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    Clinical Trial Results:
    A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of GS-5885, GS-9451, Tegobuvir and Ribavirin (RBV) Compared with GS-5885, GS-9451 with Tegobuvir or RBV in Treatment-Experienced Subjects with Chronic Genotype 1a or 1b Hepatitis C Virus (HCV) Infection

    Summary
    EudraCT number
    		 2011-002748-28
    Trial protocol
    		 DE  
    Global end of trial date
    29 Jul 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Mar 2016
    First version publication date
    05 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-248-0131
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01435226
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Clinical Trial Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.com
    Scientific contact
    Clinical Trial Mailbox, Gilead Sciences International Ltd, ClinicalTrialDisclosures@gilead.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
    29 Jul 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jul 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study was to evaluate the antiviral efficacy, safety, and tolerability of combination therapy with ledispasvir (LDV; formerly GS-5885), vedroprevir (VDV; formerly GS-9451), tegobuvir (TGV), and ribavirin (RBV) compared with LDV+VDV+TGV or LDV+VDV+RBV in treatment-experienced participants with chronic genotype 1a or 1b hepatitis C virus (HCV) infection. The treatment duration for all arms was 24 weeks. Participants who did not achieve a very rapid virologic response (vRVR, defined as HCV RNA < LLOQ at Week 2), had ontreatment virologic breakthrough, or relapse following completion of initial treatment were eligible for treatment with LDV+VDV+pegylated interferon (PEG)+RBV for an additional 24 to 48 weeks in the Rescue Therapy Substudy.
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Sep 2011
    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
    United States: 107
    Country: Number of subjects enrolled
    Germany: 62
    Worldwide total number of subjects
    169
    EEA total number of subjects
    62
    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)
    153
    From 65 to 84 years
    16
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in the United States and Germany. The first participant was screened on 21 September 2011. The last study visit occurred on 29 July 2013.

    Pre-assignment
    Screening details
    		 266 participants were screened.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LDV+VDV+TGV+RBV
    Arm description
    		 Initial treatment: ledipasvir (LDV)+vedroprevir (VDV)+tegobuvir (TGV)+ribavirin (RBV) for 24 weeks. Participants who did not achieve a very rapid virologic response (vRVR, defined as HCV RNA < LLOQ at Week 2), had ontreatment virologic breakthrough, or relapse following initial treatment were eligible for treatment with LDV+VDV+PEG+RBV for an additional 24 to 48 weeks in the Rescue Therapy Substudy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ledipasvir
    Investigational medicinal product code
    Other name
    GS-5885
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ledipasvir (LDV) 90 mg (3 x 30 mg tablets) administered orally once daily with food in the morning

    Investigational medicinal product name
    Vedroprevir
    Investigational medicinal product code
    Other name
    GS-9451
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Vedroprevir (VDV) 200 mg (2 x 100 mg tablets) administered orally once daily with food in the morning

    Investigational medicinal product name
    Tegobuvir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Tegobuvir (TGV) 60 mg (2 x 30 mg capsules) administered orally with food once in the morning and once in the evening

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Copegus®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ribavirin (RBV) tablets administered orally in a divided daily dose according to package insert weight-based dosing recommendations (< 75 kg = 1000 mg and ≥ 75 kg = 1200 mg)

    Investigational medicinal product name
    Pegylated interferon
    Investigational medicinal product code
    Other name
    PEG
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pegylated interferon alfa-2a (PEG) 180 μg was administered once weekly by subcutaneous injection for participants receiving treatment in the Rescue Therapy Substudy.

    Arm title
    		 LDV+VDV+TGV
    Arm description
    		 Initial treatment: LDV+VDV+TGV+RBV placebo for 24 weeks. Participants who did not achieve a very rapid virologic response (vRVR, defined as HCV RNA < LLOQ at Week 2), had ontreatment virologic breakthrough, or relapse following initial treatment were eligible for treatment with LDV+VDV+PEG+RBV for an additional 24 to 48 weeks in the Rescue Therapy Substudy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ledipasvir
    Investigational medicinal product code
    Other name
    GS-5885
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ledipasvir (LDV) 90 mg (3 x 30 mg tablets) administered orally once daily with food in the morning

    Investigational medicinal product name
    Vedroprevir
    Investigational medicinal product code
    Other name
    GS-9451
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Vedroprevir (VDV) 200 mg (2 x 100 mg tablets) administered orally once daily with food in the morning

    Investigational medicinal product name
    Tegobuvir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Tegobuvir (TGV) 60 mg (2 x 30 mg capsules) administered orally with food once in the morning and once in the evening

    Investigational medicinal product name
    Ribavirin placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to match ribavirin tablets administered orally in a divided daily dose

    Investigational medicinal product name
    Pegylated interferon
    Investigational medicinal product code
    Other name
    PEG
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pegylated interferon alfa-2a (PEG) 180 μg was administered once weekly by subcutaneous injection for participants receiving treatment in the Rescue Therapy Substudy.

    Arm title
    		 LDV+VDV+RBV
    Arm description
    		 Initial Treatment: LDV+VDV+TGV placebo+RBV for 24 weeks. Participants who did not achieve a very rapid virologic response (vRVR, defined as HCV RNA < LLOQ at Week 2), had ontreatment virologic breakthrough, or relapse following initial treatment were eligible for treatment with LDV+VDV+PEG+RBV for an additional 24 to 48 weeks in the Rescue Therapy Substudy.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ledipasvir
    Investigational medicinal product code
    Other name
    GS-5885
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ledipasvir (LDV) 90 mg (3 x 30 mg tablets) administered orally once daily with food in the morning

    Investigational medicinal product name
    Vedroprevir
    Investigational medicinal product code
    Other name
    GS-9451
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Vedroprevir (VDV) 200 mg (2 x 100 mg tablets) administered orally once daily with food in the morning

    Investigational medicinal product name
    Tegobuvir placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to match tegobuvir capsules administered orally with food once in the morning and once in the evening

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Copegus®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ribavirin (RBV) tablets administered orally in a divided daily dose according to package insert weight-based dosing recommendations (< 75 kg = 1000 mg and ≥ 75 kg = 1200 mg)

    Investigational medicinal product name
    Pegylated interferon
    Investigational medicinal product code
    Other name
    PEG
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Pegylated interferon alfa-2a (PEG) 180 μg was administered once weekly by subcutaneous injection for participants receiving treatment in the Rescue Therapy Substudy.

    Number of subjects in period 1
    		LDV+VDV+TGV+RBV LDV+VDV+TGV LDV+VDV+RBV
    Started
    57
    56
    56
    Entered Rescue Therapy Substudy
    30 [1]
    36
    42
    Completed
    31
    25
    19
    Not completed
    26
    31
    37
         Physician decision
    2
    -
    3
         Adverse event, non-fatal
    2
    5
    5
         Protocol violation
    1
    -
    1
         Study terminated by sponsor
    -
    -
    2
         Lost to follow-up
    1
    1
    1
         Lack of efficacy
    19
    22
    19
         Withdrawal by subject
    1
    3
    6
    Notes
    [1] - 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: The overall number completed includes participants who completed the initial treatment and did not continue in the Rescue Therapy Substudy, and those who continued after initial treatment and completed the Rescue Therapy Substudy.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LDV+VDV+TGV+RBV
    Reporting group description
    		 Initial treatment: ledipasvir (LDV)+vedroprevir (VDV)+tegobuvir (TGV)+ribavirin (RBV) for 24 weeks. Participants who did not achieve a very rapid virologic response (vRVR, defined as HCV RNA < LLOQ at Week 2), had ontreatment virologic breakthrough, or relapse following initial treatment were eligible for treatment with LDV+VDV+PEG+RBV for an additional 24 to 48 weeks in the Rescue Therapy Substudy.

    Reporting group title
    LDV+VDV+TGV
    Reporting group description
    		 Initial treatment: LDV+VDV+TGV+RBV placebo for 24 weeks. Participants who did not achieve a very rapid virologic response (vRVR, defined as HCV RNA < LLOQ at Week 2), had ontreatment virologic breakthrough, or relapse following initial treatment were eligible for treatment with LDV+VDV+PEG+RBV for an additional 24 to 48 weeks in the Rescue Therapy Substudy.

    Reporting group title
    LDV+VDV+RBV
    Reporting group description
    		 Initial Treatment: LDV+VDV+TGV placebo+RBV for 24 weeks. Participants who did not achieve a very rapid virologic response (vRVR, defined as HCV RNA < LLOQ at Week 2), had ontreatment virologic breakthrough, or relapse following initial treatment were eligible for treatment with LDV+VDV+PEG+RBV for an additional 24 to 48 weeks in the Rescue Therapy Substudy.

    Reporting group values
    		 LDV+VDV+TGV+RBV LDV+VDV+TGV LDV+VDV+RBV Total
    Number of subjects
    		 57 56 56 169
    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)
    		 53 ± 8.8 54 ± 7.6 56 ± 8.5 -
    Gender categorical
    Units: Subjects
        Female
    		 16 19 24 59
        Male
    		 41 37 32 110
    Race
    Units: Subjects
        White
    		 46 45 51 142
        Black or African American
    		 9 9 4 22
        Asian
    		 0 1 1 2
        American Indian or Alaska Native
    		 0 1 0 1
        Not Permitted
    		 1 0 0 1
        Other
    		 1 0 0 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 4 5 5 14
        Not Hispanic or Latino
    		 53 51 51 155
    HCV Genotype
    Units: Subjects
        1a
    		 35 34 35 104
        1b
    		 22 22 21 65
    IL28B Status
    CC, CT, and TT alleles are different forms of the IL28b gene.
    Units: Subjects
        CC
    		 5 1 6 12
        CT
    		 38 40 39 117
        TT
    		 14 15 11 40
    HCV RNA
    Units: log10 IU/mL
        arithmetic mean (standard deviation)
    		 6.7 ± 0.45 6.5 ± 0.57 6.5 ± 0.51 -

    End points

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    End points reporting groups
    Reporting group title
    LDV+VDV+TGV+RBV
    Reporting group description
    		 Initial treatment: ledipasvir (LDV)+vedroprevir (VDV)+tegobuvir (TGV)+ribavirin (RBV) for 24 weeks. Participants who did not achieve a very rapid virologic response (vRVR, defined as HCV RNA < LLOQ at Week 2), had ontreatment virologic breakthrough, or relapse following initial treatment were eligible for treatment with LDV+VDV+PEG+RBV for an additional 24 to 48 weeks in the Rescue Therapy Substudy.

    Reporting group title
    LDV+VDV+TGV
    Reporting group description
    		 Initial treatment: LDV+VDV+TGV+RBV placebo for 24 weeks. Participants who did not achieve a very rapid virologic response (vRVR, defined as HCV RNA < LLOQ at Week 2), had ontreatment virologic breakthrough, or relapse following initial treatment were eligible for treatment with LDV+VDV+PEG+RBV for an additional 24 to 48 weeks in the Rescue Therapy Substudy.

    Reporting group title
    LDV+VDV+RBV
    Reporting group description
    		 Initial Treatment: LDV+VDV+TGV placebo+RBV for 24 weeks. Participants who did not achieve a very rapid virologic response (vRVR, defined as HCV RNA < LLOQ at Week 2), had ontreatment virologic breakthrough, or relapse following initial treatment were eligible for treatment with LDV+VDV+PEG+RBV for an additional 24 to 48 weeks in the Rescue Therapy Substudy.

    Subject analysis set title
    LDV+VDV+TGV+RBV - Main Study
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    LDV+VDV+TGV+RBV for 24 weeks

    Subject analysis set title
    LDV+VDV+TGV - Main Study
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    LDV+VDV+TGV+RBV placebo for 24 weeks

    Subject analysis set title
    LDV+VDV+RBV - Main Study
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    LDV+VDV+TGV placebo+RBV for 24 weeks

    Subject analysis set title
    LDV+VDV+TGV+RBV - Rescue Therapy Substudy
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Initial treatment: LDV+VDV+TGV+RBV for 24 weeks. Participants who did not achieve a very rapid virologic response (vRVR, defined as HCV RNA < LLOQ at Week 2), had ontreatment virologic breakthrough, or relapse following initial treatment were eligible for treatment with LDV+VDV+PEG+RBV for an additional 24 to 48 weeks in the Rescue Therapy Substudy.

    Subject analysis set title
    LDV+VDV+TGV - Rescue Therapy Substudy
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Initial treatment: LDV+VDV+TGV+RBV placebo for 24 weeks. Participants who did not achieve a very rapid virologic response (vRVR, defined as HCV RNA < LLOQ at Week 2), had ontreatment virologic breakthrough, or relapse following initial treatment were eligible for treatment with LDV+VDV+PEG+RBV for an additional 24 to 48 weeks in the Rescue Therapy Substudy.

    Subject analysis set title
    LDV+VDV+RBV - Rescue Therapy Substudy
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Initial treatment: LDV+VDV+TGV placebo+RBV for 24 weeks. Participants who did not achieve a very rapid virologic response (vRVR, defined as HCV RNA < LLOQ at Week 2), had ontreatment virologic breakthrough, or relapse following initial treatment were eligible for treatment with LDV+VDV+PEG+RBV for an additional 24 to 48 weeks in the Rescue Therapy Substudy.

    Primary: Percentage of participants with sustained virologic response (SVR) 24 weeks after discontinuation of therapy (SVR24)

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    End point title
    		 Percentage of participants with sustained virologic response (SVR) 24 weeks after discontinuation of therapy (SVR24) [1]
    End point description
    SVR24 was defined as HCV RNA < the lower limit of quantitation (LLOQ; ie, 25 IU/mL) 24 weeks following the last dose of study drug.
    End point type
    Primary
    End point timeframe
    Posttreatment Week 24
    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: No statistical hypothesis testing was planned or performed.
    End point values
    		 LDV+VDV+TGV+RBV - Main Study LDV+VDV+TGV - Main Study LDV+VDV+RBV - Main Study
    Number of subjects analysed
    57
    54
    55
    Units: percentage of participants
        number (not applicable)
    33.3
    22.2
    9.1
    No statistical analyses for this end point

    Primary: Percentage of participants who experienced an adverse event leading to permanent discontinuation from any study drug

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    End point title
    		 Percentage of participants who experienced an adverse event leading to permanent discontinuation from any study drug [2]
    End point description
    End point type
    Primary
    End point timeframe
    Up to 24 weeks
    Notes
    [2] - 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: No statistical hypothesis testing was planned or performed.
    End point values
    		 LDV+VDV+TGV+RBV - Main Study LDV+VDV+TGV - Main Study LDV+VDV+RBV - Main Study
    Number of subjects analysed
    57
    56
    56
    Units: percentage of participants
        number (not applicable)
    0
    7.1
    3.6
    No statistical analyses for this end point

    Secondary: Percentage of participants with SVR4 and SVR12

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    End point title
    		 Percentage of participants with SVR4 and SVR12
    End point description
    SVR4 and SVR12 were defined as HCV RNA < LLOQ at 4 and 12 weeks following the last dose of study drug, respectively.
    End point type
    Secondary
    End point timeframe
    Posttreatment Weeks 4 and 12
    End point values
    		 LDV+VDV+TGV+RBV - Main Study LDV+VDV+TGV - Main Study LDV+VDV+RBV - Main Study
    Number of subjects analysed
    57
    54
    55
    Units: percentage of participants
    number (not applicable)
        SVR4
    35.1
    24.1
    10.9
        SVR12
    33.3
    22.2
    9.1
    No statistical analyses for this end point

    Secondary: In the rescue therapy substudy, percentage of participants with SVR4, SVR12, and SVR24

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    End point title
    		 In the rescue therapy substudy, percentage of participants with SVR4, SVR12, and SVR24
    End point description
    SVR4, SVR12, and SVR24 were defined as HCV RNA < LLOQ at 4, 12, and 24 weeks following the last dose of study drug during the rescue therapy substudy, respectively. This endpoint only includes data from the Rescue Therapy Substudy Analysis Set.
    End point type
    Secondary
    End point timeframe
    Posttreatment Weeks 4, 12, and 24
    End point values
    		 LDV+VDV+TGV+RBV - Rescue Therapy Substudy LDV+VDV+TGV - Rescue Therapy Substudy LDV+VDV+RBV - Rescue Therapy Substudy
    Number of subjects analysed
    30
    36
    42
    Units: percentage of participants
    number (not applicable)
        SVR4
    40
    44.4
    40.5
        SVR12
    30
    36.1
    31
        SVR24
    30
    33.3
    31
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 24 weeks plus 30 days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16
    Reporting groups
    Reporting group title
    LDV+VDV+TGV+RBV
    Reporting group description
    		 Ledipasvir (LDV) + vedroprevir (VDV) + tegobuvir (TGV) + ribavirin (RBV) for 24 weeks

    Reporting group title
    LDV+VDV+TGV
    Reporting group description
    		 LDV+VDV+TGV+RBV placebo for 24 weeks

    Reporting group title
    LDV+VDV+RBV
    Reporting group description
    		 LDV+VDV+TGV placebo+RBV for 24 weeks

    Serious adverse events
    		 LDV+VDV+TGV+RBV LDV+VDV+TGV LDV+VDV+RBV
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 57 (1.75%)
    1 / 56 (1.79%)
    1 / 56 (1.79%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
    0 / 56 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Duodenal ulcer
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
    0 / 56 (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
    Duodenitis
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
    0 / 56 (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
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 57 (0.00%)
    0 / 56 (0.00%)
    1 / 56 (1.79%)
         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
    		 LDV+VDV+TGV+RBV LDV+VDV+TGV LDV+VDV+RBV
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 57 (75.44%)
    38 / 56 (67.86%)
    41 / 56 (73.21%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 57 (5.26%)
    0 / 56 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    3
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    15 / 57 (26.32%)
    12 / 56 (21.43%)
    13 / 56 (23.21%)
         occurrences all number
    19
    15
    15
    Dizziness
         subjects affected / exposed
    4 / 57 (7.02%)
    7 / 56 (12.50%)
    0 / 56 (0.00%)
         occurrences all number
    5
    7
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 56 (0.00%)
    4 / 56 (7.14%)
         occurrences all number
    2
    0
    4
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    20 / 57 (35.09%)
    13 / 56 (23.21%)
    15 / 56 (26.79%)
         occurrences all number
    20
    13
    15
    Irritability
         subjects affected / exposed
    2 / 57 (3.51%)
    3 / 56 (5.36%)
    4 / 56 (7.14%)
         occurrences all number
    2
    3
    4
    Asthenia
         subjects affected / exposed
    5 / 57 (8.77%)
    1 / 56 (1.79%)
    2 / 56 (3.57%)
         occurrences all number
    5
    1
    2
    Chills
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
    3 / 56 (5.36%)
         occurrences all number
    1
    0
    3
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    9 / 57 (15.79%)
    8 / 56 (14.29%)
    9 / 56 (16.07%)
         occurrences all number
    13
    8
    11
    Diarrhoea
         subjects affected / exposed
    8 / 57 (14.04%)
    3 / 56 (5.36%)
    3 / 56 (5.36%)
         occurrences all number
    9
    3
    3
    Dyspepsia
         subjects affected / exposed
    10 / 57 (17.54%)
    2 / 56 (3.57%)
    2 / 56 (3.57%)
         occurrences all number
    16
    2
    2
    Vomiting
         subjects affected / exposed
    4 / 57 (7.02%)
    0 / 56 (0.00%)
    3 / 56 (5.36%)
         occurrences all number
    5
    0
    3
    Constipation
         subjects affected / exposed
    1 / 57 (1.75%)
    2 / 56 (3.57%)
    3 / 56 (5.36%)
         occurrences all number
    1
    2
    3
    Dry mouth
         subjects affected / exposed
    2 / 57 (3.51%)
    0 / 56 (0.00%)
    3 / 56 (5.36%)
         occurrences all number
    2
    0
    3
    Flatulence
         subjects affected / exposed
    1 / 57 (1.75%)
    3 / 56 (5.36%)
    1 / 56 (1.79%)
         occurrences all number
    2
    3
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    7 / 57 (12.28%)
    2 / 56 (3.57%)
    11 / 56 (19.64%)
         occurrences all number
    8
    2
    11
    Dyspnoea
         subjects affected / exposed
    3 / 57 (5.26%)
    1 / 56 (1.79%)
    5 / 56 (8.93%)
         occurrences all number
    3
    1
    5
    Dyspnoea exertional
         subjects affected / exposed
    0 / 57 (0.00%)
    1 / 56 (1.79%)
    7 / 56 (12.50%)
         occurrences all number
    0
    1
    7
    Oropharyngeal pain
         subjects affected / exposed
    3 / 57 (5.26%)
    1 / 56 (1.79%)
    1 / 56 (1.79%)
         occurrences all number
    3
    1
    1
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    10 / 57 (17.54%)
    7 / 56 (12.50%)
    7 / 56 (12.50%)
         occurrences all number
    13
    7
    8
    Rash
         subjects affected / exposed
    5 / 57 (8.77%)
    3 / 56 (5.36%)
    4 / 56 (7.14%)
         occurrences all number
    6
    3
    4
    Dry skin
         subjects affected / exposed
    4 / 57 (7.02%)
    0 / 56 (0.00%)
    4 / 56 (7.14%)
         occurrences all number
    4
    0
    4
    Photosensitivity reaction
         subjects affected / exposed
    3 / 57 (5.26%)
    2 / 56 (3.57%)
    0 / 56 (0.00%)
         occurrences all number
    3
    2
    0
    Alopecia
         subjects affected / exposed
    3 / 57 (5.26%)
    0 / 56 (0.00%)
    0 / 56 (0.00%)
         occurrences all number
    3
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    4 / 57 (7.02%)
    3 / 56 (5.36%)
    2 / 56 (3.57%)
         occurrences all number
    4
    3
    2
    Anxiety
         subjects affected / exposed
    5 / 57 (8.77%)
    0 / 56 (0.00%)
    1 / 56 (1.79%)
         occurrences all number
    5
    0
    1
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    2 / 57 (3.51%)
    4 / 56 (7.14%)
    2 / 56 (3.57%)
         occurrences all number
    2
    4
    2
    Arthralgia
         subjects affected / exposed
    4 / 57 (7.02%)
    3 / 56 (5.36%)
    0 / 56 (0.00%)
         occurrences all number
    4
    3
    0
    Back pain
         subjects affected / exposed
    4 / 57 (7.02%)
    0 / 56 (0.00%)
    1 / 56 (1.79%)
         occurrences all number
    5
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 57 (0.00%)
    4 / 56 (7.14%)
    0 / 56 (0.00%)
         occurrences all number
    0
    4
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    7 / 57 (12.28%)
    4 / 56 (7.14%)
    0 / 56 (0.00%)
         occurrences all number
    8
    5
    0
    Oral herpes
         subjects affected / exposed
    1 / 57 (1.75%)
    0 / 56 (0.00%)
    3 / 56 (5.36%)
         occurrences all number
    2
    0
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 57 (3.51%)
    2 / 56 (3.57%)
    4 / 56 (7.14%)
         occurrences all number
    2
    2
    5

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Jul 2011
    The virologic breakthrough futility rule was revised based on FDA recommendation.
    15 Sep 2011
    Due to two cases of pancytopenia/aplastic anemia observed in subjects receiving tegobuvir plus a protease inhibitor plus PEG/RBV (in different studies), the decision was made to discontinue dosing of tegobuvir when given in combination with PEG/RBV and another oral antiviral. Therefore, tegobuvir was removed from the Rescue Therapy Substudy.
    11 Apr 2012
    On 26 March 2012, the Data Monitoring Committee (DMC) determined that the protocol-specified virologic breakthrough futility rule had been met for subjects with genotype 1a HCV infection in Arm 2 and Arm 3. Based on the DMC’s recommendations, the following changes were made: - study was unblinded and the treatment assignment for every subject was provided to the treating investigator - all genotype 1a subjects in Arms 2 and 3 was offered enrollment in the Rescue Therapy Substudy (GS-5885+GS-9451+PEG+RBV for 24-48 weeks). This instruction superseded any other references to eligibility for the Rescue Therapy Substudy.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    26 Mar 2012
    On 26 March 2012, the DMC determined that the protocol-specified virologic breakthrough futility rule had been met for subjects with genotype 1a HCV infection in Arm 2 and Arm 3. As the study completed enrollment in February 2012, the DMC’s recommendations was implemented as follows: - the study was unblinded and the treatment assignment for every subject was provided to the treating investigator - all genotype 1a subjects in Arms 2 and 3 was offered enrollment in the Rescue Therapy Substudy (LDV+VDV+PEG+RBV for 24-48 weeks). This instruction superseded any other references to eligibility for the Rescue Therapy Substudy.
    11 Apr 2012

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    There were no limitations affecting the analysis or results.
    For support, Contact us.
    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
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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