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    Clinical Trial Results:
    A Phase 2, Multicenter, Open-Label, Randomized Study to Investigate the Safety and Efficacy of GS-7977 and Ribavirin Administered for 48 Weeks in Patients Infected With Chronic HCV With Cirrhosis and Portal Hypertension With or Without Liver Decompensation

    Summary
    EudraCT number
    		 2012-002457-29
    Trial protocol
    		 ES  
    Global end of trial date
    06 Oct 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Aug 2016
    First version publication date
    21 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-334-0125
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01687257
    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
    06 Oct 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Oct 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the antiviral efficacy of combination therapy with sofosbuvir (SOF) + ribavirin (RBV) for 48 weeks in compensated and decompensated subjects with chronic hepatitis C virus (HCV) infection, as measured by sustained virologic response (SVR) 12 weeks after discontinuation of therapy (SVR12 defined as HCV RNA < the lower limit of quantitation [LLOQ] 12 weeks posttreatment).
    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
    27 Nov 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    New Zealand: 6
    Country: Number of subjects enrolled
    United States: 22
    Country: Number of subjects enrolled
    Australia: 5
    Worldwide total number of subjects
    50
    EEA total number of subjects
    17
    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)
    45
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in the United States, Europe, Australia, and New Zealand. The first participant was screened on 27 November 2012. The last study visit occurred on 06 October 2015.

    Pre-assignment
    Screening details
    		 63 participants were screened.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SOF+RBV (Group 1)
    Arm description
    		 SOF+RBV for up to 48 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sofosbuvir
    Investigational medicinal product code
    Other name
    Sovaldi®, GS-7977
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sofosbuvir (SOF) 400 mg once daily

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ribavirin (RBV) tablets administered in a divided daily dose based on weight (< 75 kg = 1000 mg and ≥ 75 kg = 1200 mg)

    Arm title
    		 Observation/SOF+RBV (Group 2; Received Treatment)
    Arm description
    		 Participants completed 24 weeks of observation and then received SOF+RBV for up to 48 weeks.
    Arm type
    		 Experimental

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

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    RBV tablets administered in a divided daily dose based on weight (< 75 kg = 1000 mg and ≥ 75 kg = 1200 mg)

    Number of subjects in period 1 [1]
    		SOF+RBV (Group 1) Observation/SOF+RBV (Group 2; Received Treatment)
    Started
    25
    21
    Completed
    17
    15
    Not completed
    8
    6
         Subject Withdrew Consent
    1
    1
         Adverse event, non-fatal
    1
    -
         Efficacy Failure
    6
    5
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 4 subjects who were randomized to the Observation/SOF+RBV group discontinued study during the Observation period prior to receiving study drug and are not included in the Subject Disposition. Reasons for discontinuation were as follows: Subject Withdrew Consent (N = 1) and Investigator's Discretion (N = 3).

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SOF+RBV (Group 1)
    Reporting group description
    		 SOF+RBV for up to 48 weeks

    Reporting group title
    Observation/SOF+RBV (Group 2; Received Treatment)
    Reporting group description
    		 Participants completed 24 weeks of observation and then received SOF+RBV for up to 48 weeks.

    Reporting group values
    		 SOF+RBV (Group 1) Observation/SOF+RBV (Group 2; Received Treatment) Total
    Number of subjects
    		 25 21 46
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55 ( 7.2 ) 56 ( 7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 7 5 12
        Male
    		 18 16 34
    Race
    Units: Subjects
        Black or African American
    		 1 1 2
        White
    		 22 20 42
        Asian
    		 1 0 1
        Other
    		 1 0 1
    HCV Genotype
    Units: Subjects
        Genotype 1a
    		 10 8 18
        Genotype 1b
    		 9 5 14
        Genotype 2a/2c
    		 1 0 1
        Genotype 2b
    		 1 1 2
        Genotype 3a
    		 2 6 8
        Genotype 4
    		 1 1 2
        Genotype 4h
    		 1 0 1
    IL28b Status
    CC, CT, and TT alleles are different forms of the IL28b gene.
    Units: Subjects
        CC
    		 3 6 9
        CT
    		 14 10 24
        TT
    		 8 5 13
    HCV RNA Category
    Units: Subjects
        < 800,000 IU/mL
    		 10 5 15
        ≥ 800,000 IU/mL
    		 15 16 31
    Child-Pugh-Turcotte (CPT) Score Category
    CPT scores, widely used to grade the severity of cirrhosis and to determine the need for liver transplantation, are calculated based on a combination of laboratory values and clinical features. CPT scores can range from 5 to 15, with higher scores indicating a greater severity of disease.
    Units: Subjects
        CPT A (5-6)
    		 8 10 18
        CPT B (7-10)
    		 17 11 28
    Model for End-Stage Liver Disease (MELD) Score
    MELD scores, used to assess prognosis and suitability for transplant, are calculated based on laboratory values only and can range from 6 to 40, with higher scores indicating greater disease severity.
    Units: Subjects
        MELD Score 6
    		 1 2 3
        MELD Score 7
    		 0 3 3
        MELD Score 8
    		 5 2 7
        MELD Score 9
    		 3 1 4
        MELD Score 10
    		 5 4 9
        MELD Score 11
    		 0 4 4
        MELD Score 12
    		 4 1 5
        MELD Score 13
    		 2 1 3
        MELD Score 15
    		 3 3 6
        MELD Score 16
    		 2 0 2
    HCV RNA
    Units: log10 IU/mL
        arithmetic mean (standard deviation)
    		 6.1 ( 0.49 ) 6.2 ( 0.79 ) -
    Hepatic Venous Pressure Gradient (HVPG)
    Units: mmHg
        arithmetic mean (standard deviation)
    		 17.4 ( 4.7 ) 16.4 ( 4.88 ) -

    End points

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    End points reporting groups
    Reporting group title
    SOF+RBV (Group 1)
    Reporting group description
    		 SOF+RBV for up to 48 weeks

    Reporting group title
    Observation/SOF+RBV (Group 2; Received Treatment)
    Reporting group description
    		 Participants completed 24 weeks of observation and then received SOF+RBV for up to 48 weeks.

    Subject analysis set title
    Observation Period (Group 2)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    24 weeks of observation

    Subject analysis set title
    All SOF+RBV (Groups 1 and 2)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    This group includes participants who received SOF+RBV for up to 48 weeks in both Groups 1 and 2.

    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, 25 IU/mL) at 12 weeks after stopping study treatment. For the Observation/SOF+RBV group, SVR12 during the observational period was defined as HCV RNA < LLOQ for 12 consecutive weeks, any time during the observational period. Participants who were randomized to the study were analyzed.
    End point type
    Primary
    End point timeframe
    Posttreatment Week 12 (SOF+RBV) and up to 24 weeks (Observation)
    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+RBV (Group 1) Observation/SOF+RBV (Group 2; Received Treatment) Observation Period (Group 2)
    Number of subjects analysed
    25
    21
    25
    Units: percentage of participants
        number (not applicable)
    72
    71.4
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants With SVR at 4, 24, and 48 Weeks After Discontinuation of Therapy (SVR4, SVR24, and SVR48)

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    End point title
    		 Percentage of Participants With SVR at 4, 24, and 48 Weeks After Discontinuation of Therapy (SVR4, SVR24, and SVR48)
    End point description
    SVR4, SVR24, and SVR48 were defined as HCV RNA < LLOQ at 4, 24, and 48 weeks after stopping study treatment, respectively. Participants who were randomized and received at least 1 dose of study drug with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Posttreatment Weeks 4, 24, and 48
    End point values
    		 SOF+RBV (Group 1) Observation/SOF+RBV (Group 2; Received Treatment)
    Number of subjects analysed
    25
    21
    Units: percentage of participants
    number (not applicable)
        SVR4 (Group 1: N = 25; Group 2: N = 21)
    72
    76.2
        SVR24 (Group 1: N = 25; Group 2: N = 21)
    68
    71.4
        SVR48 (Group 1: N = 17; Group 2: N = 13)
    94.1
    100
    No statistical analyses for this end point

    Secondary: Percentage of Participants Experiencing On-Treatment Virologic Failure

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    End point title
    		 Percentage of Participants Experiencing On-Treatment Virologic Failure
    End point description
    On-treatment virologic failure was defined as: • 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). Participants who were randomized and received at least 1 dose of study drug were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 48 weeks
    End point values
    		 SOF+RBV (Group 1) Observation/SOF+RBV (Group 2; Received Treatment)
    Number of subjects analysed
    25
    21
    Units: percentage of participants
        number (not applicable)
    8
    0
    No statistical analyses for this end point

    Secondary: Percentage of Participants Experiencing Viral Relapse

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    End point title
    		 Percentage of Participants Experiencing Viral Relapse
    End point description
    Viral relapse was defined as HCV RNA ≥ LLOQ during the post-treatment period having achieved HCV RNA < LLOQ at end of treatment, confirmed with 2 consecutive values or last available post-treatment measurement. Participants who were randomized and received at least 1 dose of study drug with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to Posttreatment Week 24
    End point values
    		 SOF+RBV (Group 1) Observation/SOF+RBV (Group 2; Received Treatment)
    Number of subjects analysed
    23
    21
    Units: percentage of participants
        number (not applicable)
    17.4
    23.8
    No statistical analyses for this end point

    Secondary: Change From Baseline in Hepatic Venous Pressure Gradient (HVPG) at End of Treatment

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    End point title
    		 Change From Baseline in Hepatic Venous Pressure Gradient (HVPG) at End of Treatment
    End point description
    HVPG closely reflects the degree of portal hypertension in patients with cirrhosis. The end of treatment for the Observation group was defined as the end of the observation period. Baseline values were the last available values on or prior to first dose date of any study drug. Participants who were randomized to the study with available data at baseline and end of observation or end of treatment were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24 (Observation) and Week 48 (SOF+RBV)
    End point values
    		 SOF+RBV (Group 1) Observation/SOF+RBV (Group 2; Received Treatment) Observation Period (Group 2) All SOF+RBV (Groups 1 and 2)
    Number of subjects analysed
    19
    18
    21
    37
    Units: mmHg
        arithmetic mean (standard deviation)
    -1.6 ( 4.9 )
    -0.4 ( 2.69 )
    0.5 ( 2.52 )
    -1 ( 3.97 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Child-Pugh-Turcotte (CPT) Score

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    End point title
    		 Change From Baseline in Child-Pugh-Turcotte (CPT) Score
    End point description
    CPT scores, widely used to grade the severity of cirrhosis and to determine the need for liver transplantation, are calculated based on a combination of laboratory values and clinical features. CPT scores can range from 5 to 15, with higher scores indicating a greater severity of disease. Data are presented as improvement, no change, or worsening in CPT scores at Week 24 (Observation) and Posttreatment Week 4 (SOF+RBV groups). Improvement in CPT score was defined as having a decrease in CPT score from baseline, no change in CPT score was defined as having no change in CPT score from baseline, and worsening in CPT score was defined as having an increase in CPT score from baseline. Baseline values were the last available values on or prior to first dose date of any study drug. Participants who were randomized to the study with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24 (Observation) and Posttreatment Week 4 (SOF+RBV)
    End point values
    		 SOF+RBV (Group 1) Observation/SOF+RBV (Group 2; Received Treatment) Observation Period (Group 2) All SOF+RBV (Groups 1 and 2)
    Number of subjects analysed
    23
    18
    20
    41
    Units: percentage of participants
    number (not applicable)
        Improvement in CPT Score
    65.2
    38.9
    10
    53.7
        No Change in CPT Score
    26.1
    50
    75
    36.6
        Worsening in CPT Score
    8.7
    11.1
    15
    9.8
    No statistical analyses for this end point

    Secondary: Change From Baseline in Model for End Stage Liver Disease (MELD) Scores

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    End point title
    		 Change From Baseline in Model for End Stage Liver Disease (MELD) Scores
    End point description
    MELD scores, used to assess prognosis and suitability for transplant, are calculated based on laboratory values only and can range from 6 to 40, with higher scores indicating greater disease severity. Data are presented as improvement, no change, or worsening in MELD scores at Week 24 (Observation) and Posttreatment Week 4 (SOF+RBV groups). Improvement in MELD score was defined as having a baseline MELD score of 11-15 or 16-20 that changed to 0-10, or a baseline MELD score of 16-20 that changed to 11-15; no change in MELD score was defined as having no change in score group (0-10, 11-15, or 16-20) from baseline; and worsening in MELD score was defined as having a baseline MELD score of 0-10 that changed to 11-15 or 16-20, or a baseline MELD score of 11-15 that changed to 16-20. Baseline values were the last available values on or prior to first dose date of any study drug. Participants who were randomized to the study with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24 (Observation) and Posttreatment Week 4 (SOF+RBV)
    End point values
    		 SOF+RBV (Group 1) Observation/SOF+RBV (Group 2; Received Treatment) Observation Period (Group 2) All SOF+RBV (Groups 1 and 2)
    Number of subjects analysed
    24
    17
    20
    41
    Units: percentage of participants
    number (not applicable)
        Improvement in MELD Score
    33.3
    5.9
    20
    22
        No Change in MELD Score
    54.2
    88.2
    75
    68.3
        Worsening in MELD Score
    12.5
    5.9
    5
    9.8
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 48 weeks plus 30 days
    Adverse event reporting additional description
    Adverse event data includes all participants who were randomized to the study.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    SOF+RBV (Group 1)
    Reporting group description
    		 SOF+RBV for up to 48 weeks

    Reporting group title
    Observation Period Only (Group 2)
    Reporting group description
    		 This reporting group includes participants who were randomized to the Observation/SOF+RBV group and received up to 24 weeks of observation.

    Reporting group title
    SOF+RBV Treatment Only (Group 2)
    Reporting group description
    		 This reporting group includes participants who completed observation and received SOF+RBV for up to 48 weeks.

    Serious adverse events
    		 SOF+RBV (Group 1) Observation Period Only (Group 2) SOF+RBV Treatment Only (Group 2)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 25 (16.00%)
    3 / 25 (12.00%)
    6 / 21 (28.57%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 25 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatic cancer
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 25 (4.00%)
    0 / 21 (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
    Injury, poisoning and procedural complications
    Femur fracture
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 25 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Eye swelling
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 25 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Oesophageal varices haemorrhage
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 25 (4.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 25 (4.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 25 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rash
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 25 (0.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Drug abuse
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    1 / 21 (4.76%)
         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+RBV (Group 1) Observation Period Only (Group 2) SOF+RBV Treatment Only (Group 2)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 25 (92.00%)
    10 / 25 (40.00%)
    20 / 21 (95.24%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    0
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 25 (4.00%)
    7 / 21 (33.33%)
         occurrences all number
    2
    1
    14
    Dizziness
         subjects affected / exposed
    4 / 25 (16.00%)
    0 / 25 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    4
    0
    3
    Hepatic encephalopathy
         subjects affected / exposed
    2 / 25 (8.00%)
    3 / 25 (12.00%)
    2 / 21 (9.52%)
         occurrences all number
    3
    3
    2
    Disturbance in attention
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 25 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Encephalopathy
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    2
    Memory impairment
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 25 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Restless legs syndrome
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    2
    Syncope
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 25 (0.00%)
    5 / 21 (23.81%)
         occurrences all number
    2
    0
    5
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    6 / 25 (24.00%)
    1 / 25 (4.00%)
    9 / 21 (42.86%)
         occurrences all number
    7
    1
    10
    Asthenia
         subjects affected / exposed
    7 / 25 (28.00%)
    0 / 25 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    9
    0
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 25 (0.00%)
    3 / 25 (12.00%)
    5 / 21 (23.81%)
         occurrences all number
    0
    3
    5
    Pyrexia
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 25 (4.00%)
    4 / 21 (19.05%)
         occurrences all number
    4
    1
    7
    Peripheral swelling
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 25 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    9 / 25 (36.00%)
    1 / 25 (4.00%)
    6 / 21 (28.57%)
         occurrences all number
    11
    1
    6
    Diarrhoea
         subjects affected / exposed
    3 / 25 (12.00%)
    1 / 25 (4.00%)
    6 / 21 (28.57%)
         occurrences all number
    3
    1
    7
    Abdominal pain upper
         subjects affected / exposed
    3 / 25 (12.00%)
    0 / 25 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    3
    0
    2
    Abdominal pain
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 25 (4.00%)
    4 / 21 (19.05%)
         occurrences all number
    0
    1
    7
    Ascites
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 25 (4.00%)
    2 / 21 (9.52%)
         occurrences all number
    2
    1
    2
    Vomiting
         subjects affected / exposed
    3 / 25 (12.00%)
    1 / 25 (4.00%)
    1 / 21 (4.76%)
         occurrences all number
    3
    1
    1
    Constipation
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    0
    0
    4
    Dyspepsia
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 25 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    2
    0
    1
    Melaena
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    3
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 25 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    4 / 25 (16.00%)
    0 / 25 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    4
    0
    3
    Dyspnoea
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 25 (4.00%)
    2 / 21 (9.52%)
         occurrences all number
    3
    1
    2
    Epistaxis
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 25 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 25 (0.00%)
    0 / 25 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    0
    2
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    8 / 25 (32.00%)
    1 / 25 (4.00%)
    3 / 21 (14.29%)
         occurrences all number
    9
    1
    3
    Rash
         subjects affected / exposed
    6 / 25 (24.00%)
    3 / 25 (12.00%)
    0 / 21 (0.00%)
         occurrences all number
    8
    3
    0
    Dry skin
         subjects affected / exposed
    3 / 25 (12.00%)
    0 / 25 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    3
    0
    2
    Alopecia
         subjects affected / exposed
    2 / 25 (8.00%)
    1 / 25 (4.00%)
    1 / 21 (4.76%)
         occurrences all number
    2
    1
    1
    Skin ulcer
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 25 (4.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    1
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    6 / 25 (24.00%)
    0 / 25 (0.00%)
    7 / 21 (33.33%)
         occurrences all number
    7
    0
    7
    Anxiety
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 25 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    1
    0
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 25 (0.00%)
    3 / 21 (14.29%)
         occurrences all number
    1
    0
    3
    Back pain
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 25 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    3
    0
    1
    Muscle spasms
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    2
    Musculoskeletal pain
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 25 (0.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 25 (12.00%)
    0 / 25 (0.00%)
    4 / 21 (19.05%)
         occurrences all number
    3
    0
    4
    Influenza
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 25 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    1
    0
    2
    Urinary tract infection
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 25 (4.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    1
    3
    Gastroenteritis viral
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 25 (8.00%)
    0 / 21 (0.00%)
         occurrences all number
    0
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Aug 2012
    • Update of background, safety, and concomitant medication data • Modification of subject stopping rules pertaining to alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) and bilirubin • Modification of inclusion criteria relating to birth control • Addition of exclusion criteria for bilirubin and imaging evidence or history of portal vein thrombosis • Addition of erythropoiesis-stimulating agents • Addition of guidance surrounding HVPG measurements • Clarification of self-monitoring of pregnancy
    21 Feb 2013
    • Extension of SOF+RBV treatment from 24 to 48 weeks for both treatment groups • Clarification that HPVG measurements were to be taken at screening and Week 48 for subjects in the SOF+RBV group, and at screening and Weeks 24 and 72 for subjects in the Observation/SOF+RBV group • Update of MELD definition
    04 Jun 2013
    • Addition of laboratory assessments associated with collection of CPT score during the posttreatment follow-up period • Addition of MELD score to all posttreatment follow-up visits • Clarification on collection of pharmacokinetic (PK) sample draw times • Clarification on the posttreatment follow-up period for subjects who terminate study treatment early
    02 May 2014
    • Incorporation of additional monitoring for subjects with elevated total bilirubin and an additional stopping criterion for subjects with elevated direct bilirubin, based on recommendations of the safety review committee
    04 Mar 2015
    • Addition of an HVPG measurement at the posttreatment Week 48 visit for subjects who achieved SVR12 to determine the effect of SVR on HVPG

    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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