 dose of study drug; with missing data imputed as nonresponders
    No statistical analyses for this end point

    Secondary: Percentage of Participants With SVR12 in Participants Receiving 12 Weeks (Arm A) of Treatment Compared to Participants Receiving 16 Weeks of Treatment (Arm B)

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    End point title
    		 Percentage of Participants With SVR12 in Participants Receiving 12 Weeks (Arm A) of Treatment Compared to Participants Receiving 16 Weeks of Treatment (Arm B) [6]
    End point description
    SVR12 was defined as plasma hepatitis C virus ribonucleic acid (HCV RNA) level less than the lower limit of quantification [<LLOQ]) 12 weeks after the last dose of study drug.
    End point type
    Secondary
    End point timeframe
    12 weeks after the last actual dose of study drug
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This end point was assessed only for arms A and B, as it included a pair-wise comparison.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    59 [7]
    61 [8]
    Units: percentage of participants
        number (not applicable)
    96.6
    100
    Notes
    [7] - All subjects who received at least 1 dose of study drug; with missing data imputed as nonresponders
    [8] - All subjects who received at least 1 dose of study drug; with missing data imputed as nonresponders
    Statistical analysis title
    		 Arm A vs Arm B
    Statistical analysis description
    Within Part I (arm A and B), since superiority was demonstrated for both arms in the primary outcome measures, testing continued to the first secondary outcome measure.
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.304
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Stratum-Adjusted MH Difference
    Point estimate
    -3.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.85
         upper limit
    		 3.07
    Notes
    [9] - Treatment differences (with 95% confidence intervals) and corresponding P-value for the specified comparisons were estimated using stratum adjusted Mantel-Haenszel (MH) proportion and continuity-corrected variance, adjusting for IFN/RBV treatment history (treatment-naïve or treatment-experienced).

    Secondary: Percentage of Participants With SVR12 in Participants Receiving 16 Weeks (Arm B) of Treatment Compared to Participants Receiving 24 Weeks of Treatment (Arm C)

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    End point title
    		 Percentage of Participants With SVR12 in Participants Receiving 16 Weeks (Arm B) of Treatment Compared to Participants Receiving 24 Weeks of Treatment (Arm C) [10]
    End point description
    SVR12 was defined as plasma hepatitis C virus ribonucleic acid (HCV RNA) level less than the lower limit of quantification [<LLOQ]) 12 weeks after the last dose of study drug.
    End point type
    Secondary
    End point timeframe
    12 weeks after the last actual dose of study drug
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This end point was assessed only for arms B and C, as it included a pair-wise comparison.
    End point values
    		 Arm B Arm C
    Number of subjects analysed
    61 [11]
    57 [12]
    Units: percentage of participants
        number (not applicable)
    100
    93.4
    Notes
    [11] - All participants who received at least 1 dose of study drug; missing data imputed as nonresponders.
    [12] - All participants who received at least 1 dose of study drug; missing data imputed as nonresponders.
    Statistical analysis title
    		 Arm B vs Arm C
    Statistical analysis description
    Within Part II (arm C), since superiority was demonstrated for the primary end point, testing continued to the second secondary outcome measure.
    Comparison groups
    Arm B v Arm C
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.086
    Method
    		 Mantel-Haenszel
    Parameter type
    		 Stratum-Adjusted MH Difference
    Point estimate
    6.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.91
         upper limit
    		 13.81
    Notes
    [13] - Treatment differences (with 95% confidence intervals) and corresponding P-value for the specified comparisons were estimated using stratum adjusted Mantel-Haenszel proportion and continuity-corrected variance, adjusting for IFN/RBV treatment history (treatment-naïve or treatment-experienced).

    Secondary: Percentage of Participants in Arms A, B and C With On-treatment Virologic Failure

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    End point title
    		 Percentage of Participants in Arms A, B and C With On-treatment Virologic Failure [14]
    End point description
    On-treatment virologic failure was defined as confirmed HCV RNA ≥ LLOQ after HCV RNA < LLOQ during treatment; confirmed increase of > 1 log(subscript)10(subscript) IU/mL above the lowest value post-baseline in HCV RNA during treatment; or all on-treatment values of HCV RNA >= LLOQ with at least 6 weeks of treatment.
    End point type
    Secondary
    End point timeframe
    Up to Treatment Week 24 (end of treatment) or premature discontinuation from treatment
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Given the small number of participants planned to be enrolled in Arm D, this arm was not include in the primary or secondary endpoints in the protocol but rather was considered exploratory.
    End point values
    		 Arm A Arm B Arm C
    Number of subjects analysed
    59 [15]
    61 [16]
    61 [17]
    Units: percentage of participants
        number (confidence interval 95%)
    1.7 (0.3 to 9.0)
    0.0 (0.0 to 5.9)
    0.0 (0.0 to 5.9)
    Notes
    [15] - All participants who received at least 1 dose of study drug (ITT population).
    [16] - All participants who received at least 1 dose of study drug (ITT population).
    [17] - All participants who received at least 1 dose of study drug (ITT population).
    No statistical analyses for this end point

    Secondary: Percentage of Participants in Arms A, B and C With Post-treatment Relapse

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    End point title
    		 Percentage of Participants in Arms A, B and C With Post-treatment Relapse [18]
    End point description
    Post-treatment relapse was defined as confirmed HCV RNA ≥ LLOQ between the end of treatment and 12 weeks after the last dose of study drug among participants with HCV RNA levels < LLOQ at the end of treatment.
    End point type
    Secondary
    End point timeframe
    From the end of treatment through 12 weeks after the last dose of study drug
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Given the small number of participants planned to be enrolled in Arm D, this arm was not include in the primary or secondary endpoints in the protocol but rather was considered exploratory.
    End point values
    		 Arm A Arm B Arm C
    Number of subjects analysed
    57 [19]
    59 [20]
    56 [21]
    Units: percentage of participants
        number (confidence interval 95%)
    0.0 (0.0 to 6.3)
    0.0 (0.0 to 6.1)
    0.0 (0.0 to 6.4)
    Notes
    [19] - ITT subjects with one post-treatment HCV RNA value, completed treatment, and <LLOQ at final visit.
    [20] - ITT subjects with one post-treatment HCV RNA value, completed treatment, and <LLOQ at final visit.
    [21] - ITT subjects with one post-treatment HCV RNA value, completed treatment, and <LLOQ at final visit.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment-emergent adverse events (TEAEs) and serious adverse events (TESAEs) were collected from the time of study drug administration until 30 days after the last dose of study drug (up to 28 weeks).
    Adverse event reporting additional description
    Safety analysis population: all participants who received at least 1 dose of study drug. One participant randomized to arm B (16 weeks arm) was erroneously administered study drug for 12 weeks (as in arm A). Therefore this participant is included in arm A for the safety population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Ombitasvir/paritaprevir/ritonavir (25/150/100 mg) and Ribavirin dosed for 12 weeks for genotype 4 treatment naïve or treatment-experienced with IFN/RBV.

    Reporting group title
    Arm B
    Reporting group description
    		 Ombitasvir/paritaprevir/ritonavir (25/150/100 mg) and Ribavirin dosed for 16 weeks for genotype 4 treatment naive or treatment-experienced with IFN/RBV.

    Reporting group title
    Arm C
    Reporting group description
    		 Ombitasvir/paritaprevir/ritonavir (25/150/100 mg) and Ribavirin dosed for 24 weeks for genotype 4 treatment naive and treatment-experienced with IFN/RBV.

    Reporting group title
    Arm D
    Reporting group description
    		 Ombitasvir/paritaprevir/ritonavir (25/150/100 mg) and Ribavirin dosed for 24 weeks for genotype 4 SOF/pegIFN/RBV or SOF/RBV treatment-experienced.

    Serious adverse events
    		 Arm A Arm B Arm C Arm D
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 60 (6.67%)
    4 / 60 (6.67%)
    3 / 61 (4.92%)
    0 / 3 (0.00%)
         number of deaths (all causes)
    0
    1
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Cardiac disorders
    ACUTE CORONARY SYNDROME
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 60 (3.33%)
    0 / 61 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    SCIATICA
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    HAEMORRHAGIC ANAEMIA
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    OESOPHAGEAL VARICES HAEMORRHAGE
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    HEPATOTOXICITY
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PORTAL VEIN THROMBOSIS
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    MANIA
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUICIDAL IDEATION
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    SUICIDE ATTEMPT
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    INTERVERTEBRAL DISC PROTRUSION
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 60 (3.33%)
    0 / 61 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    CLOSTRIDIUM COLITIS
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    MENINGITIS
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA KLEBSIELLA
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm A Arm B Arm C Arm D
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 60 (76.67%)
    55 / 60 (91.67%)
    50 / 61 (81.97%)
    3 / 3 (100.00%)
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    4 / 60 (6.67%)
    1 / 60 (1.67%)
    1 / 61 (1.64%)
    0 / 3 (0.00%)
         occurrences all number
    5
    2
    1
    0
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    11 / 60 (18.33%)
    19 / 60 (31.67%)
    15 / 61 (24.59%)
    1 / 3 (33.33%)
         occurrences all number
    13
    22
    17
    2
    FATIGUE
         subjects affected / exposed
    10 / 60 (16.67%)
    20 / 60 (33.33%)
    16 / 61 (26.23%)
    0 / 3 (0.00%)
         occurrences all number
    11
    29
    17
    0
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    0 / 60 (0.00%)
    3 / 60 (5.00%)
    1 / 61 (1.64%)
    0 / 3 (0.00%)
         occurrences all number
    0
    3
    1
    0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    5 / 60 (8.33%)
    4 / 60 (6.67%)
    2 / 61 (3.28%)
    0 / 3 (0.00%)
         occurrences all number
    5
    4
    2
    0
    PYREXIA
         subjects affected / exposed
    0 / 60 (0.00%)
    3 / 60 (5.00%)
    1 / 61 (1.64%)
    0 / 3 (0.00%)
         occurrences all number
    0
    4
    2
    0
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    5 / 60 (8.33%)
    5 / 60 (8.33%)
    4 / 61 (6.56%)
    1 / 3 (33.33%)
         occurrences all number
    5
    5
    4
    1
    DYSPNOEA EXERTIONAL
         subjects affected / exposed
    2 / 60 (3.33%)
    3 / 60 (5.00%)
    0 / 61 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    4
    0
    0
    NASAL CONGESTION
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    1
    DYSPNOEA
         subjects affected / exposed
    4 / 60 (6.67%)
    4 / 60 (6.67%)
    4 / 61 (6.56%)
    0 / 3 (0.00%)
         occurrences all number
    4
    4
    4
    0
    PARANASAL SINUS DISCOMFORT
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    1
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    3 / 60 (5.00%)
    2 / 60 (3.33%)
    3 / 61 (4.92%)
    0 / 3 (0.00%)
         occurrences all number
    3
    2
    3
    0
    IRRITABILITY
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 60 (1.67%)
    1 / 61 (1.64%)
    0 / 3 (0.00%)
         occurrences all number
    2
    1
    1
    0
    INSOMNIA
         subjects affected / exposed
    5 / 60 (8.33%)
    6 / 60 (10.00%)
    5 / 61 (8.20%)
    1 / 3 (33.33%)
         occurrences all number
    5
    6
    5
    1
    SLEEP DISORDER
         subjects affected / exposed
    2 / 60 (3.33%)
    5 / 60 (8.33%)
    0 / 61 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    5
    0
    0
    Investigations
    BLOOD BILIRUBIN INCREASED
         subjects affected / exposed
    1 / 60 (1.67%)
    3 / 60 (5.00%)
    0 / 61 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    3
    0
    0
    HAEMOGLOBIN DECREASED
         subjects affected / exposed
    3 / 60 (5.00%)
    8 / 60 (13.33%)
    4 / 61 (6.56%)
    0 / 3 (0.00%)
         occurrences all number
    3
    8
    4
    0
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    4 / 60 (6.67%)
    9 / 60 (15.00%)
    0 / 61 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    4
    9
    0
    0
    MEMORY IMPAIRMENT
         subjects affected / exposed
    1 / 60 (1.67%)
    4 / 60 (6.67%)
    1 / 61 (1.64%)
    0 / 3 (0.00%)
         occurrences all number
    1
    4
    1
    0
    HEADACHE
         subjects affected / exposed
    14 / 60 (23.33%)
    14 / 60 (23.33%)
    13 / 61 (21.31%)
    0 / 3 (0.00%)
         occurrences all number
    14
    15
    15
    0
    PARAESTHESIA
         subjects affected / exposed
    2 / 60 (3.33%)
    2 / 60 (3.33%)
    0 / 61 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    2
    0
    0
    SOMNOLENCE
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 60 (3.33%)
    0 / 61 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    0
    SYNCOPE
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    7 / 60 (11.67%)
    12 / 60 (20.00%)
    7 / 61 (11.48%)
    0 / 3 (0.00%)
         occurrences all number
    8
    13
    7
    0
    Ear and labyrinth disorders
    EAR PAIN
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    4 / 60 (6.67%)
    1 / 60 (1.67%)
    2 / 61 (3.28%)
    1 / 3 (33.33%)
         occurrences all number
    4
    1
    2
    1
    CONSTIPATION
         subjects affected / exposed
    4 / 60 (6.67%)
    1 / 60 (1.67%)
    2 / 61 (3.28%)
    0 / 3 (0.00%)
         occurrences all number
    5
    1
    2
    0
    ABDOMINAL PAIN
         subjects affected / exposed
    2 / 60 (3.33%)
    4 / 60 (6.67%)
    6 / 61 (9.84%)
    0 / 3 (0.00%)
         occurrences all number
    2
    4
    6
    0
    DIARRHOEA
         subjects affected / exposed
    1 / 60 (1.67%)
    3 / 60 (5.00%)
    2 / 61 (3.28%)
    0 / 3 (0.00%)
         occurrences all number
    1
    3
    2
    0
    NAUSEA
         subjects affected / exposed
    6 / 60 (10.00%)
    8 / 60 (13.33%)
    5 / 61 (8.20%)
    1 / 3 (33.33%)
         occurrences all number
    6
    9
    7
    1
    TOOTHACHE
         subjects affected / exposed
    2 / 60 (3.33%)
    3 / 60 (5.00%)
    2 / 61 (3.28%)
    0 / 3 (0.00%)
         occurrences all number
    2
    3
    2
    0
    VOMITING
         subjects affected / exposed
    4 / 60 (6.67%)
    3 / 60 (5.00%)
    4 / 61 (6.56%)
    0 / 3 (0.00%)
         occurrences all number
    4
    4
    4
    0
    Hepatobiliary disorders
    HYPERBILIRUBINAEMIA
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 60 (3.33%)
    3 / 61 (4.92%)
    0 / 3 (0.00%)
         occurrences all number
    1
    3
    3
    0
    JAUNDICE
         subjects affected / exposed
    3 / 60 (5.00%)
    2 / 60 (3.33%)
    4 / 61 (6.56%)
    0 / 3 (0.00%)
         occurrences all number
    3
    2
    5
    0
    Skin and subcutaneous tissue disorders
    DRY SKIN
         subjects affected / exposed
    1 / 60 (1.67%)
    1 / 60 (1.67%)
    4 / 61 (6.56%)
    0 / 3 (0.00%)
         occurrences all number
    1
    1
    4
    0
    PRURITUS
         subjects affected / exposed
    5 / 60 (8.33%)
    14 / 60 (23.33%)
    12 / 61 (19.67%)
    1 / 3 (33.33%)
         occurrences all number
    5
    15
    13
    2
    RASH
         subjects affected / exposed
    4 / 60 (6.67%)
    3 / 60 (5.00%)
    2 / 61 (3.28%)
    1 / 3 (33.33%)
         occurrences all number
    6
    4
    2
    1
    PRURITUS GENERALISED
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    2 / 61 (3.28%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    2
    1
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    3 / 60 (5.00%)
    4 / 60 (6.67%)
    1 / 61 (1.64%)
    0 / 3 (0.00%)
         occurrences all number
    3
    4
    1
    0
    BACK PAIN
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 60 (3.33%)
    5 / 61 (8.20%)
    0 / 3 (0.00%)
         occurrences all number
    1
    2
    6
    0
    MYALGIA
         subjects affected / exposed
    3 / 60 (5.00%)
    6 / 60 (10.00%)
    3 / 61 (4.92%)
    0 / 3 (0.00%)
         occurrences all number
    3
    6
    3
    0
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    1 / 61 (1.64%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    1
    1
    NECK PAIN
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    0
    0
    1
    Infections and infestations
    SINUSITIS
         subjects affected / exposed
    0 / 60 (0.00%)
    3 / 60 (5.00%)
    0 / 61 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    2 / 60 (3.33%)
    5 / 60 (8.33%)
    2 / 61 (3.28%)
    0 / 3 (0.00%)
         occurrences all number
    2
    5
    2
    0
    HYPERGLYCAEMIA
         subjects affected / exposed
    0 / 60 (0.00%)
    4 / 60 (6.67%)
    1 / 61 (1.64%)
    0 / 3 (0.00%)
         occurrences all number
    0
    4
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Jan 2015
    The purpose of the amendment was to evaluate 24 weeks of treatment (Part II) in addition to the existing 12- and 16-week durations in this study. While internal simulation modeling suggested that the optimal treatment duration would be 12 or 16 weeks, this modeling had not been validated in subjects with cirrhosis. Thus, it was reasonable to also evaluate sustained virologic response (SVR) rates after 24 weeks of treatment. Additionally, a study arm for subjects with treatment history of prior virologic failure with sofosbuvir (SOF) plus pegylated interferon (pegIFN)/ ribavirin (RBV) or SOF plus RBV was added as a possible re-treatment option for such subjects with limited approved re-treatment options for hepatitis C virus (HCV) genotype 4 (GT4) infection.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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