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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of ABT-450/Ritonavir/ABT-267 (ABT-450/r/ABT-267) and ABT-333 Co-administered with Ribavirin (RBV) in Treatment-Experienced Adults with Genotype 1 Chronic Hepatitis C Virus (HCV) Infection (SAPPHIRE-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
    		 2012-002035-29
    Trial protocol
    		 DE   GB   CZ   PT   IE   NL   IT   DK   ES  
    Global end of trial date
    23 Oct 2014

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

    Trial information

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    Trial identification
    Sponsor protocol code
    M13-098
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01715415
    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
    Jeff Enejosa, MD, AbbVie, jeff.enejosa@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
    23 Oct 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Oct 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 compare the percentage of subjects achieving sustained virologic response 12 weeks postdosing (SVR12; HCV ribonucleic acid [RNA] < lower limit of quantitation [LLOQ] 12 weeks following treatment) after 12 weeks of treatment with ABT-450/r/ABT-267 and ABT-333 coadministered with RBV (the direct-acting antiviral agent [DAA] combination regimen) to the historical SVR rate of telaprevir plus pegylated interferon (pegIFN) and RBV therapy and to assess the safety of the DAA combination regimen versus placebo for 12 weeks in pegIFN/RBV treatment-experienced HCV genotype 1-infected adults without cirrhosis.
    Protection of trial subjects
    All subjects entering the study had to sign an informed consent that was explained to them and questions encouraged.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Nov 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
    Netherlands: 7
    Country: Number of subjects enrolled
    Portugal: 20
    Country: Number of subjects enrolled
    Spain: 30
    Country: Number of subjects enrolled
    United Kingdom: 21
    Country: Number of subjects enrolled
    Czech Republic: 7
    Country: Number of subjects enrolled
    Denmark: 8
    Country: Number of subjects enrolled
    France: 37
    Country: Number of subjects enrolled
    Germany: 22
    Country: Number of subjects enrolled
    Ireland: 12
    Country: Number of subjects enrolled
    Italy: 24
    Country: Number of subjects enrolled
    Australia: 14
    Country: Number of subjects enrolled
    Canada: 20
    Country: Number of subjects enrolled
    Russian Federation: 24
    Country: Number of subjects enrolled
    United States: 149
    Worldwide total number of subjects
    395
    EEA total number of subjects
    188
    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)
    362
    From 65 to 84 years
    33
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 One subject in the Placebo Followed by ABT-450/r/ ABT-267 and ABT-333, Plus RBV arm was randomized but did not received treatment; this subject was not included in the Safety Population and is accounted for in the Pre-assignment Milestones below.

    Pre-assignment period milestones
    Number of subjects started
    		 395
    Number of subjects completed
    		 394

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Randomized but not treated: 1
    Period 1
    Period 1 title
    Double-blind Treatment
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    AbbVie, investigators, and subjects were blinded to drug assignment and virologic results for the duration of the Double-blind Treatment Period.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ABT-450/r/ABT-267 and ABT-333, Plus RBV
    Arm description
    		 Double-blind ABT-450/r/ABT-267 (150 mg/100 mg/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based RBV (dosed 1,000 to 1,200 mg/day divided twice daily) for 12 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    ABT-450/r/ABT-267
    Investigational medicinal product code
    ABT-450/r/ABT-267
    Other name
    ABT-267 also known as ombitasvir, ABT-450 also known as paritaprevir, (with ABT-333) Viekira PAK
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    At the double-blind (DB) Day 1 Visit, subjects were administered study drugs by the study site personnel and received instructions for self-administration of all study drugs from Study Day 2 through Study Week 12 of the DB Treatment Period.

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    At the DB Day 1 Visit, subjects were administered study drugs by the study site personnel and received instructions for self-administration of all study drugs from Study Day 2 through Study Week 12 of the DB Treatment Period.

    Investigational medicinal product name
    ABT-333
    Investigational medicinal product code
    ABT-333
    Other name
    dasabuvir, (with ABT-450/r/ABT-267) Viekira PAK
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    At the DB Day 1 Visit, subjects were administered study drugs by the study site personnel and received instructions for self-administration of all study drugs from Study Day 2 through Study Week 12 of the DB Treatment Period.

    Arm title
    		 Placebo Followed by ABT-450/r/ ABT-267 and ABT-333, Plus RBV
    Arm description
    		 Double-blind placebo for 12 weeks
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    At the DB Day 1 Visit, subjects were administered study drugs by the study site personnel and received instructions for self-administration of all study drugs from Study Day 2 through Study Week 12 of the DB Treatment Period.

    Number of subjects in period 1 [1]
    		ABT-450/r/ABT-267 and ABT-333, Plus RBV Placebo Followed by ABT-450/r/ ABT-267 and ABT-333, Plus RBV
    Started
    297
    97
    Completed
    292
    96
    Not completed
    5
    1
         Not specified
    1
    -
         Adverse event
    3
    -
         Withdrawal by subject
    1
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: One subject in the Placebo Followed by ABT-450/r/ ABT-267 and ABT-333, Plus RBV arm were randomized but did not received treatment; these subjects were not included in the Safety Population. The Pre-assignment Milestones, above, accounts for the worldwide number enrolled.
    Period 2
    Period 2 title
    Open-label Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Placebo Followed by ABT-450/r/ ABT-267 and ABT-333, Plus RBV
    Arm description
    		 Open-label ABT-450/r/ABT-267 (150 mg/100 mg/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based RBV (RBV; dosed 1,000 to 1,200 mg/day divided twice daily) for 12 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    ABT-450/r/ABT-267
    Investigational medicinal product code
    ABT-450/r/ABT-267
    Other name
    ABT-267 also known as ombitasvir, ABT-450 also known as paritaprevir, (with ABT-333) Viekira PAK
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects entering the open-label (OL) Treatment Period were given drugs at the DB Week 12 Visit, along with instructions to begin dosing the next day.

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects entering the OL Treatment Period were given drugs at the DB Week 12 Visit, along with instructions to begin dosing the next day.

    Investigational medicinal product name
    ABT-333
    Investigational medicinal product code
    ABT-333
    Other name
    dasabuvir, (with ABT-450/r/ABT-267) Viekira PAK
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects entering the OL Treatment Period were given drugs at the DB Week 12 Visit, along with instructions to begin dosing the next day.

    Number of subjects in period 2 [2]
    		Placebo Followed by ABT-450/r/ ABT-267 and ABT-333, Plus RBV
    Started
    96
    Completed
    94
    Not completed
    2
         Adverse event
    1
         Subject noncompliant
    1
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Only subjects in the Placebo Followed by ABT-450/r/ ABT-267 and ABT-333, Plus RBV arm (n=96) were continued on to Period 2, per protocol.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ABT-450/r/ABT-267 and ABT-333, Plus RBV
    Reporting group description
    		 Double-blind ABT-450/r/ABT-267 (150 mg/100 mg/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based RBV (dosed 1,000 to 1,200 mg/day divided twice daily) for 12 weeks

    Reporting group title
    Placebo Followed by ABT-450/r/ ABT-267 and ABT-333, Plus RBV
    Reporting group description
    		 Double-blind placebo for 12 weeks

    Reporting group values
    		 ABT-450/r/ABT-267 and ABT-333, Plus RBV Placebo Followed by ABT-450/r/ ABT-267 and ABT-333, Plus RBV Total
    Number of subjects
    		 297 97 394
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 51.7 ( 10.26 ) 54.9 ( 8.46 ) -
    Gender categorical
    Units: Subjects
        Female
    		 130 37 167
        Male
    		 167 60 227

    End points

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    End points reporting groups
    Reporting group title
    ABT-450/r/ABT-267 and ABT-333, Plus RBV
    Reporting group description
    		 Double-blind ABT-450/r/ABT-267 (150 mg/100 mg/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based RBV (dosed 1,000 to 1,200 mg/day divided twice daily) for 12 weeks

    Reporting group title
    Placebo Followed by ABT-450/r/ ABT-267 and ABT-333, Plus RBV
    Reporting group description
    		 Double-blind placebo for 12 weeks
    Reporting group title
    Placebo Followed by ABT-450/r/ ABT-267 and ABT-333, Plus RBV
    Reporting group description
    		 Open-label ABT-450/r/ABT-267 (150 mg/100 mg/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based RBV (RBV; dosed 1,000 to 1,200 mg/day divided twice daily) for 12 weeks

    Subject analysis set title
    ABT-450/r/ABT-267 and ABT-333, Plus RBV
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intent-to-treat (ITT) Population: All randomized subjects in the ABT-450/r/ABT-267 and ABT-333, Plus RBV arm who received at least 1 dose of blinded study drug.

    Subject analysis set title
    Placebo Followed by ABT-450/r/ ABT-267 and ABT-333, Plus RBV
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intent-to-treat (ITT) Population: All randomized subjects in the Placebo Followed by ABT-450/r/ ABT-267 and ABT-333, Plus RBV arm who received at least 1 dose of blinded study drug.

    Primary: Percentage of Subjects With Sustained Virologic Response 12 Weeks After Treatment

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    End point title
    		 Percentage of Subjects With Sustained Virologic Response 12 Weeks After Treatment [1]
    End point description
    The percentage of subjects with sustained virologic response (plasma HCV RNA level < 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 active 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: See attached zip file (M-13-098 Statistical Analysis for Primary Endpoint.pdf) for the statistical analysis data, which could not be entered directly due to EudraCT system limitations.
    End point values
    		 ABT-450/r/ABT-267 and ABT-333, Plus RBV
    Number of subjects analysed
    297
    Units: percentage of subjects
        number (not applicable)
    96.3
    Attachments
    		 Untitled (Filename: M13-098 Statistical Analysis for Primary Endpoint.pdf)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Normalization of Alanine Aminotransferase (ALT) at Final Treatment Visit During the Double-Blind Treatment Period

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    End point title
    		 Percentage of Subjects With Normalization of Alanine Aminotransferase (ALT) at Final Treatment Visit During the Double-Blind Treatment Period
    End point description
    Normalization is defined as alanine aminotransferase less than or equal to the upper limit of normal (ULN) at final treatment visit for subjects with alanine aminotransferase greater than ULN at baseline.
    End point type
    Secondary
    End point timeframe
    At 12 weeks
    End point values
    		 ABT-450/r/ABT-267 and ABT-333, Plus RBV Placebo Followed by ABT-450/r/ ABT-267 and ABT-333, Plus RBV
    Number of subjects analysed
    224 [2]
    78 [3]
    Units: percentage of subjects
        number (not applicable)
    96.9
    12.8
    Notes
    [2] - Subjects in the ITT population who had ALT ≥ ULN of the reference range at baseline
    [3] - Subjects in the ITT population who had ALT ≥ ULN of the reference range at baseline
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    In order to control the Type I error rate at 0.05, a fixed-sequence testing procedure was used to proceed through the primary and the first 3 secondary endpoints.
    Comparison groups
    Placebo Followed by ABT-450/r/ ABT-267 and ABT-333, Plus RBV v ABT-450/r/ABT-267 and ABT-333, Plus RBV
    Number of subjects included in analysis
    302
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Percentage of HCV Genotype 1a-infected Subjects With Sustained Virologic Response 12 Weeks After Treatment

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    End point title
    		 Percentage of HCV Genotype 1a-infected Subjects With Sustained Virologic Response 12 Weeks After Treatment
    End point description
    The percentage of subjects with sustained virologic response (plasma HCV RNA level < LLOQ) 12 weeks after the last dose of study drug. One subject, who had genotype 1 HCV with an indeterminate subgenotype, is not included in this analysis.
    End point type
    Secondary
    End point timeframe
    12 weeks after the last actual dose of active study drug
    End point values
    		 ABT-450/r/ABT-267 and ABT-333, Plus RBV
    Number of subjects analysed
    173 [4]
    Units: percentage of subjects
        number (not applicable)
    96
    Attachments
    		 Untitled (Filename: M13-098 Statistical Analysis for Secondary Endpoint 3.docx)
    Notes
    [4] - Subjects in ITT population with HCV genotype 1a who received at least 1 dose of blinded study drug.
    No statistical analyses for this end point

    Secondary: Percentage of HCV Genotype 1b-infected Subjects With Sustained Virologic Response 12 Weeks After Treatment

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    End point title
    		 Percentage of HCV Genotype 1b-infected Subjects With Sustained Virologic Response 12 Weeks After Treatment
    End point description
    The percentage of subjects with sustained virologic response (HCV RNA level < LLOQ) 12 weeks after the last dose of study drug. One subject, who had genotype 1 HCV with an indeterminate subgenotype, is not included in this analysis.
    End point type
    Secondary
    End point timeframe
    12 weeks after the last actual dose of active study drug
    End point values
    		 ABT-450/r/ABT-267 and ABT-333, Plus RBV
    Number of subjects analysed
    123 [5]
    Units: percentage of subjects
        number (not applicable)
    96.7
    Attachments
    		 Untitled (Filename: M13-098 Statistical Analysis for Secondary Endpoint 4.docx.pdf)
    Notes
    [5] - Subjects in ITT population with HCV genotype 1b who received at least 1 dose of blinded study drug.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With On-treatment Virologic Failure During the Double-blind Treatment Period: ABT-450/r/ ABT-267 and ABT-333, Plus RBV Arm

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    End point title
    		 Percentage of Subjects With On-treatment Virologic Failure During the Double-blind Treatment Period: ABT-450/r/ ABT-267 and ABT-333, Plus RBV Arm
    End point description
    Virologic failure was defined as rebound (HCV RNA ≥ LLOQ after HCV RNA < LLOQ or increase in HCV RNA of at least 1 log10 IU/mL) or failure to suppress (all on-treatment values of plasma HCV RNA ≥ LLOQ with at least 36 days of treatment) during treatment.
    End point type
    Secondary
    End point timeframe
    12 weeks after the last actual dose of active study drug
    End point values
    		 ABT-450/r/ABT-267 and ABT-333, Plus RBV
    Number of subjects analysed
    297
    Units: percentage of subjects
        number (confidence interval 95%)
    0 (0 to 0)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With Virologic Relapse After Treatment: ABT-450/r/ABT-267 and ABT-333, Plus RBV Arm

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    End point title
    		 Percentage of Subjects With Virologic Relapse After Treatment: ABT-450/r/ABT-267 and ABT-333, Plus RBV Arm
    End point description
    Subjects were considered to have virologic relapse after treatment if they had confirmed quantifiable plasma HCV RNA ≥ LLOQ between the end of treatment and 12 weeks after the last dose of study drug among subjects who completed treatment with HCV RNA < LLOQ at the end of treatment.
    End point type
    Secondary
    End point timeframe
    Within 12 weeks post-treatment
    End point values
    		 ABT-450/r/ABT-267 and ABT-333, Plus RBV
    Number of subjects analysed
    293 [6]
    Units: percentage of subjects
        number (confidence interval 95%)
    2.4 (0.6 to 4.1)
    Notes
    [6] - Subjects with HCV RNA < LLOQ at the final treatment visit who completed treatment in the DB period.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) were collected from the start of active study drug administration (DB or OL active) to 30 days after the last dose of active study drug (total 16 weeks).
    Adverse event reporting additional description
    DB Placebo Arm: AEs collected from start of placebo until 30 days following discontinuation of placebo and prior to the OL period (if applicable; total 16 weeks). Serious AEs collected from informed consent until the end of participation in the study (12 weeks, DB period; 12 weeks, OL period + 48-week post-treatment period; total 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
    Double Blind ABT-450/r/ABT-267 and ABT-333, Plus RBV
    Reporting group description
    		 Double-blind ABT-450/r/ABT-267 (150 mg/100 mg/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based RBV (dosed 1,000 to 1,200 mg/day divided twice daily) for 12 weeks

    Reporting group title
    Double Blind Placebo
    Reporting group description
    		 Double-blind placebo for 12 weeks

    Reporting group title
    Open Label ABT-450/r/ABT-267 and ABT-333, Plus RBV
    Reporting group description
    		 Open-label ABT-450/r/ABT-267 (150 mg/100 mg/25 mg once daily) and ABT-333 (250 mg twice daily), plus weight-based RBV (dosed 1,000 to 1,200 mg/day divided twice daily) for 12 weeks

    Serious adverse events
    		 Double Blind ABT-450/r/ABT-267 and ABT-333, Plus RBV Double Blind Placebo Open Label ABT-450/r/ABT-267 and ABT-333, Plus RBV
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 297 (2.02%)
    1 / 97 (1.03%)
    3 / 96 (3.13%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    ATRIAL FIBRILLATION
         subjects affected / exposed
    0 / 297 (0.00%)
    1 / 97 (1.03%)
    0 / 96 (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
    BRADYCARDIA
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    CEREBROVASCULAR ACCIDENT
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 97 (0.00%)
    0 / 96 (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
    DIZZINESS
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    INTESTINAL OBSTRUCTION
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 97 (0.00%)
    0 / 96 (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
    NAUSEA
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 97 (0.00%)
    0 / 96 (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
    VOMITING
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 97 (0.00%)
    0 / 96 (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
    Hepatobiliary disorders
    BILE DUCT STONE
         subjects affected / exposed
    0 / 297 (0.00%)
    0 / 97 (0.00%)
    1 / 96 (1.04%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    CHRONIC OBSTRUCTIVE PULMONARY DISEASE
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 97 (0.00%)
    0 / 96 (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
    Skin and subcutaneous tissue disorders
    ANGIOEDEMA
         subjects affected / exposed
    0 / 297 (0.00%)
    0 / 97 (0.00%)
    1 / 96 (1.04%)
         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 and urinary disorders
    CALCULUS URETERIC
         subjects affected / exposed
    0 / 297 (0.00%)
    0 / 97 (0.00%)
    1 / 96 (1.04%)
         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 FAILURE ACUTE
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 97 (0.00%)
    0 / 96 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    PNEUMONIA
         subjects affected / exposed
    1 / 297 (0.34%)
    0 / 97 (0.00%)
    0 / 96 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Double Blind ABT-450/r/ABT-267 and ABT-333, Plus RBV Double Blind Placebo Open Label ABT-450/r/ABT-267 and ABT-333, Plus RBV
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    254 / 297 (85.52%)
    74 / 97 (76.29%)
    74 / 96 (77.08%)
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    25 / 297 (8.42%)
    5 / 97 (5.15%)
    5 / 96 (5.21%)
         occurrences all number
    27
    6
    5
    DYSGEUSIA
         subjects affected / exposed
    10 / 297 (3.37%)
    5 / 97 (5.15%)
    3 / 96 (3.13%)
         occurrences all number
    10
    5
    3
    HEADACHE
         subjects affected / exposed
    108 / 297 (36.36%)
    34 / 97 (35.05%)
    18 / 96 (18.75%)
         occurrences all number
    126
    37
    21
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    16 / 297 (5.39%)
    0 / 97 (0.00%)
    3 / 96 (3.13%)
         occurrences all number
    19
    0
    3
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    47 / 297 (15.82%)
    11 / 97 (11.34%)
    13 / 96 (13.54%)
         occurrences all number
    60
    13
    15
    FATIGUE
         subjects affected / exposed
    99 / 297 (33.33%)
    22 / 97 (22.68%)
    16 / 96 (16.67%)
         occurrences all number
    99
    23
    17
    IRRITABILITY
         subjects affected / exposed
    16 / 297 (5.39%)
    8 / 97 (8.25%)
    6 / 96 (6.25%)
         occurrences all number
    17
    8
    6
    Gastrointestinal disorders
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    16 / 297 (5.39%)
    6 / 97 (6.19%)
    9 / 96 (9.38%)
         occurrences all number
    17
    6
    10
    CONSTIPATION
         subjects affected / exposed
    4 / 297 (1.35%)
    6 / 97 (6.19%)
    0 / 96 (0.00%)
         occurrences all number
    4
    6
    0
    DIARRHOEA
         subjects affected / exposed
    39 / 297 (13.13%)
    12 / 97 (12.37%)
    8 / 96 (8.33%)
         occurrences all number
    40
    14
    8
    DYSPEPSIA
         subjects affected / exposed
    18 / 297 (6.06%)
    3 / 97 (3.09%)
    7 / 96 (7.29%)
         occurrences all number
    19
    3
    7
    NAUSEA
         subjects affected / exposed
    59 / 297 (19.87%)
    17 / 97 (17.53%)
    13 / 96 (13.54%)
         occurrences all number
    66
    18
    13
    VOMITING
         subjects affected / exposed
    19 / 297 (6.40%)
    0 / 97 (0.00%)
    3 / 96 (3.13%)
         occurrences all number
    21
    0
    3
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    32 / 297 (10.77%)
    5 / 97 (5.15%)
    11 / 96 (11.46%)
         occurrences all number
    33
    5
    11
    DYSPNOEA
         subjects affected / exposed
    37 / 297 (12.46%)
    10 / 97 (10.31%)
    13 / 96 (13.54%)
         occurrences all number
    40
    10
    13
    DYSPNOEA EXERTIONAL
         subjects affected / exposed
    12 / 297 (4.04%)
    5 / 97 (5.15%)
    8 / 96 (8.33%)
         occurrences all number
    13
    5
    8
    Skin and subcutaneous tissue disorders
    DRY SKIN
         subjects affected / exposed
    22 / 297 (7.41%)
    3 / 97 (3.09%)
    5 / 96 (5.21%)
         occurrences all number
    23
    3
    5
    PRURITUS
         subjects affected / exposed
    41 / 297 (13.80%)
    5 / 97 (5.15%)
    12 / 96 (12.50%)
         occurrences all number
    43
    5
    12
    PRURITUS GENERALISED
         subjects affected / exposed
    11 / 297 (3.70%)
    5 / 97 (5.15%)
    3 / 96 (3.13%)
         occurrences all number
    11
    5
    3
    RASH
         subjects affected / exposed
    26 / 297 (8.75%)
    6 / 97 (6.19%)
    8 / 96 (8.33%)
         occurrences all number
    27
    8
    9
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    14 / 297 (4.71%)
    4 / 97 (4.12%)
    7 / 96 (7.29%)
         occurrences all number
    14
    4
    7
    DEPRESSED MOOD
         subjects affected / exposed
    5 / 297 (1.68%)
    5 / 97 (5.15%)
    1 / 96 (1.04%)
         occurrences all number
    5
    5
    1
    INSOMNIA
         subjects affected / exposed
    42 / 297 (14.14%)
    7 / 97 (7.22%)
    10 / 96 (10.42%)
         occurrences all number
    46
    7
    11
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    19 / 297 (6.40%)
    7 / 97 (7.22%)
    2 / 96 (2.08%)
         occurrences all number
    20
    8
    2
    BACK PAIN
         subjects affected / exposed
    15 / 297 (5.05%)
    3 / 97 (3.09%)
    3 / 96 (3.13%)
         occurrences all number
    15
    3
    3
    MYALGIA
         subjects affected / exposed
    23 / 297 (7.74%)
    10 / 97 (10.31%)
    5 / 96 (5.21%)
         occurrences all number
    23
    10
    6
    Infections and infestations
    NASOPHARYNGITIS
         subjects affected / exposed
    21 / 297 (7.07%)
    5 / 97 (5.15%)
    8 / 96 (8.33%)
         occurrences all number
    24
    5
    8
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    20 / 297 (6.73%)
    2 / 97 (2.06%)
    4 / 96 (4.17%)
         occurrences all number
    21
    2
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Oct 2012
    The purpose of this amendment was to: ● update secondary endpoints to remove rapid virological response and end-of-treatment response, which are irrelevant in the absence of SVR, and to include rebound and relapse rates which are relevant in clinical practice when using DAAs; ● clarify inclusion/exclusion criteria to ensure the appropriate subject population was enrolled; ● clarify the timing of efficacy analyses based on the availability of post-treatment virologic data; ● update plan for resistance analysis throughout the protocol in order to clarify and more accurately reflect plans for assessing resistance development; ● update RBV toxicity management in a manner that aligns with the RBV label; ● address inconsistencies throughout the protocol.
    01 Mar 2013
    The purpose of this amendment was to: ● include SVR12 rates within HCV subgenotypes (1a, 1b) as secondary endpoints. ● update the thresholds for success of the primary and secondary efficacy 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 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 the timing of primary and follow-up efficacy analyses based on the availability of post-treatment virologic data. ● address inconsistencies throughout the protocol.
    08 Apr 2013
    ● prohibit the use of hormonal contraceptives during study drug administration. Rationale: Hormonal contraceptives are not expected to be effective when dosed with the DAA regimen and may be associated with an increased risk for ALT elevation. ● correct typographical error for sponsor/emergency contact mobile number.

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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