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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-Naïve Adults with Genotype 1 Chronic Hepatitis C Virus (HCV) Infection (SAPPHIRE-I)

    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
    2012-002019-25
    Trial protocol
    SE   GB   HU   DE   AT   IT   ES  
    Global end of trial date
    09 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
    M11-646
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01716585
    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
    Nancy Shulman, MD, AbbVie, nancy.shulman@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
    09 Oct 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 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 show the noninferiority in sustained virologic response 12 weeks postdosing (SVR12) rates (the percentage of subjects achieving a 12-week sustained virologic response [HCV ribonucleic acid {RNA} < lower limit of quantitation {LLOQ} 12 weeks following therapy]) 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 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
    27 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
    Spain: 36
    Country: Number of subjects enrolled
    Sweden: 29
    Country: Number of subjects enrolled
    United Kingdom: 35
    Country: Number of subjects enrolled
    Austria: 18
    Country: Number of subjects enrolled
    France: 42
    Country: Number of subjects enrolled
    Germany: 45
    Country: Number of subjects enrolled
    Hungary: 25
    Country: Number of subjects enrolled
    Italy: 29
    Country: Number of subjects enrolled
    Australia: 37
    Country: Number of subjects enrolled
    Canada: 41
    Country: Number of subjects enrolled
    New Zealand: 10
    Country: Number of subjects enrolled
    Switzerland: 23
    Country: Number of subjects enrolled
    United States: 266
    Worldwide total number of subjects
    636
    EEA total number of subjects
    259
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    607
    From 65 to 84 years
    29
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 4 subjects in the ABT-450/r/ABT-267 and ABT-333, Plus RBV arm and 1 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, and are accounted for in the Pre-assignment Milestones below.

    Pre-assignment period milestones
    Number of subjects started
    636
    Number of subjects completed
    631

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Randomized but not treated: 5
    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 or 1,200 mg daily divided twice a day) 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
    473
    158
    Completed
    464
    157
    Not completed
    9
    1
         Withdrawal by Subject
             3
             -
         Adverse Event
             2
             1
         Not Specified
             1
             -
         Subject Noncompliant
             1
             -
         Lost to follow-up
             2
             -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A total of 4 subjects in the ABT-450/r/ABT-267 and ABT-333, Plus RBV arm and 1 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 table 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 or 1,200 mg daily divided twice a day) 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
    157
    Completed
    150
    Not completed
    7
         Withdrawal by Subject
             3
         Virologic Failure
             2
         Adverse Event
             2
    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=157) 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 or 1,200 mg daily divided twice a day) 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
    473 158 631
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    49.4 ± 10.98 51.2 ± 10.23 -
    Gender categorical
    Units: Subjects
        Female
    202 85 287
        Male
    271 73 344

    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 or 1,200 mg daily divided twice a day) 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 or 1,200 mg daily divided twice a day) 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 (M11-646 Primary Endpoint Statistical Analysis.docx) 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
    473
    Units: percentage of subjects
        number (not applicable)
    96.4
    Attachments
    Untitled (Filename: M11-646 Primary Endpoint Statistical Analysis.docx)
    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
    363 [2]
    114 [3]
    Units: percentage of subjects
        number (not applicable)
    97
    15.8
    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 will be used to proceed through the primary and first 3 secondary efficacy endpoints in the order numbered below.
    Comparison groups
    ABT-450/r/ABT-267 and ABT-333, Plus RBV v Placebo Followed by ABT-450/r/ ABT-267 and ABT-333, Plus RBV
    Number of subjects included in analysis
    477
    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.
    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
    322 [4]
    Units: percentage of subjects
        number (not applicable)
    95.7
    Attachments
    Untitled (Filename: M11-646 Secondary Endpoint 3 Statistical Analysis.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 (plasma HCV RNA level < 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 active study drug
    End point values
    ABT-450/r/ABT-267 and ABT-333, Plus RBV
    Number of subjects analysed
    151 [5]
    Units: percentage of subjects
        number (not applicable)
    98
    Attachments
    Untitled (Filename: M11-646 Secondary Endpoint 4 Statistical Analysis.docx)
    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
    473
    Units: percentage of subjects
        number (confidence interval 95%)
    0.2 (0 to 0.6)
    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
    463 [6]
    Units: percentage of subjects
        number (confidence interval 95%)
    1.5 (0.4 to 2.6)
    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/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 or 1,200 mg daily divided twice a day) 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 or 1,200 mg daily divided twice a day) 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
    10 / 473 (2.11%)
    0 / 158 (0.00%)
    2 / 157 (1.27%)
         number of deaths (all causes)
    1
    0
    1
         number of deaths resulting from adverse events
    Vascular disorders
    AORTIC STENOSIS
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 158 (0.00%)
    0 / 157 (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
    Injury, poisoning and procedural complications
    LUMBAR VERTEBRAL FRACTURE
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 158 (0.00%)
    0 / 157 (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
    OVERDOSE
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 158 (0.00%)
    0 / 157 (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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    NON-SMALL CELL LUNG CANCER
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 158 (0.00%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardiac disorders
    SINUS TACHYCARDIA
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 158 (0.00%)
    0 / 157 (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
    VENTRICULAR EXTRASYSTOLES
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 158 (0.00%)
    0 / 157 (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
    Respiratory, thoracic and mediastinal disorders
    ACUTE RESPIRATORY FAILURE
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 158 (0.00%)
    0 / 157 (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
    HYPOXIA
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 158 (0.00%)
    0 / 157 (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
    MEDIASTINAL MASS
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 158 (0.00%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 158 (0.00%)
    0 / 157 (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
    ENCEPHALOPATHY
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 158 (0.00%)
    0 / 157 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    CHILLS
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 158 (0.00%)
    0 / 157 (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
    NON-CARDIAC CHEST PAIN
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 158 (0.00%)
    0 / 157 (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
    ABDOMINAL PAIN
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 158 (0.00%)
    0 / 157 (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
    DIARRHOEA
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 158 (0.00%)
    0 / 157 (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
    NAUSEA
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 158 (0.00%)
    0 / 157 (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
    VOMITING
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 158 (0.00%)
    0 / 157 (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
    Hepatobiliary disorders
    BILIARY COLIC
         subjects affected / exposed
    0 / 473 (0.00%)
    0 / 158 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CHOLECYSTITIS
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 158 (0.00%)
    0 / 157 (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
    APPENDICITIS
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 158 (0.00%)
    0 / 157 (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
    LOBAR PNEUMONIA
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 158 (0.00%)
    0 / 157 (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
    POSTOPERATIVE WOUND INFECTION
         subjects affected / exposed
    1 / 473 (0.21%)
    0 / 158 (0.00%)
    0 / 157 (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
    SUBCUTANEOUS ABSCESS
         subjects affected / exposed
    0 / 473 (0.00%)
    0 / 158 (0.00%)
    1 / 157 (0.64%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         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
    391 / 473 (82.66%)
    108 / 158 (68.35%)
    117 / 157 (74.52%)
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    34 / 473 (7.19%)
    8 / 158 (5.06%)
    7 / 157 (4.46%)
         occurrences all number
    40
    8
    8
    DYSPNOEA
         subjects affected / exposed
    38 / 473 (8.03%)
    4 / 158 (2.53%)
    12 / 157 (7.64%)
         occurrences all number
    39
    4
    12
    DYSPNOEA EXERTIONAL
         subjects affected / exposed
    24 / 473 (5.07%)
    3 / 158 (1.90%)
    8 / 157 (5.10%)
         occurrences all number
    25
    3
    8
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    24 / 473 (5.07%)
    0 / 158 (0.00%)
    14 / 157 (8.92%)
         occurrences all number
    25
    0
    15
    Nervous system disorders
    DIZZINESS
         subjects affected / exposed
    38 / 473 (8.03%)
    6 / 158 (3.80%)
    5 / 157 (3.18%)
         occurrences all number
    40
    6
    5
    HEADACHE
         subjects affected / exposed
    156 / 473 (32.98%)
    42 / 158 (26.58%)
    26 / 157 (16.56%)
         occurrences all number
    182
    54
    31
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    59 / 473 (12.47%)
    6 / 158 (3.80%)
    10 / 157 (6.37%)
         occurrences all number
    80
    10
    11
    FATIGUE
         subjects affected / exposed
    164 / 473 (34.67%)
    45 / 158 (28.48%)
    35 / 157 (22.29%)
         occurrences all number
    182
    49
    38
    IRRITABILITY
         subjects affected / exposed
    26 / 473 (5.50%)
    4 / 158 (2.53%)
    6 / 157 (3.82%)
         occurrences all number
    26
    4
    6
    Psychiatric disorders
    ANXIETY
         subjects affected / exposed
    22 / 473 (4.65%)
    5 / 158 (3.16%)
    8 / 157 (5.10%)
         occurrences all number
    23
    6
    8
    INSOMNIA
         subjects affected / exposed
    67 / 473 (14.16%)
    12 / 158 (7.59%)
    21 / 157 (13.38%)
         occurrences all number
    70
    12
    22
    SLEEP DISORDER
         subjects affected / exposed
    24 / 473 (5.07%)
    4 / 158 (2.53%)
    4 / 157 (2.55%)
         occurrences all number
    25
    4
    4
    Gastrointestinal disorders
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    29 / 473 (6.13%)
    5 / 158 (3.16%)
    8 / 157 (5.10%)
         occurrences all number
    31
    7
    9
    DIARRHOEA
         subjects affected / exposed
    65 / 473 (13.74%)
    11 / 158 (6.96%)
    19 / 157 (12.10%)
         occurrences all number
    77
    12
    24
    DRY MOUTH
         subjects affected / exposed
    19 / 473 (4.02%)
    9 / 158 (5.70%)
    0 / 157 (0.00%)
         occurrences all number
    19
    10
    0
    DYSPEPSIA
         subjects affected / exposed
    26 / 473 (5.50%)
    7 / 158 (4.43%)
    6 / 157 (3.82%)
         occurrences all number
    29
    7
    6
    NAUSEA
         subjects affected / exposed
    112 / 473 (23.68%)
    22 / 158 (13.92%)
    24 / 157 (15.29%)
         occurrences all number
    129
    23
    28
    VOMITING
         subjects affected / exposed
    23 / 473 (4.86%)
    6 / 158 (3.80%)
    9 / 157 (5.73%)
         occurrences all number
    25
    6
    12
    Skin and subcutaneous tissue disorders
    DRY SKIN
         subjects affected / exposed
    27 / 473 (5.71%)
    2 / 158 (1.27%)
    7 / 157 (4.46%)
         occurrences all number
    29
    2
    7
    PRURITUS
         subjects affected / exposed
    80 / 473 (16.91%)
    7 / 158 (4.43%)
    16 / 157 (10.19%)
         occurrences all number
    87
    7
    16
    RASH
         subjects affected / exposed
    51 / 473 (10.78%)
    9 / 158 (5.70%)
    8 / 157 (5.10%)
         occurrences all number
    62
    9
    9
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    23 / 473 (4.86%)
    9 / 158 (5.70%)
    9 / 157 (5.73%)
         occurrences all number
    23
    11
    9
    BACK PAIN
         subjects affected / exposed
    22 / 473 (4.65%)
    7 / 158 (4.43%)
    9 / 157 (5.73%)
         occurrences all number
    26
    7
    10
    MYALGIA
         subjects affected / exposed
    21 / 473 (4.44%)
    8 / 158 (5.06%)
    6 / 157 (3.82%)
         occurrences all number
    23
    9
    7
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    37 / 473 (7.82%)
    5 / 158 (3.16%)
    11 / 157 (7.01%)
         occurrences all number
    39
    6
    11
    Infections and infestations
    NASOPHARYNGITIS
         subjects affected / exposed
    33 / 473 (6.98%)
    10 / 158 (6.33%)
    11 / 157 (7.01%)
         occurrences all number
    36
    11
    13
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    22 / 473 (4.65%)
    8 / 158 (5.06%)
    10 / 157 (6.37%)
         occurrences all number
    24
    8
    11

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Nov 2012
    The purpose of this amendment was to: ● update the thresholds for the primary endpoints to be based on historical SVR rates from telaprevir plus pegIFN and RBV therapy. ● update secondary endpoints to remove rapid virologic response and end-of-treatment response and to include rebound and relapse rates. ● 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. ● incorporate Administrative Changes. ● address inconsistencies throughout the protocol.
    08 Apr 2013
    The purpose of this amendment was to: ● prohibit the use of hormonal contraceptives during study drug administration. Rationale: Hormonal contraceptives were not expected to be effective when dosed with the DAA regimen and could have been associated with an increased risk for ALT elevation.

    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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