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    Clinical Trial Results:
    A Phase 2b, Open-Label Study of 200 mg or 400 mg Sofosbuvir+RBV for 24 Weeks in Genotype 1 or 3 and Ledipasvir/Sofosbuvir (LDV/SOF) Fixed-Dose Combination (FDC) Tablet for 12 weeks in Genotype 1 or 4 HCV-Infected Subjects with Renal Insufficiency

    Summary
    EudraCT number
    		 2013-002897-30
    Trial protocol
    		 DE   AT   NL  
    Global end of trial date
    19 Oct 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Aug 2018
    First version publication date
    23 Aug 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-334-0154
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01958281
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 DRKS00006432: German Clinical Trials Register
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com
    Scientific contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@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
    19 Oct 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Jul 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Oct 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this study were to evaluate the safety and efficacy of sofosbuvir (SOF) plus ribavirin (RBV) for 24 weeks and ledipasvir/sofosbuvir (LDV/SOF) for 12 weeks, and to evaluate the steady state pharmacokinetics (PK) of SOF and its metabolites and LDV in participants with genotype (GT) 1, 3, or 4 HCV infection who have chronic renal insufficiency (impaired kidney function).
    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
    07 Oct 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    New Zealand: 14
    Country: Number of subjects enrolled
    United States: 24
    Worldwide total number of subjects
    38
    EEA total number of subjects
    0
    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)
    30
    From 65 to 84 years
    8
    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 New Zealand. The first participant was screened on 07 October 2013. The last study visit occurred on 19 October 2017.

    Pre-assignment
    Screening details
    		 32 participants were screened for Cohorts 1 and 2 and 33 participants were screened for Cohort 3.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SOF 200 mg + RBV 200 mg (Cohort 1)
    Arm description
    		 Participants with genotype 1 or 3 HCV infection received SOF 200 mg + RBV for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sofosbuvir
    Investigational medicinal product code
    Other name
    Sovaldi®, SOF, GS-7977
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg tablet or 2 x 100 mg tablets administered once daily

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    RBV
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg administered once daily

    Arm title
    		 SOF 400 mg + RBV 200 mg (Cohort 2)
    Arm description
    		 Participants with genotype 1 or 3 HCV infection received SOF 400 mg + RBV for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sofosbuvir
    Investigational medicinal product code
    Other name
    Sovaldi®, SOF, GS-7977
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg tablet or 4 x 100 mg tablets administered once daily

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    RBV
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg administered once daily

    Arm title
    		 LDV/SOF (Cohort 3)
    Arm description
    		 Participants with genotype 1 HCV infection received LDV/SOF for 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ledipasvir/sofosbuvir
    Investigational medicinal product code
    Other name
    Harvoni®, LDV/SOF, GS-5885/GS-7977
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    90/400 mg fixed-dose combination (FDC) tablet administered once daily

    Number of subjects in period 1
    		SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2) LDV/SOF (Cohort 3)
    Started
    10
    10
    18
    Completed
    4
    6
    18
    Not completed
    6
    4
    0
         Withdrew Consent
    1
    -
    -
         Adverse event, non-fatal
    -
    2
    -
         Lack of efficacy
    5
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SOF 200 mg + RBV 200 mg (Cohort 1)
    Reporting group description
    		 Participants with genotype 1 or 3 HCV infection received SOF 200 mg + RBV for 24 weeks.

    Reporting group title
    SOF 400 mg + RBV 200 mg (Cohort 2)
    Reporting group description
    		 Participants with genotype 1 or 3 HCV infection received SOF 400 mg + RBV for 24 weeks.

    Reporting group title
    LDV/SOF (Cohort 3)
    Reporting group description
    		 Participants with genotype 1 HCV infection received LDV/SOF for 12 weeks.

    Reporting group values
    		 SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2) LDV/SOF (Cohort 3) Total
    Number of subjects
    		 10 10 18 38
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62 ( 6.5 ) 58 ( 9.0 ) 57 ( 7.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 4 2 12 18
        Male
    		 6 8 6 20
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 2 1 4 7
        Not Hispanic or Latino
    		 8 9 14 31
    Race
    Units: Subjects
        Black or African American
    		 5 4 10 19
        White
    		 2 5 8 15
        Asian
    		 1 0 0 1
        Hawaiian or Pacific Islander
    		 0 1 0 1
        Other
    		 2 0 0 2
    HCV genotype
    Units: Subjects
        Genotype 1a
    		 7 6 14 27
        Genotype 1b
    		 2 2 4 8
        Genotype 3a
    		 1 2 0 3
    IL28b Status
    The CC, CT, and TT alleles are different forms of the IL28b gene.
    Units: Subjects
        CC
    		 2 5 1 8
        CT
    		 6 4 11 21
        TT
    		 2 1 6 9
    HCV RNA Category
    Units: Subjects
        < 6 log10 IU/ mL
    		 3 4 5 12
        ≥ 6 log10 IU/ mL
    		 7 6 13 26
    HCV RNA (log10 IU/mL)
    Units: log10 IU/mL
        arithmetic mean (standard deviation)
    		 6.4 ( 0.47 ) 6.3 ( 0.50 ) 6.2 ( 0.54 ) -

    End points

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    End points reporting groups
    Reporting group title
    SOF 200 mg + RBV 200 mg (Cohort 1)
    Reporting group description
    		 Participants with genotype 1 or 3 HCV infection received SOF 200 mg + RBV for 24 weeks.

    Reporting group title
    SOF 400 mg + RBV 200 mg (Cohort 2)
    Reporting group description
    		 Participants with genotype 1 or 3 HCV infection received SOF 400 mg + RBV for 24 weeks.

    Reporting group title
    LDV/SOF (Cohort 3)
    Reporting group description
    		 Participants with genotype 1 HCV infection received LDV/SOF for 12 weeks.

    Primary: Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12)

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    End point title
    		 Percentage of Participants With Sustained Virologic Response (SVR) 12 Weeks After Discontinuation of Therapy (SVR12) [1]
    End point description
    SVR12 was defined as HCV RNA < the lower limit of quantitation (LLOQ; ie, 15 IU/mL) at 12 weeks after stopping study treatment. Participants in the Full Analysis Set (participants who were enrolled and took at least 1 dose of study drug) were analyzed.
    End point type
    Primary
    End point timeframe
    Posttreatment Week 12
    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 comparison was planned or performed.
    End point values
    		 SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2) LDV/SOF (Cohort 3)
    Number of subjects analysed
    10
    10
    18
    Units: percentage of participants
        number (confidence interval 95%)
    40.0 (12.2 to 73.8)
    60.0 (26.2 to 87.8)
    100.0 (81.5 to 100.0)
    No statistical analyses for this end point

    Primary: Percentage of Participants Experiencing Treatment-Emergent Adverse Events

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    End point title
    		 Percentage of Participants Experiencing Treatment-Emergent Adverse Events [2]
    End point description
    Participants in the Safety Analysis Set (participants who took at least 1 dose of study drug) were analyzed.
    End point type
    Primary
    End point timeframe
    Up to 24 weeks plus 30 days
    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 comparison was planned or performed.
    End point values
    		 SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2) LDV/SOF (Cohort 3)
    Number of subjects analysed
    10
    10
    18
    Units: percentage of participants
        number (not applicable)
    100.0
    90.0
    72.2
    No statistical analyses for this end point

    Primary: Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities

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    End point title
    		 Percentage of Participants Experiencing Treatment-Emergent Laboratory Abnormalities [3]
    End point description
    Treatment-emergent laboratory abnormalities were defined as values that increased by at least 1 toxicity grade from baseline at any time postbaseline up to the date of last dose of study drug plus 30 days. Participants in the Safety Analysis Set were analyzed.
    End point type
    Primary
    End point timeframe
    Up to 24 weeks plus 30 days
    Notes
    [3] - 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 comparison was planned or performed.
    End point values
    		 SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2) LDV/SOF (Cohort 3)
    Number of subjects analysed
    10
    10
    18
    Units: percentage of participants
        number (not applicable)
    100.0
    100.0
    100.0
    No statistical analyses for this end point

    Primary: Percentage of Participants Experiencing Clinically Significant 12-lead Electrocardiogram (ECG) Abnormalities

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    End point title
    		 Percentage of Participants Experiencing Clinically Significant 12-lead Electrocardiogram (ECG) Abnormalities [4]
    End point description
    Participant in the Safety Analysis Set were analyzed.
    End point type
    Primary
    End point timeframe
    Up to 24 weeks plus 30 days
    Notes
    [4] - 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 comparison was planned or performed.
    End point values
    		 SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2) LDV/SOF (Cohort 3)
    Number of subjects analysed
    10
    10
    18
    Units: percentage of participants
        number (not applicable)
    0
    0
    5.6
    No statistical analyses for this end point

    Primary: Percentage of Participants Experiencing Treatment-Emergent Adverse Events Associated with Vital Sign Abnormalities

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    End point title
    		 Percentage of Participants Experiencing Treatment-Emergent Adverse Events Associated with Vital Sign Abnormalities [5]
    End point description
    Participants in the Safety Analysis Set were analyzed.
    End point type
    Primary
    End point timeframe
    Up to 24 weeks plus 30 days
    Notes
    [5] - 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 comparison was planned or performed.
    End point values
    		 SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2) LDV/SOF (Cohort 3)
    Number of subjects analysed
    10
    10
    18
    Units: percentage of participants
        number (not applicable)
    10.0
    0
    0
    No statistical analyses for this end point

    Primary: PK Parameter: AUCtau of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2)

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    End point title
    		 PK Parameter: AUCtau of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2) [6] [7]
    End point description
    AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval). Participants in the PK Analysis Set (all enrolled participants who took at least 1 dose of study drug and have at least 1 nonmissing postdose PK concentration value) from Cohorts 1 and 2 with available data were analyzed.
    End point type
    Primary
    End point timeframe
    Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2
    Notes
    [6] - 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 comparison was planned or performed.
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Cohort 3 are presented as a separate endpoint because the time frames are different.
    End point values
    		 SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2)
    Number of subjects analysed
    10
    10
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        SOF (Cohort 1: N = 8; Cohort 2: N = 10)
    1093.9 ( 703.03 )
    1630.5 ( 851.33 )
        GS-566500 (Cohort 1: N = 10; Cohort 2: N = 10)
    2120.2 ( 837.51 )
    4026.2 ( 1848.50 )
        GS-331007 (Cohort 1: N = 10; Cohort 2: N = 10)
    31859.4 ( 12621.62 )
    51989.6 ( 29461.91 )
        RBV (Cohort 1: N = 10; Cohort 2: N = 10)
    22253.9 ( 6860.72 )
    23595.5 ( 9636.77 )
    No statistical analyses for this end point

    Primary: PK Parameter: AUCtau of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2)

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    End point title
    		 PK Parameter: AUCtau of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2) [8] [9]
    End point description
    AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval). Participants in the PK Analysis Set from Cohorts 1 and 2 with available data were analyzed.
    End point type
    Primary
    End point timeframe
    Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 12
    Notes
    [8] - 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 comparison was planned or performed.
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Cohort 3 are presented as a separate endpoint because the time frames are different.
    End point values
    		 SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2)
    Number of subjects analysed
    10
    8
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        SOF (Cohort 1: N = 9; Cohort 2: N = 8)
    1302.7 ( 652.18 )
    1571.3 ( 944.71 )
        GS-566500 (Cohort 1: N = 10; Cohort 2: N = 8)
    2223.2 ( 877.20 )
    3213.9 ( 1221.71 )
        GS-331007 (Cohort 1: N = 10; Cohort 2: N = 8)
    31078.3 ( 16745.94 )
    46810.1 ( 25249.07 )
        RBV (Cohort 1: N = 8; Cohort 2: N = 8)
    45341.9 ( 8712.71 )
    50471.2 ( 23077.43 )
    No statistical analyses for this end point

    Primary: PK Parameter: AUCtau of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3)

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    End point title
    		 PK Parameter: AUCtau of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3) [10] [11]
    End point description
    AUCtau is defined as concentration of drug over time (the area under the concentration verses time curve over the dosing interval). Participants in the PK Analysis Set from Cohort 3 with available data were analyzed.
    End point type
    Primary
    End point timeframe
    Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 or 4
    Notes
    [10] - 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 comparison was planned or performed.
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Cohorts 1 and 2 are presented as a separate endpoint because the time frames are different.
    End point values
    		 LDV/SOF (Cohort 3)
    Number of subjects analysed
    17
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        SOF
    3536.8 ( 2040.59 )
        GS-566500
    7716.6 ( 3534.76 )
        GS-331007
    71463.3 ( 28979.92 )
        LDV
    18460.1 ( 19999.95 )
    No statistical analyses for this end point

    Primary: PK Parameter: Cmax of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2)

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    End point title
    		 PK Parameter: Cmax of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2) [12] [13]
    End point description
    Cmax is defined as the maximum concentration of drug. Participants in the PK Analysis Set from Cohorts 1 and 2 were analyzed.
    End point type
    Primary
    End point timeframe
    Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2
    Notes
    [12] - 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 comparison was planned or performed.
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Cohort 3 are presented as a separate endpoint because the time frames are different.
    End point values
    		 SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2)
    Number of subjects analysed
    10
    10
    Units: ng/mL
    arithmetic mean (standard deviation)
        SOF
    575.9 ( 487.66 )
    976.8 ( 712.04 )
        GS-566500
    308.3 ( 132.60 )
    538.3 ( 241.51 )
        GS-331007
    1750.0 ( 578.56 )
    2721.4 ( 1452.86 )
        RBV
    1373.1 ( 496.37 )
    1373.8 ( 550.23 )
    No statistical analyses for this end point

    Primary: PK Parameter: Cmax of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2)

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    End point title
    		 PK Parameter: Cmax of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2) [14] [15]
    End point description
    Cmax is defined as the maximum concentration of drug. Participants in the PK Analysis Set from Cohorts 1 and 2 with available data were analyzed.
    End point type
    Primary
    End point timeframe
    Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 12
    Notes
    [14] - 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 comparison was planned or performed.
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Cohort 3 are presented as a separate endpoint because the time frames are different.
    End point values
    		 SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2)
    Number of subjects analysed
    10
    8
    Units: ng/mL
    arithmetic mean (standard deviation)
        SOF (Cohort 1: N = 10; Cohort 2: N = 8)
    903.9 ( 598.55 )
    1422.9 ( 1390.47 )
        GS-566500 (Cohort 1: N = 10; Cohort 2: N = 8)
    352.2 ( 127.83 )
    509.1 ( 216.71 )
        GS-331007 (Cohort 1: N = 10; Cohort 2: N = 8)
    1727.0 ( 775.37 )
    2645.0 ( 1482.10 )
        RBV (Cohort 1: N = 8; Cohort 2: N = 8)
    2458.8 ( 437.54 )
    2589.4 ( 1159.66 )
    No statistical analyses for this end point

    Primary: PK Parameter: Cmax of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3)

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    End point title
    		 PK Parameter: Cmax of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3) [16] [17]
    End point description
    Cmax is defined as the maximum concentration of drug. Participants in the PK Analysis Set from Cohort 3 with available data were analyzed.
    End point type
    Primary
    End point timeframe
    Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 or 4
    Notes
    [16] - 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 comparison was planned or performed.
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Cohorts 1 and 2 are presented as a separate endpoint because the time frames are different.
    End point values
    		 LDV/SOF (Cohort 3)
    Number of subjects analysed
    17
    Units: ng/mL
    arithmetic mean (standard deviation)
        SOF
    2018.1 ( 1110.56 )
        GS-566500
    1021.6 ( 359.13 )
        GS-331007
    3570.0 ( 1325.31 )
        LDV
    903.4 ( 844.70 )
    No statistical analyses for this end point

    Primary: PK Parameter: Ctau of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2)

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    End point title
    		 PK Parameter: Ctau of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2) [18] [19]
    End point description
    Ctau is defined as the observed drug concentration at the end of the dosing interval. Participants in the PK Analysis Set from Cohorts 1 and 2 were analyzed. PK data for SOF are not presented because all values were below the limit of quantitation.
    End point type
    Primary
    End point timeframe
    Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2
    Notes
    [18] - 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 comparison was planned or performed.
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Cohort 3 are presented as a separate endpoint because the time frames are different.
    End point values
    		 SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2)
    Number of subjects analysed
    10
    10
    Units: ng/mL
    arithmetic mean (standard deviation)
        GS-566500
    3.7 ( 7.88 )
    20.8 ( 20.51 )
        GS-331007
    1023.0 ( 477.15 )
    1736.1 ( 1110.41 )
        RBV
    759.1 ( 240.04 )
    818.8 ( 323.67 )
    No statistical analyses for this end point

    Primary: PK Parameter: Ctau of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2)

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    End point title
    		 PK Parameter: Ctau of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2) [20] [21]
    End point description
    Ctau is defined as the observed drug concentration at the end of the dosing interval. Participants in the PK Analysis Set from Cohorts 1 and 2 with available data were analyzed. PK data for SOF are not presented because all values were below the limit of quantitation.
    End point type
    Primary
    End point timeframe
    Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 12
    Notes
    [20] - 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 comparison was planned or performed.
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Cohort 3 are presented as a separate endpoint because the time frames are different.
    End point values
    		 SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2)
    Number of subjects analysed
    10
    9
    Units: ng/mL
    arithmetic mean (standard deviation)
        GS-566500 (Cohort 1: N = 10; Cohort 2: N = 9)
    2.3 ( 7.12 )
    10.4 ( 11.07 )
        GS-331007 (Cohort 1: N = 10; Cohort 2: N = 9)
    952.5 ( 586.51 )
    1356.0 ( 681.23 )
        RBV (Cohort 1: N = 10; Cohort 2: N = 9)
    1567.5 ( 529.35 )
    1968.6 ( 884.99 )
    No statistical analyses for this end point

    Primary: PK Parameter: Ctau of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3)

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    End point title
    		 PK Parameter: Ctau of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3) [22] [23]
    End point description
    Ctau is defined as the observed drug concentration at the end of the dosing interval. Participants in the PK Analysis Set from Cohort 3 with available data were analyzed.
    End point type
    Primary
    End point timeframe
    Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 or 4
    Notes
    [22] - 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 comparison was planned or performed.
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Cohorts 1 and 2 are presented as a separate endpoint because the time frames are different.
    End point values
    		 LDV/SOF (Cohort 3)
    Number of subjects analysed
    16
    Units: ng/mL
    arithmetic mean (standard deviation)
        SOF
    2.9 ( 1.57 )
        GS-566500
    59.3 ( 88.08 )
        GS-331007
    2568.2 ( 1106.81 )
        LDV
    705.0 ( 876.54 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With SVR at 4 Weeks After Discontinuation of Therapy (SVR4)

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    End point title
    		 Percentage of Participants With SVR at 4 Weeks After Discontinuation of Therapy (SVR4)
    End point description
    SVR4 was defined as HCV RNA < LLOQ at 4 weeks after stopping study treatment. Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Posttreatment Week 4
    End point values
    		 SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2) LDV/SOF (Cohort 3)
    Number of subjects analysed
    10
    10
    18
    Units: percentage of participants
        number (confidence interval 95%)
    40.0 (12.2 to 73.8)
    60.0 (26.2 to 87.8)
    100.0 (81.5 to 100.0)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With SVR at 24 Weeks After Discontinuation of Therapy (SVR24)

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    End point title
    		 Percentage of Participants With SVR at 24 Weeks After Discontinuation of Therapy (SVR24)
    End point description
    SVR4 was defined as HCV RNA < LLOQ at 24 weeks after stopping study treatment. Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Posttreatment Week 24
    End point values
    		 SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2) LDV/SOF (Cohort 3)
    Number of subjects analysed
    10
    10
    18
    Units: percentage of participants
        number (confidence interval 95%)
    40.0 (12.2 to 73.8)
    60.0 (26.2 to 87.8)
    100.0 (81.5 to 100.0)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Overall Virologic Failure

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    End point title
    		 Percentage of Participants With Overall Virologic Failure
    End point description
    Virologic failure was defined as: • On-treatment virologic failure: • Breakthrough (confirmed HCV RNA ≥ LLOQ after having previously had HCV RNA < LLOQ while on treatment), or • Rebound (confirmed > 1 log10 IU/mL increase in HCV RNA from nadir while on treatment), or • Non-response (HCV RNA persistently ≥ LLOQ through 8 weeks of treatment) • Virologic relapse: • Confirmed HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA < LLOQ at last on-treatment visit. Participants in the Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to Posttreatment Week 24
    End point values
    		 SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2) LDV/SOF (Cohort 3)
    Number of subjects analysed
    10
    10
    18
    Units: percentage of participants
        number (not applicable)
    50.0
    40.0
    0
    No statistical analyses for this end point

    Secondary: PK Parameter: AUClast of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2)

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    End point title
    		 PK Parameter: AUClast of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2) [24]
    End point description
    AUClast is defined as the concentration of drug from time zero to the last observable concentration. Participants in the PK Analysis Set from Cohorts 1 and 2 were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Cohort 3 are presented as a separate endpoint because the time frames are different.
    End point values
    		 SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2)
    Number of subjects analysed
    10
    10
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        SOF
    885.0 ( 710.72 )
    1607.7 ( 854.70 )
        GS-566500
    1973.3 ( 851.52 )
    3965.7 ( 1900.25 )
        GS-331007
    31859.4 ( 12621.62 )
    51989.6 ( 29461.91 )
        RBV
    22253.9 ( 6860.72 )
    23595.5 ( 9636.77 )
    No statistical analyses for this end point

    Secondary: PK Parameter: AUClast of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2)

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    End point title
    		 PK Parameter: AUClast of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2) [25]
    End point description
    AUClast is defined as the concentration of drug from time zero to the last observable concentration. Participants in the PK Analysis Set from Cohorts 1 and 2 with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 12
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Cohort 3 are presented as a separate endpoint because the time frames are different.
    End point values
    		 SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2)
    Number of subjects analysed
    10
    10
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        SOF (Cohort 1: N = 10; Cohort 2: N = 8)
    1177.7 ( 674.86 )
    1548.1 ( 955.12 )
        GS-566500 (Cohort 1: N = 10; Cohort 2: N = 8)
    1867.1 ( 839.39 )
    3133.0 ( 1230.39 )
        GS-331007 (Cohort 1: N = 10; Cohort 2: N = 8)
    31078.3 ( 16745.94 )
    46810.1 ( 25249.07 )
        RBV (Cohort 1: N = 10; Cohort 2: N = 10)
    45341.9 ( 8712.71 )
    50471.2 ( 23077.43 )
    No statistical analyses for this end point

    Secondary: PK Parameter: AUClast of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3)

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    End point title
    		 PK Parameter: AUClast of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3) [26]
    End point description
    AUClast is defined as the concentration of drug from time zero to the last observable concentration. Participants in the PK Analysis Set from Cohort 3 with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 or 4
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Cohorts 1 and 2 are presented as a separate endpoint because the time frames are different.
    End point values
    		 LDV/SOF (Cohort 3)
    Number of subjects analysed
    17
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        SOF
    3519.3 ( 2045.64 )
        GS-566500
    7657.6 ( 3555.57 )
        GS-331007
    69177.7 ( 31267.56 )
        LDV
    18044.3 ( 20210.19 )
    No statistical analyses for this end point

    Secondary: PK Parameter: Clast of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2)

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    End point title
    		 PK Parameter: Clast of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2) [27]
    End point description
    Clast is defined as the last observable concentration of drug. Participants in the PK Analysis Set from Cohorts 1 and 2 were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2
    Notes
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Cohort 3 are presented as a separate endpoint because the time frames are different.
    End point values
    		 SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2)
    Number of subjects analysed
    10
    10
    Units: ng/mL
    arithmetic mean (standard deviation)
        SOF
    68.0 ( 100.22 )
    21.3 ( 22.22 )
        GS-566500
    37.6 ( 18.84 )
    35.8 ( 21.06 )
        GS-331007
    1023.0 ( 477.15 )
    1736.1 ( 1110.41 )
        RBV
    759.1 ( 240.04 )
    818.8 ( 323.67 )
    No statistical analyses for this end point

    Secondary: PK Parameter: Clast of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2)

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    End point title
    		 PK Parameter: Clast of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2) [28]
    End point description
    Clast is defined as the last observable concentration of drug. Participants in the PK Analysis Set from Cohorts 1 and 2 with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 12
    Notes
    [28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Cohort 3 are presented as a separate endpoint because the time frames are different.
    End point values
    		 SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2)
    Number of subjects analysed
    10
    8
    Units: ng/mL
    arithmetic mean (standard deviation)
        SOF (Cohort 1: N = 10; Cohort 2: N = 8)
    100.7 ( 158.83 )
    22.7 ( 30.15 )
        GS-566500 (Cohort 1: N = 10; Cohort 2: N = 8)
    72.2 ( 80.16 )
    32.1 ( 22.04 )
        GS-331007 (Cohort 1: N = 10; Cohort 2: N = 8)
    952.5 ( 586.51 )
    1412.9 ( 705.06 )
        RBV (Cohort 1: N = 10; Cohort 2: N = 8)
    1741.3 ( 417.42 )
    2040.9 ( 917.23 )
    No statistical analyses for this end point

    Secondary: PK Parameter: Clast of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3)

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    End point title
    		 PK Parameter: Clast of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3) [29]
    End point description
    Clast is defined as the last observable concentration of drug. Participants in the PK Analysis Set from Cohort 3 with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 or 4
    Notes
    [29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Cohorts 1 and 2 are presented as a separate endpoint because the time frames are different.
    End point values
    		 LDV/SOF (Cohort 3)
    Number of subjects analysed
    17
    Units: ng/mL
    arithmetic mean (standard deviation)
        SOF
    56.3 ( 216.91 )
        GS-566500
    70.5 ( 97.14 )
        GS-331007
    2570.6 ( 1071.71 )
        LDV
    700.6 ( 848.90 )
    No statistical analyses for this end point

    Secondary: PK Parameter: Tmax of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2)

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    End point title
    		 PK Parameter: Tmax of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2) [30]
    End point description
    Tmax is defined as the time (observed time point) of Cmax. Participants in the PK Analysis Set from Cohorts 1 and 2 were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2
    Notes
    [30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Cohort 3 are presented as a separate endpoint because the time frames are different.
    End point values
    		 SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2)
    Number of subjects analysed
    10
    10
    Units: hours
    median (inter-quartile range (Q1-Q3))
        SOF
    1.00 (0.50 to 2.00)
    1.50 (1.00 to 2.13)
        GS-566500
    2.17 (2.00 to 3.97)
    4.00 (2.00 to 4.00)
        GS-331007
    4.00 (4.00 to 4.00)
    6.00 (4.00 to 6.00)
        RBV
    2.00 (1.00 to 2.00)
    2.00 (1.00 to 2.00)
    No statistical analyses for this end point

    Secondary: PK Parameter: Tmax of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2)

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    End point title
    		 PK Parameter: Tmax of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2) [31]
    End point description
    Tmax is defined as the time (observed time point) of Cmax. Participants in the PK Analysis Set from Cohorts 1 and 2 with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 12
    Notes
    [31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Cohort 3 are presented as a separate endpoint because the time frames are different.
    End point values
    		 SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2)
    Number of subjects analysed
    10
    8
    Units: hours
    median (inter-quartile range (Q1-Q3))
        SOF (Cohort 1: N = 10; Cohort 2: N = 8)
    1.04 (1.00 to 2.00)
    0.50 (0.50 to 1.50)
        GS-566500 (Cohort 1: N = 10; Cohort 2: N = 8)
    2.17 (1.93 to 4.00)
    2.00 (1.50 to 4.00)
        GS-331007 (Cohort 1: N = 10; Cohort 2: N = 8)
    5.11 (4.00 to 6.05)
    5.00 (4.00 to 6.00)
        RBV (Cohort 1: N = 8; Cohort 2: N = 8)
    2.00 (1.00 to 2.17)
    1.50 (1.00 to 3.00)
    No statistical analyses for this end point

    Secondary: PK Parameter: Tmax of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3)

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    End point title
    		 PK Parameter: Tmax of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3) [32]
    End point description
    Tmax is defined as the time (observed time point) of Cmax. Participants in the PK Analysis Set from Cohort 3 with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 or 4
    Notes
    [32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Cohorts 1 and 2 are presented as a separate endpoint because the time frames are different.
    End point values
    		 LDV/SOF (Cohort 3)
    Number of subjects analysed
    17
    Units: hours
    median (inter-quartile range (Q1-Q3))
        SOF
    1.00 (0.50 to 1.10)
        GS-566500
    2.00 (2.00 to 2.02)
        GS-331007
    4.02 (4.00 to 6.02)
        LDV
    6.00 (4.00 to 8.00)
    No statistical analyses for this end point

    Secondary: PK Parameter: Tlast of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2)

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    End point title
    		 PK Parameter: Tlast of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2) [33]
    End point description
    Tlast is defined as the time (observed time point) of Clast. Participants in the PK Analysis Set from Cohorts 1 and 2 were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2
    Notes
    [33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Cohort 3 are presented as a separate endpoint because the time frames are different.
    End point values
    		 SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2)
    Number of subjects analysed
    10
    10
    Units: hours
    median (inter-quartile range (Q1-Q3))
        SOF
    4.00 (3.92 to 4.13)
    6.00 (4.00 to 8.13)
        GS-566500
    12.00 (11.97 to 12.00)
    24.00 (12.00 to 24.00)
        GS-331007
    24.00 (24.00 to 24.00)
    24.00 (24.00 to 24.00)
        RBV
    24.00 (24.00 to 24.00)
    24.00 (24.00 to 24.00)
    No statistical analyses for this end point

    Secondary: PK Parameter: Tlast of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2)

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    End point title
    		 PK Parameter: Tlast of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2) [34]
    End point description
    Tlast is defined as the time (observed time point) of Clast. Participants in the PK Analysis Set from Cohorts 1 and 2 with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 12
    Notes
    [34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Cohort 3 are presented as a separate endpoint because the time frames are different.
    End point values
    		 SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2)
    Number of subjects analysed
    10
    8
    Units: hours
    median (inter-quartile range (Q1-Q3))
        SOF (Cohort 1: N = 10; Cohort 2: N = 8)
    4.00 (2.33 to 4.00)
    4.03 (4.00 to 6.00)
        GS-566500 (Cohort 1: N = 10; Cohort 2: N = 8)
    12.00 (10.00 to 12.02)
    24.00 (12.00 to 24.00)
        GS-331007 (Cohort 1: N = 10; Cohort 2: N = 8)
    24.00 (24.00 to 24.00)
    24.00 (24.00 to 24.00)
        RBV (Cohort 1: N = 8; Cohort 2: N = 8)
    24.00 (24.00 to 24.00)
    24.00 (24.00 to 24.00)
    No statistical analyses for this end point

    Secondary: PK Parameter: Tlast of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3)

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    End point title
    		 PK Parameter: Tlast of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3) [35]
    End point description
    Tlast is defined as the time (observed time point) of Clast. Participants in the PK Analysis Set from Cohort 3 with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 or 4 Analysis Population
    Notes
    [35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Cohorts 1 and 2 are presented as a separate endpoint because the time frames are different.
    End point values
    		 LDV/SOF (Cohort 3)
    Number of subjects analysed
    17
    Units: hours
    median (inter-quartile range (Q1-Q3))
        SOF
    12.00 (12.00 to 12.00)
        GS-566500
    24.00 (24.00 to 24.00)
        GS-331007
    24.00 (24.00 to 24.00)
        LDV
    24.00 (24.00 to 24.00)
    No statistical analyses for this end point

    Secondary: PK Parameter: λz of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2)

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    End point title
    		 PK Parameter: λz of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2) [36]
    End point description
    λz is defined as the terminal elimination rate constant, estimated by linear regression of the terminal elimination phase of the log plasma concentration of drug versus time curve of the drug. Participants in the PK Analysis Set from Cohorts 1 and 2 were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2
    Notes
    [36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Cohort 3 are presented as a separate endpoint because the time frames are different.
    End point values
    		 SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2)
    Number of subjects analysed
    10
    10
    Units: 1/hour
    arithmetic mean (standard deviation)
        SOF
    1.0419 ( 0.28621 )
    1.0155 ( 0.33118 )
        GS-566500
    0.2078 ( 0.04748 )
    0.1771 ( 0.05802 )
        GS-331007
    0.0275 ( 0.01331 )
    0.0273 ( 0.01711 )
        RBV
    0.0165 ( 0.00524 )
    0.0141 ( 0.00658 )
    No statistical analyses for this end point

    Secondary: PK Parameter: λz of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2)

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    End point title
    		 PK Parameter: λz of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2) [37]
    End point description
    λz is defined as the terminal elimination rate constant, estimated by linear regression of the terminal elimination phase of the log plasma concentration of drug versus time curve of the drug. Participants in the PK Analysis Set from Cohorts 1 and 2 with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 12
    Notes
    [37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Cohort 3 are presented as a separate endpoint because the time frames are different.
    End point values
    		 SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2)
    Number of subjects analysed
    10
    8
    Units: 1/hour
    arithmetic mean (standard deviation)
        SOF (Cohort 1: N = 9; Cohort 2: N = 8)
    1.4002 ( 0.29086 )
    1.2154 ( 0.24100 )
        GS-566500 (Cohort 1: N = 10; Cohort 2: N = 8)
    0.2232 ( 0.05244 )
    0.1818 ( 0.06121 )
        GS-331007 (Cohort 1: N = 10; Cohort 2: N = 8)
    0.0332 ( 0.01388 )
    0.0313 ( 0.02100 )
        RBV (Cohort 1: N = 8; Cohort 2: N = 8)
    0.0124 ( 0.00580 )
    0.0085 ( 0.02100 )
    No statistical analyses for this end point

    Secondary: PK Parameter: λz of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3)

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    End point title
    		 PK Parameter: λz of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3) [38]
    End point description
    λz is defined as the terminal elimination rate constant, estimated by linear regression of the terminal elimination phase of the log plasma concentration of drug versus time curve of the drug. Participants in the PK Analysis Set from Cohort 3 with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 or 4
    Notes
    [38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Cohorts 1 and 2 are presented as a separate endpoint because the time frames are different.
    End point values
    		 LDV/SOF (Cohort 3)
    Number of subjects analysed
    16
    Units: 1/hour
    arithmetic mean (standard deviation)
        SOF
    0.6033 ( 0.24057 )
        GS-566500
    0.1705 ( 0.04602 )
        GS-331007
    0.0214 ( 0.01222 )
        LDV
    0.0305 ( 0.01226 )
    No statistical analyses for this end point

    Secondary: PK Parameter: t1/2 of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2)

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    End point title
    		 PK Parameter: t1/2 of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 2 (Cohorts 1 and 2) [39]
    End point description
    t1/2 is defined as the estimate of the terminal elimination half-life of the drug. Participants in the PK Analysis Set from Cohorts 1 and 2 with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2
    Notes
    [39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Cohort 3 are presented as a separate endpoint because the time frames are different.
    End point values
    		 SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2)
    Number of subjects analysed
    10
    10
    Units: hours
    median (inter-quartile range (Q1-Q3))
        SOF (Cohort 1: N = 8; Cohort 2: N = 10)
    0.67 (0.59 to 0.75)
    0.67 (0.57 to 0.87)
        GS-566500 (Cohort 1: N = 10; Cohort 2: N = 10)
    3.31 (2.95 to 3.98)
    3.88 (3.17 to 4.44)
        GS-331007 (Cohort 1: N = 10; Cohort 2: N = 10)
    30.53 (19.14 to 43.25)
    29.05 (17.29 to 35.15)
        RBV (Cohort 1: N = 10; Cohort 2: N = 10)
    46.89 (41.03 to 47.87)
    56.43 (43.06 to 71.53)
    No statistical analyses for this end point

    Secondary: PK Parameter: t1/2 of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2)

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    End point title
    		 PK Parameter: t1/2 of SOF, Its Metabolites (GS-566500 and GS-331007), and RBV at Week 12 (Cohorts 1 and 2) [40]
    End point description
    t1/2 is defined as the estimate of the terminal elimination half-life of the drug. Participants in the PK Analysis Set from Cohorts 1 and 2 with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 12
    Notes
    [40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Cohort 3 are presented as a separate endpoint because the time frames are different.
    End point values
    		 SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2)
    Number of subjects analysed
    10
    8
    Units: hours
    median (inter-quartile range (Q1-Q3))
        SOF (Cohort 1: N = 9; Cohort 2: N = 8)
    0.48 (0.45 to 0.49)
    0.57 (0.48 to 0.67)
        GS-566500 (Cohort 1: N = 10; Cohort 2: N = 8)
    3.03 (2.72 to 3.96)
    3.88 (2.93 to 4.79)
        GS-331007 (Cohort 1: N = 10; Cohort 2: N = 8)
    22.03 (18.76 to 27.96)
    33.54 (13.61 to 45.15)
        RBV (Cohort 1: N = 8; Cohort 2: N = 8)
    61.25 (45.37 to 88.73)
    91.62 (54.00 to 171.91)
    No statistical analyses for this end point

    Secondary: PK Parameter: t1/2 of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3)

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    End point title
    		 PK Parameter: t1/2 of SOF, Its Metabolites (GS-566500 and GS-331007), and LDV at Week 2 or 4 (Cohort 3) [41]
    End point description
    t1/2 is defined as the estimate of the terminal elimination half-life of the drug. Participants in the PK Analysis Set from Cohort 3 with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Predose, 0.25, 0.5, 1, 2, 4, 6, 8, 10, and 12 hours postdose at Week 2 or 4
    Notes
    [41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data for Cohorts 1 and 2 are presented as a separate endpoint because the time frames are different.
    End point values
    		 LDV/SOF (Cohort 3)
    Number of subjects analysed
    16
    Units: hours
    median (inter-quartile range (Q1-Q3))
        SOF
    1.18 (1.11 to 1.47)
        GS-566500
    4.02 (3.57 to 4.68)
        GS-331007
    39.30 (30.38 to 54.89)
        LDV
    25.96 (18.25 to 31.89)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to end of treatment (Week 12 or Week 24) plus 30 days
    Adverse event reporting additional description
    Safety Analysis Set: participants who took at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    SOF 200 mg + RBV 200 mg (Cohort 1)
    Reporting group description
    		 Participants with genotype 1 or 3 HCV infection received SOF 200 mg + RBV for 24 weeks.

    Reporting group title
    SOF 400 mg + RBV 200 mg (Cohort 2)
    Reporting group description
    		 Participants with genotype 1 or 3 HCV infection received SOF 400 mg + RBV for 24 weeks.

    Reporting group title
    LDV/SOF (Cohort 3)
    Reporting group description
    		 Participants with genotype 1 HCV infection received LDV/SOF for 12 weeks.

    Serious adverse events
    		 SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2) LDV/SOF (Cohort 3)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 10 (20.00%)
    4 / 18 (22.22%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (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
    Syncope
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (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
    General disorders and administration site conditions
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Haematemesis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (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
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 18 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (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
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemic hyperosmolar nonketotic syndrome
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (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
    Hypoglycaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         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
    		 SOF 200 mg + RBV 200 mg (Cohort 1) SOF 400 mg + RBV 200 mg (Cohort 2) LDV/SOF (Cohort 3)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    9 / 10 (90.00%)
    12 / 18 (66.67%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Extranodal marginal zone B-cell lymphoma (MALT type)
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    Vascular disorders
    Hot flush
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    0
    1
    Hypertension
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
    4 / 18 (22.22%)
         occurrences all number
    1
    1
    4
    Chills
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Peripheral swelling
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Reproductive system and breast disorders
    Breast tenderness
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    1
    Cough
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    Dysphonia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Nasal congestion
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    Productive cough
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 10 (10.00%)
    1 / 18 (5.56%)
         occurrences all number
    2
    1
    1
    Irritability
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    0
    Anxiety
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    Depressed mood
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Tearfulness
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Weight decreased
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Injury, poisoning and procedural complications
    Muscle strain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Overdose
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Skin abrasion
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    0
    Hypertensive heart disease
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Palpitations
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 10 (40.00%)
    0 / 10 (0.00%)
    4 / 18 (22.22%)
         occurrences all number
    4
    0
    6
    Dizziness
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 10 (20.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    2
    1
    Hypoaesthesia
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    0
    Lethargy
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    1
    0
    Hyperaesthesia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 10 (30.00%)
    3 / 10 (30.00%)
    0 / 18 (0.00%)
         occurrences all number
    3
    3
    0
    Haemolytic anaemia
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
    2 / 18 (11.11%)
         occurrences all number
    1
    1
    2
    Diarrhoea
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    1
    2
    Constipation
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    0
    1
    Nausea
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    0
    2
    Abdominal distension
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Abdominal pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Abdominal wall haematoma
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Breath odour
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Dyspepsia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    Retching
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    2
    Swollen tongue
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    Toothache
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    0
    Rash pruritic
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    0
    Dry skin
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Eczema
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Pruritus
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Rash erythematous
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Rash generalised
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Rash papular
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Skin lesion
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    Nocturia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Renal failure
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
    2 / 18 (11.11%)
         occurrences all number
    1
    1
    2
    Arthralgia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    1
    Muscle spasms
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    2
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    0
    1
    Joint swelling
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    2
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    1
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    1
    Ear infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Eczema infected
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Herpes virus infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Influenza
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1
    Laryngitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Pharyngitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    0 / 18 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 10 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    1
    0
    2
    Hyperkalaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    3 / 18 (16.67%)
         occurrences all number
    0
    0
    3
    Gout
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 10 (10.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    2
    Hypoglycaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 10 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Sep 2013
    ● The study design was changed from a randomized study to reflect a 2-part step-wise design to allow a full review of safety, efficacy, and PK data through posttreatment Week 4 of both doses of SOF (200 mg or 400 mg) + RBV in subjects with creatinine clearance < 30 mL/min before proceeding to the cohort of subjects on dialysis. ● The assay to assess the HCV RNA levels was changed to the COBAS® AmpliPrep/COBAS® TaqMan® HCV Quantitative Test, v2.0. ● Additional echocardiogram assessments and cardiac parameters were added to the study procedures, inclusion/exclusion criteria, treatment discontinuation criteria, medical history requirements, safety procedures, and stopping rules for toxicity. ● Inclusion Criterion 5h was updated to clarify the creatinine clearance laboratory parameter values allowed for inclusion in the study. ● Hematologic stimulating agents were added to the concomitant medications list as prohibited medications.
    20 Feb 2014
    ● Exclusion criteria for electrocardiograms (ECG) were updated to reflect the QTcF interval ● The RBV dosage and administration was modified to allow the investigator to modify the dose of RBV if he/she felt it was medically necessary ● An external Data Monitoring Committee (DMC) was added to this protocol to review the progress of the study and evaluate the safety, efficacy, and PK data ● Exclusion Criterion 8d was updated to include clarification on cardiac exclusion criteria: subjects with significant cardiac disease resulting in pulmonary hypertension within 1 year of screening were excluded from the study ● Clarification of when echocardiograms in Part B will be performed ● Updated safety language for the reporting of adverse events (AEs) and serious adverse events (SAEs).
    23 Feb 2015
    ● Removed Part 2 dose group scheduled to receive SOF+RBV for 24 weeks in HCV-infected subjects on dialysis. Added Cohort 3 to include subjects with genotype 1 or 4 HCV infection with severe renal impairment (estimated glomerular filtration rate [eGFR] calculated using the Cockcroft-Gault equation < 30 mL/min) to receive LDV/SOF (90/400 mg) for 12 weeks. ● Updated the approximate number of planned subjects from 40 to 30
    23 Apr 2015
    ● Amiodarone was moved to the “Agents Disallowed” list based on risk of symptomatic bradycardia with coadministration of amiodarone with LDV/SOF. Postmarketing cases of symptomatic bradycardia have been reported in patients receiving amiodarone who were coadministered Harvoni (LDV/SOF). ● For Cohort 3, increased the number of enrolled subjects to 15 subjects to obtain 10 evaluable subjects. ● Updated the approximate number of planned subjects to approximately 35 from 30 ● The grading scale for severity of AEs and laboratory abnormalities was updated.

    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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