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    Clinical Trial Results:
    A Randomized, Open-Label Study to Evaluate the Safety and Efficacy of ABT-450/Ritonavir/ABT-267 (ABT-450/r/ABT-267) and ABT-333 Coadministered with Ribavirin (RBV) in Adults with Genotype 1 Chronic Hepatitis C Virus (HCV) Infection and Cirrhosis (TURQUOISE-II)

    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
    		 2012-003088-23
    Trial protocol
    		 BE   DE   GB   ES   IT   FR  
    Global end of trial date
    24 Sep 2014

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

    Trial information

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    Trial identification
    Sponsor protocol code
    M13-099
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01704755
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AbbVie Deutschland GmbH & Co. KG
    Sponsor organisation address
    Abbott House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire , United Kingdom, SL6 4XE
    Public contact
    Global Medical Information, AbbVie, 001 800-633-9110,
    Scientific contact
    Roger Trinh, MD, AbbVie, roger.trinh@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
    24 Sep 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this study were to assess the safety and to compare the SVR12 rates (the percentage of subjects achieving a 12-week sustained virologic response, SVR12 [HCV ribonucleic acid (RNA) < lower limit of quantification (LLOQ) 12 weeks following treatment]) of coformulated ABT-450, ritonavir and ABT-267 (ABT-450/r/ABT-267) and ABT-333 coadministered with ribavirin (RBV) for 12 or 24 weeks to the historical SVR rate of telaprevir plus pegIFN and RBV in HCV genotype 1-infected adults with compensated cirrhosis.
    Protection of trial subjects
    Subject read and understood the information provided about the study and gave written permission.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Oct 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: 19
    Country: Number of subjects enrolled
    United Kingdom: 49
    Country: Number of subjects enrolled
    Belgium: 19
    Country: Number of subjects enrolled
    France: 53
    Country: Number of subjects enrolled
    Germany: 30
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    Canada: 34
    Country: Number of subjects enrolled
    United States: 165
    Worldwide total number of subjects
    381
    EEA total number of subjects
    182
    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)
    332
    From 65 to 84 years
    49
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The study included a screening period of 35 days.

    Period 1
    Period 1 title
    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
    		 ABT-450/r/ABT-267 and ABT-333, plus RBV for 12 weeks
    Arm description
    		 ABT-450/r/ABT-267 (150/100/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based ribavirin (RBV; 1,000 mg/day if <75 kg or 1,200 mg/day if ≥75 kg, divided twice daily) for 12 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    ABT-450/r/ABT-267
    Investigational medicinal product code
    Other name
    ABT-450 coformulated with ritonavir and ABT-267; ABT-450 also known as paritaprevir; ABT-267 also known as ombitasvir
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    ABT-450/r/ABT-267 (150/100/25 mg once daily) for 12 weeks

    Investigational medicinal product name
    ABT-333
    Investigational medicinal product code
    Other name
    Dasabuvir
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    250 mg twice daily for 12 weeks

    Investigational medicinal product name
    Ribavirin (RBV)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1,000 mg/day if <75 kg or 1,200 mg/day if ≥75 kg, divided twice daily for 12 weeks

    Arm title
    		 ABT-450/r/ABT-267 and ABT-333, plus RBV for 24 weeks
    Arm description
    		 ABT-450/r/ABT-267 (150/100/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based ribavirin (RBV; 1,000 mg/day if <75 kg or 1,200 mg/day if ≥75 kg, divided twice daily) for 24 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    ABT-450/r/ABT-267
    Investigational medicinal product code
    Other name
    ABT-450 coformulated with ritonavir and ABT-267; ABT-450 also known as paritaprevir; ABT-267 also known as ombitasvir
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    ABT-450/r/ABT-267 (150/100/25 mg once daily) for 24 weeks

    Investigational medicinal product name
    ABT-333
    Investigational medicinal product code
    Other name
    Dasabuvir
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    250 mg twice daily for 24 weeks

    Investigational medicinal product name
    Ribavirin (RBV)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1,000 mg/day if <75 kg or 1,200 mg/day if ≥75 kg, divided twice daily for 24 weeks

    Number of subjects in period 1 [1]
    		ABT-450/r/ABT-267 and ABT-333, plus RBV for 12 weeks ABT-450/r/ABT-267 and ABT-333, plus RBV for 24 weeks
    Started
    208
    172
    Completed study drug
    204
    163 [2]
    Completed
    196
    165
    Not completed
    12
    7
         Consent withdrawn by subject
    1
    1
         Adverse event, non-fatal
    4
    1
         Withdrew consent and personal issues
    1
    -
         Other (not specified)
    3
    1
         Lost to follow-up
    3
    4
    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: In the 12-week treatment group, one participant withdrew from the study before receiving study drug.
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: In the 24-week treatment group, 9 participants prematurely discontinued study drug.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ABT-450/r/ABT-267 and ABT-333, plus RBV for 12 weeks
    Reporting group description
    		 ABT-450/r/ABT-267 (150/100/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based ribavirin (RBV; 1,000 mg/day if <75 kg or 1,200 mg/day if ≥75 kg, divided twice daily) for 12 weeks

    Reporting group title
    ABT-450/r/ABT-267 and ABT-333, plus RBV for 24 weeks
    Reporting group description
    		 ABT-450/r/ABT-267 (150/100/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based ribavirin (RBV; 1,000 mg/day if <75 kg or 1,200 mg/day if ≥75 kg, divided twice daily) for 24 weeks

    Reporting group values
    		 ABT-450/r/ABT-267 and ABT-333, plus RBV for 12 weeks ABT-450/r/ABT-267 and ABT-333, plus RBV for 24 weeks Total
    Number of subjects
    		 208 172 380
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.1 ( 7.01 ) 56.5 ( 7.87 ) -
    Gender categorical
    Units: Subjects
        Female
    		 62 51 113
        Male
    		 146 121 267

    End points

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    End points reporting groups
    Reporting group title
    ABT-450/r/ABT-267 and ABT-333, plus RBV for 12 weeks
    Reporting group description
    		 ABT-450/r/ABT-267 (150/100/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based ribavirin (RBV; 1,000 mg/day if <75 kg or 1,200 mg/day if ≥75 kg, divided twice daily) for 12 weeks

    Reporting group title
    ABT-450/r/ABT-267 and ABT-333, plus RBV for 24 weeks
    Reporting group description
    		 ABT-450/r/ABT-267 (150/100/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based ribavirin (RBV; 1,000 mg/day if <75 kg or 1,200 mg/day if ≥75 kg, divided twice daily) for 24 weeks

    Subject analysis set title
    Overall study
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All participants who received at least 1 dose of study drug.

    Primary: Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment

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    End point title
    		 Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment [1]
    End point description
    The percentage of participants with sustained virologic response (plasma Hepatitis C virus ribonucleic acid [HCV RNA] level less than the lower limit of quantitation [< LLOQ]) 12 weeks after the last dose of study drug. Primary efficacy endpoints were: noninferiority of 12-week Tx to the SVR rate for telaprevir plus pegIFN and RBV therapy; superiority of 12-week Tx to the historical SVR rate for telaprevir plus pegIFN and RBV therapy; noninferiority of 24-week Tx to the historical SVR rate for telaprevir plus pegIFN and RBV therapy; and superiority of 24-week Tx to the historical SVR rate for telaprevir plus pegIFN and RBV therapy. Based on a 2-sided significance level of 0.05 and assuming that 68% of subjects in each arm would achieve SVR12, a total of 380 subjects provides ≥ 90% power to demonstrate non-inferiority and superiority with a 2-sided 97.5% lower confidence bound greater than 43% and 54%, respectively, based on the normal approximation of a single binomial proportion.
    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% CI for the percentage of participants with sustained virologic response at 12 weeks after treatment must have exceeded 43% to achieve noninferiority. The lower confidence bound of the 2-sided 97.5% CI for the percentage of participants with sustained virologic response at 12 weeks after treatment must have exceeded 54% to achieve superiority.
    End point values
    		 ABT-450/r/ABT-267 and ABT-333, plus RBV for 12 weeks ABT-450/r/ABT-267 and ABT-333, plus RBV for 24 weeks
    Number of subjects analysed
    208 [2]
    172 [3]
    Units: Percentage of participants
        number (confidence interval 97.5%)
    91.8 (87.6 to 96.1)
    96.5 (93.4 to 99.7)
    Notes
    [2] - All randomized participants who received at least 1 dose of study drug.
    [3] - All randomized participants who received at least 1 dose of study drug.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment in the 24-week Arm Compared to the 12-week Arm

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    End point title
    		 Percentage of Participants With Sustained Virologic Response 12 Weeks Post-treatment in the 24-week Arm Compared to the 12-week Arm
    End point description
    A sustained virologic response is defined as plasma Hepatitis C virus ribonucleic acid (HCV RNA) 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
    End point values
    		 ABT-450/r/ABT-267 and ABT-333, plus RBV for 12 weeks ABT-450/r/ABT-267 and ABT-333, plus RBV for 24 weeks
    Number of subjects analysed
    208 [4]
    172 [5]
    Units: Percentage of participants
        number (not applicable)
    91.8
    96.5
    Notes
    [4] - All randomized participants who received at least 1 dose of study drug.
    [5] - All randomized participants who received at least 1 dose of study drug.
    Statistical analysis title
    		 Logistic Regression
    Statistical analysis description
    To test the hypothesis that the percentages of participants who achieved sustained virologic response 12 weeks after treatment was different between the two treatment groups, the percentages were compared using a logistic regression model with treatment group, baseline log(subscript)10(subscript) HCV RNA level, HCV subgenotype (1a, non-1a), IL28B genotype (CC, non CC), and peginterferon-ribavirin treatment history (treatment-naïve or treatment-experienced) as predictors.
    Comparison groups
    ABT-450/r/ABT-267 and ABT-333, plus RBV for 12 weeks v ABT-450/r/ABT-267 and ABT-333, plus RBV for 24 weeks
    Number of subjects included in analysis
    380
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.051
    Method
    		 Regression, Logistic
    Confidence interval

    Secondary: Percentage of Participants in Each Arm With On-treatment Virologic Failure During the Treatment Period

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    End point title
    		 Percentage of Participants in Each Arm With On-treatment Virologic Failure During the Treatment Period
    End point description
    Virologic failure during treatment was defined as rebound (confirmed HCV RNA greater than or equal to the lower limit of quantitation [≥ LLOQ] after HCV RNA < LLOQ during treatment, or confirmed increase from the lowest value post baseline in HCV RNA [2 consecutive HCV RNA measurements > 1 log(subscript)10(subscript) IU/mL above the lowest value post baseline] at any time point during treatment), or fail to suppress (HCV RNA ≥ LLOQ persistently during treatment with at least 6 weeks [≥ 36 days] of treatment).
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), and Treatment Weeks 1, 2, 4, 6, 8, 10, 12, 16, 20, and 24
    End point values
    		 ABT-450/r/ABT-267 and ABT-333, plus RBV for 12 weeks ABT-450/r/ABT-267 and ABT-333, plus RBV for 24 weeks
    Number of subjects analysed
    208 [6]
    172 [7]
    Units: Percentage of participants
        number (confidence interval 95%)
    0.5 (0 to 1.4)
    1.7 (0 to 3.7)
    Notes
    [6] - All randomized participants who received at least 1 dose of study drug.
    [7] - All randomized participants who received at least 1 dose of study drug.
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Virologic Relapse After Treatment

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    End point title
    		 Percentage of Participants With Virologic Relapse After Treatment
    End point description
    Participants were considered to have virologic relapse after treatment if they had confirmed quantifiable plasma Hepatitis C virus ribonucleic acid (HCV RNA) ≥ lower limit of quantification (LLOQ) between the end of treatment and 12 weeks after the last dose of study drug among participants who completed treatment with HCV RNA < LLOQ at the end of treatment.
    End point type
    Secondary
    End point timeframe
    within 12 weeks after the last dose of study drug
    End point values
    		 ABT-450/r/ABT-267 and ABT-333, plus RBV for 12 weeks ABT-450/r/ABT-267 and ABT-333, plus RBV for 24 weeks
    Number of subjects analysed
    203 [8]
    164 [9]
    Units: Percentage of Participants
        number (confidence interval 95%)
    5.9 (2.7 to 9.2)
    0.6 (0 to 1.8)
    Notes
    [8] - Subjects had at least 1 dose of study drug with HCV RNA < LLOQ at last Tx visit and finished Tx.
    [9] - Subjects had at least 1 dose of study drug with HCV RNA < LLOQ at last Tx visit and finished Tx.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected from the time of study drug administration until 30 days after the last dose, 16 weeks for the 12-week treatment group and 28 weeks for the 24-week treatment group.
    Adverse event reporting additional description
    Serious adverse events were collected from the time of informed consent until the end of participation in the study (up to 72 weeks).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    ABT-450/r/ABT-267 and ABT-333, plus RBV for 12 weeks
    Reporting group description
    		 ABT-450/r/ABT-267 (150/100/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based ribavirin (RBV; 1,000 mg/day if <75 kg or 1,200 mg/day if ≥75 kg, divided twice daily) for 12 weeks

    Reporting group title
    ABT-450/r/ABT-267 and ABT-333, plus RBV for 24 weeks
    Reporting group description
    		 ABT-450/r/ABT-267 (150/100/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based ribavirin (RBV; 1,000 mg/day if <75 kg or 1,200 mg/day if ≥75 kg, divided twice daily) for 24 weeks

    Serious adverse events
    		 ABT-450/r/ABT-267 and ABT-333, plus RBV for 12 weeks ABT-450/r/ABT-267 and ABT-333, plus RBV for 24 weeks
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 208 (6.25%)
    7 / 172 (4.07%)
         number of deaths (all causes)
    3
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Multi-organ failure
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Major depression
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood glucose increased
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Extradural haematoma
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Intracranial aneurysm
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 208 (0.48%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Haematemesis
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heptatitis acute
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Candidiasis
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 208 (0.00%)
    1 / 172 (0.58%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal bacteraemia
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pharyngitis
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Lactic acidosis
         subjects affected / exposed
    1 / 208 (0.48%)
    0 / 172 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ABT-450/r/ABT-267 and ABT-333, plus RBV for 12 weeks ABT-450/r/ABT-267 and ABT-333, plus RBV for 24 weeks
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    175 / 208 (84.13%)
    146 / 172 (84.88%)
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    12 / 208 (5.77%)
    9 / 172 (5.23%)
         occurrences all number
    13
    10
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    18 / 208 (8.65%)
    10 / 172 (5.81%)
         occurrences all number
    20
    14
    Headache
         subjects affected / exposed
    58 / 208 (27.88%)
    53 / 172 (30.81%)
         occurrences all number
    71
    60
    Memory impairment
         subjects affected / exposed
    5 / 208 (2.40%)
    12 / 172 (6.98%)
         occurrences all number
    5
    12
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    15 / 208 (7.21%)
    17 / 172 (9.88%)
         occurrences all number
    17
    25
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    29 / 208 (13.94%)
    22 / 172 (12.79%)
         occurrences all number
    38
    31
    Fatigue
         subjects affected / exposed
    68 / 208 (32.69%)
    80 / 172 (46.51%)
         occurrences all number
    80
    89
    Irritability
         subjects affected / exposed
    16 / 208 (7.69%)
    21 / 172 (12.21%)
         occurrences all number
    17
    23
    Oedema peripheral
         subjects affected / exposed
    12 / 208 (5.77%)
    10 / 172 (5.81%)
         occurrences all number
    12
    11
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    6 / 208 (2.88%)
    9 / 172 (5.23%)
         occurrences all number
    6
    10
    Abdominal pain upper
         subjects affected / exposed
    12 / 208 (5.77%)
    16 / 172 (9.30%)
         occurrences all number
    13
    16
    Diarrhoea
         subjects affected / exposed
    31 / 208 (14.90%)
    29 / 172 (16.86%)
         occurrences all number
    33
    34
    Gastrooesophageal reflux disease
         subjects affected / exposed
    7 / 208 (3.37%)
    10 / 172 (5.81%)
         occurrences all number
    7
    10
    Nausea
         subjects affected / exposed
    37 / 208 (17.79%)
    35 / 172 (20.35%)
         occurrences all number
    39
    39
    Vomiting
         subjects affected / exposed
    6 / 208 (2.88%)
    14 / 172 (8.14%)
         occurrences all number
    7
    15
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    15 / 208 (7.21%)
    2 / 172 (1.16%)
         occurrences all number
    15
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    24 / 208 (11.54%)
    19 / 172 (11.05%)
         occurrences all number
    24
    23
    Dyspnoea
         subjects affected / exposed
    12 / 208 (5.77%)
    21 / 172 (12.21%)
         occurrences all number
    12
    23
    Dyspnoea exertional
         subjects affected / exposed
    13 / 208 (6.25%)
    11 / 172 (6.40%)
         occurrences all number
    13
    11
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    18 / 208 (8.65%)
    11 / 172 (6.40%)
         occurrences all number
    20
    11
    Pruritus
         subjects affected / exposed
    38 / 208 (18.27%)
    33 / 172 (19.19%)
         occurrences all number
    43
    37
    Pruritus generalised
         subjects affected / exposed
    10 / 208 (4.81%)
    12 / 172 (6.98%)
         occurrences all number
    11
    12
    Rash
         subjects affected / exposed
    23 / 208 (11.06%)
    25 / 172 (14.53%)
         occurrences all number
    24
    30
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    15 / 208 (7.21%)
    14 / 172 (8.14%)
         occurrences all number
    16
    14
    Depression
         subjects affected / exposed
    8 / 208 (3.85%)
    12 / 172 (6.98%)
         occurrences all number
    8
    13
    Insomnia
         subjects affected / exposed
    32 / 208 (15.38%)
    32 / 172 (18.60%)
         occurrences all number
    35
    32
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    10 / 208 (4.81%)
    14 / 172 (8.14%)
         occurrences all number
    11
    15
    Back pain
         subjects affected / exposed
    4 / 208 (1.92%)
    13 / 172 (7.56%)
         occurrences all number
    5
    13
    Muscle spasms
         subjects affected / exposed
    14 / 208 (6.73%)
    14 / 172 (8.14%)
         occurrences all number
    15
    16
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    13 / 208 (6.25%)
    13 / 172 (7.56%)
         occurrences all number
    14
    16
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 208 (1.92%)
    13 / 172 (7.56%)
         occurrences all number
    4
    14
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    12 / 208 (5.77%)
    14 / 172 (8.14%)
         occurrences all number
    12
    15

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Nov 2012
    ● update secondary endpoints to remove RVR and EOTR, and to include virologic failure during treatment and relapse post-treatment ● update the thresholds for the primary endpoints to be based on historical SVR rates from telaprevir plus pegIFN and RBV therapy ● clarify inclusion/exclusion criteria to ensure the appropriate subject population was enrolled ● update the plan for resistance analysis throughout the protocol in order to clarify and more accurately reflect plans for assessing resistance development; ● update RBV toxicity management to clarify parameters for management of hemoglobin decreases; ● to update sponsor from Abbott to AbbVie
    07 Mar 2013
    ● update the definition of relapse to prior pegIFN and RBV treatment to allow the measurement of a detectable HCV RNA to be within 52 weeks post-treatment due to clinical practice standards of assessment of HCV RNA in some regions ● clarify that some study visits during the Treatment Period and Post-Treatment Period may have been conducted outside the study site ● update to include that depo-progesterone may not have been an effective form of contraception for a female subject in the trial ● update to provide guidance to address female subjects with borderline serum hCG test results ● update Section 5.2.1 Inclusion Criterion No. 4. Rationale for update: To include that depo-progesterone may have been an effective form of contraception for female partners of male subjects in the trial ● update to provide guidance to address subjects with steatosis and steatohepatitis ● allow subjects with ALT up to 7 × ULN and/or AST up to 7 × ULN to enroll in the trial in accordance with the typical liver function tests of this patient population ● update Section 5.3.1.1 Study Procedures (Screening: Liver Biopsy or FibroScan) to be consistent with Inclusion Criterion No. 11 ● add urine archive specimen for toxicity management of CrCl and tests for management of transaminase elevations ● clarify that subjects who became pregnant must have discontinued the study drug, but may have continued to be monitored in the Post-Treatment Period ● update Management of Transaminase Elevations in Section 6.7.4, including Table 10 to be consistent with Exclusion Criterion No. 17 to allow for management of subjects with ALT/AST > 7 × ULN ● make minor clerical updates throughout the protocol for clarification and consistency
    08 Apr 2013
    ● prohibit the use of hormonal contraceptives during study drug administration
    07 May 2013
    ● update the approximate number of subjects to be enrolled into the study from approximately 300 to approximately 380

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/24725237
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