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    Clinical Trial Results:
    Stratified Treatment OPtimisation for HCV-1 (STOPHCV-1)

    Summary
    EudraCT number
    		 2015-005004-28
    Trial protocol
    		 GB  
    Global end of trial date
    04 Apr 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Feb 2020
    First version publication date
    14 Feb 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    15SM3025
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Imperial College London
    Sponsor organisation address
    London, London, United Kingdom,
    Public contact
    Helen Ainscough, MRC CTU at UCL, Institute of Clinical Trials and Methodology, +44 020 7670 4652,
    Scientific contact
    Helen Ainscough, MRC CTU at UCL, Institute of Clinical Trials and Methodology, +44 020 7670 4652,
    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
    15 Apr 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Apr 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Apr 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    1)To evaluate if short course HCV first line treatment (duration based on the viral load in the blood) followed by 12 weeks re-treatment of those failing therapy is non-inferior to a fixed duration of 8 weeks first line treatment followed by 12 weeks re-treatment of those failing therapy, looking at overall HCV cure in patients with minimal fibrosis and chronic HCV (type 1 and 4) infection. 2)To test the benefits and risks of adding adjunctive ribavirin with 4-8 weeks first line therapy.
    Protection of trial subjects
    Retreatment was offered to all participants who failed on first-line treatment
    Background therapy
    		 All participants took DAAs: either ombitasvir/paritaprevir/dasabuvir/ritonavir for genotype 1a or 1b participants, ombitasvir/paritaprevir/ritonavir for genotype 4 participants or glecaprevir/pibrentasvir for any genotype participants. All participants on retreatment took sofosbuvir/ledipasvir and ribavirin.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Feb 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 204
    Worldwide total number of subjects
    204
    EEA total number of subjects
    204
    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)
    197
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment was open from 15th March 2016 to 31st August 2018 in 15 sites within the UK. The first participant was recruited on 18th March 2016 and the last on 28th August 2018. 14 sites recruited at least one participant.

    Pre-assignment
    Screening details
    		 Eligibility criteria include aged 18 years or older, infected with HCV 1a or 1b or 4 for at least 6 months, no significant liver fibrosis, HCV VL <10,000,000 IU/ml, no previous DAA exposure for current infection, BMI 18 kg/m2 or higher. If HIV co-infected, HIV VL <50 copies/ml for >24 weeks.

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

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Variable duration
    Arm description
    		 Participants randomised to receive variable duration treatment - the length of treatment is the intervention being tested
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ombitasvir/paritaprevir/ritonavir
    Investigational medicinal product code
    Other name
    Viekirax
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 4-7 weeks of treatment based on screening HCV viral load. Two tablets (12.5/75/50mg) to be taken once daily (total daily dose: 25/150/100mg). For all participants who are not taking glecaprevir/pibrentasvir.

    Investigational medicinal product name
    Dasabuvir
    Investigational medicinal product code
    Other name
    Exviera
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 4-7 weeks of treatment based on screening HCV viral load. One 250mg tablet twice daily (total daily dosage: 500mg). Taken only by 1a and 1b participants who are also taking ombitasvir/paritaprevir/ritonavir

    Investigational medicinal product name
    Glecaprevir/pibrentasvir
    Investigational medicinal product code
    Other name
    Maviret
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 4-7 weeks of treatment based on screening HCV viral load. Three tablets (100/40mg) taken once a day (total daily dose 300/120mg). Taken by all participants who are not taking ombitasvir/paritaprevir/ritonavir/(dasabuvir).

    Arm title
    		 Fixed duration
    Arm description
    		 Participants randomised to receive fixed duration treatment
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ombitasvir/paritaprevir/ritonavir
    Investigational medicinal product code
    Other name
    Viekirax
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 8 weeks of treatment. Two tablets (12.5/75/50mg) to be taken once daily (total daily dose: 25/150/100mg). For all participants who are not taking glecaprevir/pibrentasvir.

    Investigational medicinal product name
    Dasabuvir
    Investigational medicinal product code
    Other name
    Exviera
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 8 weeks of treatment. One 250mg tablet twice daily (total daily dosage: 500mg). Taken only by 1a and 1b participants who are also taking ombitasvir/paritaprevir/ritonavir

    Investigational medicinal product name
    Glecaprevir/pibrentasvir
    Investigational medicinal product code
    Other name
    Maviret
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 8 weeks of treatment. Three tablets (100/40mg) taken once a day (total daily dose 300/120mg). Taken by all participants who are not taking ombitasvir/paritaprevir/ritonavir/(dasabuvir).

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    For those randomised to ribavirin or those receiving retreatment, to be taken alongside DAAs. To be taken twice daily, dosing depending on weight and to be lowered in the case of AEs. For first-line treatment, 8 weeks. For retreatment, 12 weeks.

    Investigational medicinal product name
    Sofosbuvir/ledipasvir
    Investigational medicinal product code
    Other name
    Harvoni
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants receiving retreatment only. One 400/90mg tablet to be taken once day for 12 weeks.

    Arm title
    		 Ribavirin
    Arm description
    		 Participants randomised to receive ribavirin
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All participants on first-line and those receiving retreatment, to be taken alongside DAAs. To be taken twice daily, dosing depending on weight and to be lowered in the case of AEs. For first-line treatment, 4-7 or 8 weeks depending on duration randomisation allocation and screening HCV VL. For retreatment, 12 weeks.

    Arm title
    		 No ribavirin
    Arm description
    		 Participants randomised to receive no ribavirin
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Variable duration Fixed duration Ribavirin No ribavirin
    Started
    102
    102
    101
    103
    Completed
    95
    93
    92
    96
    Not completed
    7
    9
    9
    7
         Consent withdrawn by subject
    1
    -
    -
    1
         Lost to follow-up
    4
    9
    8
    5
         Randomised in error
    2
    -
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Two participants were randomised in error and withdrawn from the study before receiving study medication. As per the statistical analysis plan they have not been included in any analysis, including of the baseline characteristics
    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 202 202
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 45.5 (37.5 to 53.0) -
    Gender categorical
    Units: Subjects
        Female
    		 62 62
        Male
    		 140 140
    Ethnicity
    Units: Subjects
        White
    		 176 176
        South Asian
    		 1 1
        South East Asian
    		 2 2
        Hispanic/Latino
    		 9 9
        Black Caribbean/American
    		 3 3
        Black African
    		 2 2
        Mixed ethnic group
    		 1 1
        Other
    		 8 8
    HCV genotype/subgenotype
    Units: Subjects
        G1a
    		 166 166
        G1b
    		 34 34
        G4
    		 2 2
    HIV coinfected
    Units: Subjects
        Yes
    		 68 68
        No
    		 134 134
    IL28b genotype
    Units: Subjects
        CC
    		 60 60
        CT
    		 106 106
        TT
    		 27 27
        No result
    		 9 9
    Resistance associated substitution to any prescribed first-line drug
    Units: Subjects
        Yes
    		 27 27
        No
    		 161 161
        Unknown
    		 14 14
    Ever spontaneously cleared and re-infected
    Units: Subjects
        Yes
    		 6 6
        No
    		 196 196
    Ever successfully treated and re-infected
    Units: Subjects
        Yes
    		 10 10
        No
    		 192 192
    Previously unsuccessfully treated with interferon
    Units: Subjects
        Yes
    		 24 24
        No
    		 178 178
    Current/recent alcoholism/alcohol abuse
    Units: Subjects
        Yes
    		 13 13
        No
    		 189 189
    Current/recent illicit substance abuse
    Units: Subjects
        Yes
    		 64 64
        No
    		 138 138
    Mode of HCV infection: no known risk factor
    Units: Subjects
        Yes
    		 18 18
        No
    		 179 179
        Not recorded
    		 5 5
    Mode of HCV infection: injecting drug use
    Units: Subjects
        Yes
    		 99 99
        No
    		 101 101
        Not recorded
    		 2 2
    Mode of HCV infection: blood/blood products
    Units: Subjects
        Yes
    		 11 11
        No
    		 186 186
        Not recorded
    		 5 5
    Mode of HCV infection: perinatal exposure
    Units: Subjects
        Yes
    		 4 4
        No
    		 193 193
        Not recorded
    		 5 5
    Mode of HCV infection: known HCV positive sexual partner
    Units: Subjects
        Yes
    		 21 21
        No
    		 176 176
        Not recorded
    		 5 5
    Mode of HCV infection: born abroad
    Units: Subjects
        Yes
    		 27 27
        No
    		 170 170
        Not recorded
    		 5 5
    Mode of HCV infection: high risk sexual partner
    Units: Subjects
        Yes
    		 71 71
        No
    		 130 130
        Not recorded
    		 1 1
    Mode of HCV infection: tattoo
    Units: Subjects
        Yes
    		 27 27
        No
    		 170 170
        Not recorded
    		 5 5
    Mode of HCV infection: healthcare exposure
    Units: Subjects
        Yes
    		 19 19
        No
    		 178 178
        Not recorded
    		 5 5
    Mode of HCV infection: other
    Units: Subjects
        Yes
    		 20 20
        No
    		 176 176
        Not recorded
    		 6 6
    BMI
    Units: kg/m^2
        median (inter-quartile range (Q1-Q3))
    		 24.9 (22.2 to 27.2) -
    Screening HCV viral load
    Units: IU/ml
        median (inter-quartile range (Q1-Q3))
    		 711423 (218776 to 1995262) -
    Enrolment HCV viral load
    Units: IU/ml
        median (inter-quartile range (Q1-Q3))
    		 741946 (249097 to 1872136) -
    Fibroscan result
    Units: kPa
        median (inter-quartile range (Q1-Q3))
    		 4.9 (4.2 to 5.8) -
    Haemoglobin
    Units: g/dl
        median (inter-quartile range (Q1-Q3))
    		 14.7 (14.0 to 15.6) -
    ALT
    Units: IU/ml
        median (inter-quartile range (Q1-Q3))
    		 52 (34 to 87) -
    AST
    Units: IU/ml
        median (inter-quartile range (Q1-Q3))
    		 38 (30 to 57) -
    ALP
    Units: IU/ml
        median (inter-quartile range (Q1-Q3))
    		 72 (59 to 91) -
    eGFR
    Units: ml/min
        median (inter-quartile range (Q1-Q3))
    		 109 (93 to 131) -
    Bilirubin
    Units: umol/l
        median (inter-quartile range (Q1-Q3))
    		 9 (6 to 12) -

    End points

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    End points reporting groups
    Reporting group title
    Variable duration
    Reporting group description
    		 Participants randomised to receive variable duration treatment - the length of treatment is the intervention being tested

    Reporting group title
    Fixed duration
    Reporting group description
    		 Participants randomised to receive fixed duration treatment

    Reporting group title
    Ribavirin
    Reporting group description
    		 Participants randomised to receive ribavirin

    Reporting group title
    No ribavirin
    Reporting group description
    		 Participants randomised to receive no ribavirin

    Subject analysis set title
    Per-protocol: variable duration group
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Defined as those receiving >90% and <110% of the prescribed duration of first-line treatment based on prescription and temporary/permanent discontinuation, and where the difference between screening and enrolment HCV RNA values would have led to a difference of ≤2 days in allocated duration of DAAs had they been allocated to the varying duration group.

    Subject analysis set title
    Per-protocol: fixed duration group
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Defined as those receiving >90% and <110% of the prescribed duration of first-line treatment based on prescription and temporary/permanent discontinuation, and where the difference between screening and enrolment HCV RNA values would have led to a difference of ≤2 days in allocated duration of DAAs had they been allocated to the varying duration group.

    Subject analysis set title
    All missing outcomes are failures: variable duration group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants with missing data for SVR12 are considered as failing and not achieving SVR12 (sensitivity analysis, worst case scenario)

    Subject analysis set title
    All missing outcomes are failures: fixed duration group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants with missing SVR12 data are considered as failed and not achieving SVR12 (sensitivity analysis, worst case scenario)

    Subject analysis set title
    All missing outcomes are cures: variable duration group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants with missing SVR12 are considered as acheiving SVR12 (sensitivity analysis, best case scenario)

    Subject analysis set title
    All missing outcomes are cures: fixed duration group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants with missing SVR12 data are considered as achieving SVR12 (sensitivity analysis, best case scenario)

    Subject analysis set title
    Received VUS1: variable duration group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants randomised before 1st April 2007 and receiving treatment that ranged between 4-6 weeks.

    Subject analysis set title
    Received VUS1: fixed duration group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants randomised before 1st April 2007 and would have received treatment that ranged between 4-6 weeks if randomised to variable duration

    Subject analysis set title
    Received VUS2: variable duration group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants randomised after 1st April 2007 and receiving treatment that ranged between 4-7 weeks.

    Subject analysis set title
    Received VUS2: fixed duration group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Participants randomised after 1st April 2007 and would have received treatment that ranged between 4-7 weeks if randomised to variable duration group.

    Subject analysis set title
    Per-protocol: ribavirin group
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Defined as those receiving >90% and <110% of the prescribed duration of first-line treatment based on prescription and temporary/permanent discontinuation, and where the difference between screening and enrolment HCV RNA values would have led to a difference of ≤2 days in allocated duration of DAAs had they been allocated to the varying duration group.

    Subject analysis set title
    Per-protocol: no ribavirin group
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Defined as those receiving >90% and <110% of the prescribed duration of first-line treatment based on prescription and temporary/permanent discontinuation, and where the difference between screening and enrolment HCV RNA values would have led to a difference of ≤2 days in allocated duration of DAAs had they been allocated to the varying duration group.

    Subject analysis set title
    All missing outcomes are failures: ribavirin group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants with missing SVR12 outcomes are considered as failing and not achieving SVR12 (sensitivity analysis, worst case scenario)

    Subject analysis set title
    All missing outcomes are failures: no ribavirin group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants with missing SVR12 outcomes are considered as failing and not achieving SVR12 (sensitivity analysis, worst case scenario)

    Subject analysis set title
    All missing outcomes are cures: ribavirin group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants with missing SVR12 outcomes are considered as cures and achieving SVR12 (sensitivity analysis, best case scenario)

    Subject analysis set title
    All missing outcomes are cures: no ribavirin group
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All participants with missing SVR12 outcomes are considered as cures and achieving SVR12 (sensitivity analysis, best case scenario)

    Primary: SVR12 after first-line or retreatment (duration comparison)

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    End point title
    		 SVR12 after first-line or retreatment (duration comparison) [1]
    End point description
    End point type
    Primary
    End point timeframe
    12 weeks after first-line or any retreatment
    Notes
    [1] - 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: SVR12 after first-line and retreatment is a primary outcome for the duration comparison but a secondary outcome for the ribavirin comparison. The outcome has been split for the two comparisons to reflect this
    End point values
    		 Variable duration Fixed duration Per-protocol: variable duration group Per-protocol: fixed duration group All missing outcomes are failures: variable duration group All missing outcomes are failures: fixed duration group All missing outcomes are cures: variable duration group All missing outcomes are cures: fixed duration group
    Number of subjects analysed
    97
    100
    69
    71
    100
    102
    100
    102
    Units: participants
    97
    100
    69
    71
    97
    100
    100
    102
    Statistical analysis title
    		 Primary analysis: risk difference between groups
    Comparison groups
    Variable duration v Fixed duration
    Number of subjects included in analysis
    197
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.038
         upper limit
    		 0.037
    Notes
    [2] - 4% non-inferiority margin
    Statistical analysis title
    		 Per-protocol: risk difference between groups
    Statistical analysis description
    Difference between groups limited to the per-protocol population
    Comparison groups
    Per-protocol: variable duration group v Per-protocol: fixed duration group
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.05
    Notes
    [3] - 4% non-inferiority margin
    Statistical analysis title
    		 All missing=failures: difference between groups
    Statistical analysis description
    Difference between groups assuming all participants with missing SVR12 failed treatment
    Comparison groups
    All missing outcomes are failures: variable duration group v All missing outcomes are failures: fixed duration group
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    P-value
    		 = 0.64
    Method
    		 Regression, binomial with identity link
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.03
    Notes
    [4] - 4% non-inferiority margin
    Statistical analysis title
    		 All missing=cured: difference between groups
    Statistical analysis description
    Difference between groups assuming all participants with missing SVR12 data achieved SVR12
    Comparison groups
    All missing outcomes are cures: fixed duration group v All missing outcomes are cures: variable duration group
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [5]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.037
         upper limit
    		 0.036
    Notes
    [5] - 4% non-inferiority margin

    Primary: SVR12 after first-line only (ribavirin comparison)

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    End point title
    		 SVR12 after first-line only (ribavirin comparison) [6]
    End point description
    End point type
    Primary
    End point timeframe
    12 weeks after only first-line treatment only
    Notes
    [6] - 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: SVR12 after first-line only is a primary outcome for the ribavirin comparison but a secondary outcome for the duration comparison. The outcome has been split for the two comparisons to reflect this
    End point values
    		 Ribavirin No ribavirin Per-protocol: ribavirin group Per-protocol: no ribavirin group All missing outcomes are failures: ribavirin group All missing outcomes are failures: no ribavirin group All missing outcomes are cures: ribavirin group All missing outcomes are cures: no ribavirin group
    Number of subjects analysed
    98
    101
    66
    74
    100
    102
    100
    102
    Units: participants
    69
    70
    48
    50
    69
    70
    71
    71
    Attachments
    		 Forest plot of subgroup analysis: ribavirin
    Suppressed VL by visit and VUS: ribavirin
    Statistical analysis title
    		 Primary analysis: risk difference between groups
    Comparison groups
    No ribavirin v Ribavirin
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.48
    Method
    		 Regression, binomial with identity link
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 0.06
    Statistical analysis title
    		 Per-protocol: difference between groups
    Statistical analysis description
    Difference between groups limited to the per-protocol population
    Comparison groups
    Per-protocol: ribavirin group v Per-protocol: no ribavirin group
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.93
    Method
    		 Regression, binomial with identity link
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.11
         upper limit
    		 0.1
    Statistical analysis title
    		 All missing=failures: difference between groups
    Statistical analysis description
    Difference between groups assuming all participants with missing SVR12 data failed treatment
    Comparison groups
    All missing outcomes are failures: ribavirin group v All missing outcomes are failures: no ribavirin group
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.37
    Method
    		 Regression, binomial with identity link
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.14
         upper limit
    		 0.05
    Statistical analysis title
    		 All missing=cured: difference between groups
    Statistical analysis description
    Difference between groups assuming all participants with missing SVR12 data achieved SVR12
    Comparison groups
    All missing outcomes are cures: no ribavirin group v All missing outcomes are cures: ribavirin group
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.48
    Method
    		 Regression, binomial with identity link
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.03
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.12
         upper limit
    		 0.06
    Statistical analysis title
    		 Suppressed viral load by visit
    Comparison groups
    Ribavirin v No ribavirin
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.82 [7]
    Method
    		 Regression, binomial GEE
    Confidence interval
    Notes
    [7] - Global p-value is comparing ribavirin vs no ribavirin (VUS combined). Time point p-values (chi-squared or Fisher exact): D3 p=0.33, D7 p=0.54, D14 p=0.57, D28 p=0.26, D42 p=0.74, EOT p=0.30, EOT+4 p=0.30, EOT+8 p=0.63, EOT+12 p=0.83, EOT+24 p=0.71

    Secondary: SVR12 after first-line only (duration comparison)

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    End point title
    		 SVR12 after first-line only (duration comparison) [8]
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks after only first-line treatment
    Notes
    [8] - 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: SVR12 after first-line only is a primary outcome for the ribavirin comparison but a secondary outcome for the duration comparison. The outcome has been split for the two comparisons to reflect this
    End point values
    		 Variable duration Fixed duration Per-protocol: variable duration group Per-protocol: fixed duration group All missing outcomes are failures: variable duration group All missing outcomes are failures: fixed duration group All missing outcomes are cures: variable duration group All missing outcomes are cures: fixed duration group Received VUS1: variable duration group Received VUS1: fixed duration group Received VUS2: variable duration group Received VUS2: fixed duration group
    Number of subjects analysed
    98
    101
    69
    71
    100
    102
    100
    102
    66
    67
    32
    34
    Units: participants
    47
    92
    32
    66
    47
    92
    49
    93
    24
    62
    23
    30
    Attachments
    		 SVR by visit first suppressed
    Forest plot of subgroup analysis: duration
    Suppressed VL by visit: duration
    Statistical analysis title
    		 Primary analysis: difference between groups
    Comparison groups
    Fixed duration v Variable duration
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [9]
    P-value
    		 < 0.001
    Method
    		 Regression, binomial with identity link
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.54
         upper limit
    		 -0.32
    Notes
    [9] - 4% non-inferiority margin Estimate is an average over both DAA strategies and taken from a model which includes an interaction between randomisation and DAA strategy (p=0.001).
    Statistical analysis title
    		 VUS1: difference between groups
    Statistical analysis description
    Difference between groups limited to participants randomised before 1st April 2017, when variable duration participants received between 4-6 weeks of treatment.
    Comparison groups
    Received VUS1: fixed duration group v Received VUS1: variable duration group
    Number of subjects included in analysis
    133
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority [10]
    P-value
    		 < 0.001
    Method
    		 Regression, binomial with identity link
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.69
         upper limit
    		 -0.43
    Notes
    [10] - 4% non-inferiority margin
    Statistical analysis title
    		 VUS2: difference between groups
    Statistical analysis description
    Difference between groups limited to participants randomised after 1st April 2017 when variable duration participants received 4-7 weeks of treatment
    Comparison groups
    Received VUS2: fixed duration group v Received VUS2: variable duration group
    Number of subjects included in analysis
    66
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority [11]
    P-value
    		 = 0.09
    Method
    		 Regression, binomial with identity link
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.35
         upper limit
    		 0.03
    Notes
    [11] - 4% non-inferiority margin
    Statistical analysis title
    		 Per-protocol: difference between groups
    Statistical analysis description
    Difference between groups limited to the per-protocol population
    Comparison groups
    Per-protocol: variable duration group v Per-protocol: fixed duration group
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [12]
    P-value
    		 < 0.001
    Method
    		 Regression, binomial with identity link
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.59
         upper limit
    		 -0.33
    Notes
    [12] - 4% non-inferiority margin Estimate is an average over both DAA strategies and taken from a model which includes an interaction between randomisation and DAA strategy (p=0.07).
    Statistical analysis title
    		 All missing=failures: difference between groups
    Statistical analysis description
    Difference between groups assuming all participants with missing SVR12 data failed treatment
    Comparison groups
    All missing outcomes are failures: variable duration group v All missing outcomes are failures: fixed duration group
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [13]
    P-value
    		 < 0.001
    Method
    		 Regression, binomial with identity link
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.54
         upper limit
    		 -0.32
    Notes
    [13] - 4% non-inferiority margin Estimate is an average over both DAA strategies and taken from a model which includes an interaction between randomisation and DAA strategy (p=0.001).
    Statistical analysis title
    		 All missing=cured: difference between groups
    Statistical analysis description
    Difference between groups assuming all participants with missing SVR12 data achieved SVR12
    Comparison groups
    All missing outcomes are cures: fixed duration group v All missing outcomes are cures: variable duration group
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [14]
    P-value
    		 < 0.001
    Method
    		 Regression, binomial with identity link
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.53
         upper limit
    		 -0.31
    Notes
    [14] - 4% non-inferiority margin Estimate is an average over both DAA strategies and taken from a model which includes an interaction between randomisation and DAA strategy (p=0.001).
    Statistical analysis title
    		 Suppressed VL by visit
    Comparison groups
    Variable duration v Fixed duration
    Number of subjects included in analysis
    199
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.001 [15]
    Method
    		 Regression, binomial GEE
    Confidence interval
    Notes
    [15] - Global p-value comparing variable duration vs fixed duration. p-values at each of the visits (chi-squared or Fisher exact): D3 p=0.53, D7 p=0.69, D14 p=0.39, D28 p=0.08, EOT p=0.28, EOT+4 p<0.001, EOT+8 p<0.001 EOT+12 p<0.001, EOT+24 p<0.001.

    Secondary: SVR12 after first-line and retreatment (ribavirin comparison)

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    End point title
    		 SVR12 after first-line and retreatment (ribavirin comparison) [16]
    End point description
    End point type
    Secondary
    End point timeframe
    12 weeks after first-line and any retreatment
    Notes
    [16] - 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: SVR12 after first-line and retreatment is a primary outcome for the duration comparison but a secondary outcome for the ribavirin comparison. The outcome has been split for the two comparisons to reflect this
    End point values
    		 Ribavirin No ribavirin Per-protocol: ribavirin group Per-protocol: no ribavirin group All missing outcomes are failures: ribavirin group All missing outcomes are failures: no ribavirin group All missing outcomes are cures: ribavirin group All missing outcomes are cures: no ribavirin group
    Number of subjects analysed
    97
    100
    66
    74
    100
    102
    100
    102
    Units: Participants
    97
    100
    66
    74
    97
    100
    100
    102
    Statistical analysis title
    		 Primary analysis: risk difference between groups
    Comparison groups
    No ribavirin v Ribavirin
    Number of subjects included in analysis
    197
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.038
         upper limit
    		 0.037
    Statistical analysis title
    		 Per-protocol: difference between groups
    Statistical analysis description
    Difference between groups limited to the per-protocol population
    Comparison groups
    Per-protocol: ribavirin group v Per-protocol: no ribavirin group
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.06
         upper limit
    		 0.05
    Statistical analysis title
    		 All missing=failures: difference between groups
    Statistical analysis description
    Difference between groups assuming all participants with missing SVR12 data failed treatment
    Comparison groups
    All missing outcomes are failures: no ribavirin group v All missing outcomes are failures: ribavirin group
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.64
    Method
    		 Regression, binomial with identity link
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.05
         upper limit
    		 0.03
    Statistical analysis title
    		 All missing=cured: difference between groups
    Statistical analysis description
    Difference between groups assuming that all participants with missing SVR12 data achieved SVR12
    Comparison groups
    All missing outcomes are cures: no ribavirin group v All missing outcomes are cures: ribavirin group
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.037
         upper limit
    		 0.036

    Secondary: SVR24 after first-line or retreatment

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    End point title
    		 SVR24 after first-line or retreatment
    End point description
    End point type
    Secondary
    End point timeframe
    24 weeks after first-line and any retreatment
    End point values
    		 Variable duration Fixed duration Ribavirin No ribavirin
    Number of subjects analysed
    96
    98
    96
    98
    Units: Participants
    96
    98
    96
    98
    Statistical analysis title
    		 Duration comparison: difference between groups
    Comparison groups
    Fixed duration v Variable duration
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [17]
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.038
         upper limit
    		 0.038
    Notes
    [17] - 4% non-inferiority margin
    Statistical analysis title
    		 Ribavirin comparison: difference between groups
    Comparison groups
    No ribavirin v Ribavirin
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.038
         upper limit
    		 0.038

    Secondary: SVR24 after first-line only

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    End point title
    		 SVR24 after first-line only
    End point description
    End point type
    Secondary
    End point timeframe
    24 weeks after only first-line treatment
    End point values
    		 Variable duration Fixed duration Ribavirin No ribavirin Received VUS1: variable duration group Received VUS1: fixed duration group Received VUS2: variable duration group Received VUS2: fixed duration group
    Number of subjects analysed
    97
    99
    97
    99
    65
    68
    32
    31
    Units: Participants
    46
    88
    68
    66
    23
    61
    23
    27
    Statistical analysis title
    		 Duration comparison: difference between groups
    Comparison groups
    Fixed duration v Variable duration
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [18]
    P-value
    		 < 0.001
    Method
    		 Regression, binomial with identity link
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.53
         upper limit
    		 -0.31
    Notes
    [18] - 4% non-inferiority margin Estimate is an average over both DAA strategies and taken from a model which includes an interaction between randomisation and DAA strategy (p=0.001).
    Statistical analysis title
    		 VUS1 duration comparison: difference between group
    Statistical analysis description
    Difference between duration randomisation groups limited to participants randomised before 1st April 2017 when variable duration participants received between 4-6 weeks of treatment
    Comparison groups
    Received VUS1: fixed duration group v Received VUS1: variable duration group
    Number of subjects included in analysis
    133
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority [19]
    P-value
    		 < 0.001
    Method
    		 Regression, binomial with identity link
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.68
         upper limit
    		 -0.41
    Notes
    [19] - 4% non-inferiority margin
    Statistical analysis title
    		 VUS2 duration comparison: difference between group
    Statistical analysis description
    Difference between duration randomisation groups limited to participants randomised after 1st April 2017 when variable duration participants received between 4-7 weeks of treatment
    Comparison groups
    Received VUS2: variable duration group v Received VUS2: fixed duration group
    Number of subjects included in analysis
    63
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority [20]
    P-value
    		 = 0.13
    Method
    		 Regression, binomial with identity link
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.35
         upper limit
    		 0.04
    Notes
    [20] - 4% non-inferiority margin
    Statistical analysis title
    		 Ribavirin comparison: difference between groups
    Comparison groups
    Ribavirin v No ribavirin
    Number of subjects included in analysis
    196
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.87
    Method
    		 Regression, binomial with identity link
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.09
         upper limit
    		 0.11

    Secondary: Primary first-line treatment failure

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    End point title
    		 Primary first-line treatment failure
    End point description
    Primary first-line treatment failure is defined as confirmed >1log10 increase in HCV VL above nadir on treatment and >2000 IU/ml
    End point type
    Secondary
    End point timeframe
    While on first-line treatment and up to 24 weeks after completing first-line treatment or meeting a failure criteria
    End point values
    		 Variable duration Fixed duration Ribavirin No ribavirin Received VUS1: variable duration group Received VUS1: fixed duration group Received VUS2: variable duration group Received VUS2: fixed duration group
    Number of subjects analysed
    100
    102
    100
    102
    68
    68
    32
    34
    Units: Participants
    16
    5
    10
    11
    16
    2
    0
    3
    Attachments
    		 Cumulative incidence primary FL failure: duration
    Cumulative incidence primary FL failure: ribavirin
    Statistical analysis title
    		 Duration comparison: difference between groups
    Comparison groups
    Fixed duration v Variable duration
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [21]
    P-value
    		 = 0.008
    Method
    		 Regression, binomial with identity link
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 0.18
    Notes
    [21] - 4% non-inferiority margin
    Statistical analysis title
    		 Duration comparison: HR between groups
    Comparison groups
    Variable duration v Fixed duration
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.01
    Method
    		 Regression, Cox
    Parameter type
    		 Cause-specific hazard ratio
    Point estimate
    3.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.33
         upper limit
    		 9.92
    Statistical analysis title
    		 VUS1 duration comparison: difference between group
    Statistical analysis description
    Difference between duration randomisation groups restricted to participants randomised before 1st April 2017 when variable duration participants received between 4-6 weeks of treatment
    Comparison groups
    Received VUS1: variable duration group v Received VUS1: fixed duration group
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [22]
    P-value
    		 < 0.001
    Method
    		 Regression, binomial with identity link
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 0.31
    Notes
    [22] - 4% non-inferiority margin
    Statistical analysis title
    		 VUS1 duration comparison: HR between groups
    Comparison groups
    Received VUS1: variable duration group v Received VUS1: fixed duration group
    Number of subjects included in analysis
    136
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.003
    Method
    		 Regression, Cox
    Parameter type
    		 Cause-specific hazard ratio
    Point estimate
    9.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.09
         upper limit
    		 39.54
    Statistical analysis title
    		 Ribavirin comparison: difference between groups
    Comparison groups
    No ribavirin v Ribavirin
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.84
    Method
    		 Regression, binomial with identity link
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.07
         upper limit
    		 0.08
    Statistical analysis title
    		 Ribavirin comparison: HR between groups
    Comparison groups
    Ribavirin v No ribavirin
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.83
    Method
    		 Regression, Cox
    Parameter type
    		 Cause specific hazard ratio
    Point estimate
    0.91
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.39
         upper limit
    		 2.14

    Secondary: HCV viral load rebound

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    End point title
    		 HCV viral load rebound
    End point description
    HCV VL rebound is defined as having confirmed detectable HCV VL after two consecutive visits of undetectable HCV VL, with the confirmatory VL >2000 IU/ml
    End point type
    Secondary
    End point timeframe
    While on first-line treatment and up to 24 weeks after completing first-line treatment or until meeting failure criteria
    End point values
    		 Variable duration Fixed duration Ribavirin No ribavirin Received VUS1: variable duration group Received VUS1: fixed duration group Received VUS2: variable duration group Received VUS2: fixed duration group
    Number of subjects analysed
    100
    102
    100
    102
    68
    68
    32
    34
    Units: Participants
    35
    6
    19
    22
    26
    5
    9
    1
    Attachments
    		 Cumulative incidence HCV VL rebound: duration
    Cumulative incidence HCV VL rebound: ribavirin
    Statistical analysis title
    		 Duration comparison: difference between groups
    Comparison groups
    Fixed duration v Variable duration
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [23]
    P-value
    		 < 0.001
    Method
    		 Regression, binomial with identity link
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.18
         upper limit
    		 0.39
    Notes
    [23] - 4% non-inferiority margin
    Statistical analysis title
    		 Duration comparison: HR between groups
    Comparison groups
    Fixed duration v Variable duration
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [24]
    P-value
    		 < 0.001
    Method
    		 Regression, Cox
    Parameter type
    		 Cause specific hazard ratio
    Point estimate
    8.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.48
         upper limit
    		 22.73
    Notes
    [24] - 4% non-inferiority margin
    Statistical analysis title
    		 VUS1 duration comparison: difference between group
    Statistical analysis description
    Difference between duration comparison groups limited to participants randomised before 1st April 2017 when variable duration participants received between 4-6 weeks of treatment
    Comparison groups
    Received VUS1: variable duration group v Received VUS1: fixed duration group
    Number of subjects included in analysis
    136
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority [25]
    P-value
    		 < 0.001
    Method
    		 Regression, binomial with identity link
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.31
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.18
         upper limit
    		 0.44
    Notes
    [25] - 4% non-inferiority margin
    Statistical analysis title
    		 VUS2 duration comparison: difference between group
    Statistical analysis description
    Difference between duration randomisation groups limited to participants randomised after 1st April 2017 when variable duration participants received between 4-7 weeks of treatment
    Comparison groups
    Received VUS2: variable duration group v Received VUS2: fixed duration group
    Number of subjects included in analysis
    66
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority [26]
    P-value
    		 = 0.004
    Method
    		 Regression, binomial with identity link
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.25
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.09
         upper limit
    		 0.42
    Notes
    [26] - 4% non-inferiority margin
    Statistical analysis title
    		 VUS1 duration comparison: HR between group
    Statistical analysis description
    Cause specific hazard ratio between duration randomisation groups limited to participants randomised before 1st April 2017 when variable duration participants received between 4-6 weeks of treatment
    Comparison groups
    Received VUS1: fixed duration group v Received VUS1: variable duration group
    Number of subjects included in analysis
    136
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.001
    Method
    		 Regression, Cox
    Parameter type
    		 Cause specific hazard ratio
    Point estimate
    8.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.86
         upper limit
    		 23.56
    Statistical analysis title
    		 VUS2 duration comparison: HR between groups
    Statistical analysis description
    Cause specific hazard ratio between duration randomisation groups limited to participants randomised before 1st April 2017 when variable duration participants received between 4-6 weeks of treatment
    Comparison groups
    Received VUS2: variable duration group v Received VUS2: fixed duration group
    Number of subjects included in analysis
    66
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.02
    Method
    		 Regression, Cox
    Parameter type
    		 Cause specific hazard ratio
    Point estimate
    11.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.42
         upper limit
    		 88.48
    Statistical analysis title
    		 Ribavirin comparison: difference between groups
    Comparison groups
    No ribavirin v Ribavirin
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.59
    Method
    		 Regression, binomial with identity link
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 0.09
    Statistical analysis title
    		 Ribavirin comparison: HR between groups
    Comparison groups
    Ribavirin v No ribavirin
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.59
    Method
    		 Regression, Cox
    Parameter type
    		 Cause specific hazard ratio
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 1.56

    Secondary: Detectable HCV VL 4 weeks after randomisation

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    End point title
    		 Detectable HCV VL 4 weeks after randomisation
    End point description
    End point type
    Secondary
    End point timeframe
    4 weeks after randomisation
    End point values
    		 Variable duration Fixed duration Ribavirin No ribavirin
    Number of subjects analysed
    96
    101
    97
    100
    Units: Participants
    15
    26
    17
    24
    Statistical analysis title
    		 Duration comparison: difference between groups
    Comparison groups
    Fixed duration v Variable duration
    Number of subjects included in analysis
    197
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [27]
    P-value
    		 = 0.08
    Method
    		 Regression, binomial with identity link
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.21
         upper limit
    		 0.01
    Notes
    [27] - 4% non-inferiority margin
    Statistical analysis title
    		 Ribavirin comparison: difference between groups
    Comparison groups
    No ribavirin v Ribavirin
    Number of subjects included in analysis
    197
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.26
    Method
    		 Regression, binomial with identity link
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.18
         upper limit
    		 0.05

    Secondary: Proportion with emergent RAVs to first-line treatment

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    End point title
    		 Proportion with emergent RAVs to first-line treatment
    End point description
    RAVs=resistance associated variants
    End point type
    Secondary
    End point timeframe
    After failing first-line treatment
    End point values
    		 Variable duration Fixed duration Ribavirin No ribavirin
    Number of subjects analysed
    46
    10
    27
    29
    Units: Participants
    11
    3
    3
    11
    Statistical analysis title
    		 Duration comparison: difference between groups
    Comparison groups
    Fixed duration v Variable duration
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [28]
    P-value
    		 = 0.77
    Method
    		 Regression, binomial with identity link
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.36
         upper limit
    		 0.27
    Notes
    [28] - 4% non-inferiority margin
    Statistical analysis title
    		 Ribavirin comparison: difference between groups
    Comparison groups
    No ribavirin v Ribavirin
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 Regression, binomial with identity link
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.48
         upper limit
    		 -0.06

    Secondary: Proportion with SAEs

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    End point title
    		 Proportion with SAEs
    End point description
    End point type
    Secondary
    End point timeframe
    Up until 24 weeks after completing first-line or any retreatment
    End point values
    		 Variable duration Fixed duration Ribavirin No ribavirin
    Number of subjects analysed
    100
    102
    100
    102
    Units: Participants
    5
    5
    5
    5
    Attachments
    		 Kaplan-Meier plot of first SAE: duration
    Kaplan-Meier plot of first SAE: ribavirin
    Statistical analysis title
    		 Duration comparison: difference between groups
    Comparison groups
    Fixed duration v Variable duration
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Duration comparison: HR between groups
    Comparison groups
    Fixed duration v Variable duration
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.69
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.21
         upper limit
    		 2.8
    Statistical analysis title
    		 Ribavirin comparison: difference between groups
    Comparison groups
    Ribavirin v No ribavirin
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Ribavirin comparison: HR between groups
    Comparison groups
    No ribavirin v Ribavirin
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.59
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 3.63

    Secondary: Proportion with grade 3/4 AEs

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    End point title
    		 Proportion with grade 3/4 AEs
    End point description
    End point type
    Secondary
    End point timeframe
    Up to
    End point values
    		 Variable duration Fixed duration Ribavirin No ribavirin
    Number of subjects analysed
    100
    102
    100
    102
    Units: Participants
    9
    5
    9
    5
    Attachments
    		 Kaplan-Meier plot of first G3/4 AE: duration
    Kaplan-Meier plot of first G3/4 AE: ribavirin
    Statistical analysis title
    		 Duration comparison: difference between groups
    Comparison groups
    Fixed duration v Variable duration
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.28
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Duration comparison: HR between groups
    Comparison groups
    Fixed duration v Variable duration
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.33
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.74
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.58
         upper limit
    		 5.24
    Statistical analysis title
    		 Ribavirin comparison: difference between groups
    Comparison groups
    Ribavirin v No ribavirin
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.28
    Method
    		 Chi-squared
    Confidence interval
    Statistical analysis title
    		 Ribavirin comparison: HR between groups
    Comparison groups
    Ribavirin v No ribavirin
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.59
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.64
         upper limit
    		 5.72

    Secondary: Proportion with grade 3/4 AEs judged definitely/probably related to first-line drugs

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    End point title
    		 Proportion with grade 3/4 AEs judged definitely/probably related to first-line drugs
    End point description
    End point type
    Secondary
    End point timeframe
    Up until 24 weeks after completing first-line or any retreatment
    End point values
    		 Variable duration Fixed duration Ribavirin No ribavirin
    Number of subjects analysed
    100
    102
    100
    102
    Units: Participant
    3
    1
    3
    1
    Statistical analysis title
    		 Duration comparison: difference between groups
    Comparison groups
    Fixed duration v Variable duration
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.37
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Ribavirin comparison: difference between groups
    Comparison groups
    Ribavirin v No ribavirin
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.37
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Proportion with grade 3/4 AEs judged definitely/probably related to retreatment

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    End point title
    		 Proportion with grade 3/4 AEs judged definitely/probably related to retreatment
    End point description
    End point type
    Secondary
    End point timeframe
    Up until 24 weeks after completing first-line or any retreatment
    End point values
    		 Variable duration Fixed duration Ribavirin No ribavirin
    Number of subjects analysed
    100
    102
    100
    102
    Units: Participants
    3
    1
    2
    2
    Statistical analysis title
    		 Duration comparison: difference between groups
    Comparison groups
    Fixed duration v Variable duration
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.37
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Ribavirin comparison: difference between groups
    Comparison groups
    No ribavirin v Ribavirin
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Proportion with first-line drug changes due to AEs

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    End point title
    		 Proportion with first-line drug changes due to AEs
    End point description
    End point type
    Secondary
    End point timeframe
    Up until 24 weeks after completing first-line or any retreatment
    End point values
    		 Variable duration Fixed duration Ribavirin No ribavirin
    Number of subjects analysed
    100
    102
    100
    102
    Units: Participants
    3
    1
    4
    0
    Statistical analysis title
    		 Duration comparison: difference between groups
    Comparison groups
    Fixed duration v Variable duration
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.37
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Ribavirin comparison: difference between groups
    Comparison groups
    No ribavirin v Ribavirin
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.058
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Proportion with retreatment drug changes due to AEs

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    End point title
    		 Proportion with retreatment drug changes due to AEs
    End point description
    End point type
    Secondary
    End point timeframe
    Up until 24 weeks after completing first-line or any retreatment
    End point values
    		 Variable duration Fixed duration Ribavirin No ribavirin
    Number of subjects analysed
    100
    102
    100
    102
    Units: Participants
    6
    1
    4
    3
    Statistical analysis title
    		 Duration comparison: difference between groups
    Comparison groups
    Fixed duration v Variable duration
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.06
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Ribavirin comparison: difference between groups
    Comparison groups
    Ribavirin v No ribavirin
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.72
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Proportion with grade 3/4 anaemias

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    End point title
    		 Proportion with grade 3/4 anaemias
    End point description
    End point type
    Secondary
    End point timeframe
    Up until 24 weeks after completing first-line or any retreatment
    End point values
    		 Variable duration Fixed duration Ribavirin No ribavirin
    Number of subjects analysed
    100
    102
    100
    102
    Units: Participants
    3
    0
    3
    0
    Statistical analysis title
    		 Duration comparison: difference between groups
    Comparison groups
    Variable duration v Fixed duration
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.12
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Ribavirin comparison: difference between groups
    Comparison groups
    No ribavirin v Ribavirin
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.12
    Method
    		 Fisher exact
    Confidence interval

    Other pre-specified: Change in safety lab values from randomisation to EOT+24

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    End point title
    		 Change in safety lab values from randomisation to EOT+24
    End point description
    End point type
    Other pre-specified
    End point timeframe
    While enrolled in the trial
    End point values
    		 Variable duration Fixed duration Ribavirin No ribavirin
    Number of subjects analysed
    100
    102
    100
    102
    Units: Participants with EOT+24 measurements
    45
    83
    63
    65
    Attachments
    		 Change in Hb: duration
    Change in ALT: duration
    Change in AST: duration
    Change in ALP: duration
    Change in eGFR: duration
    Change in bilirubin: duration
    Change in Hb: ribavirin
    Change in ALT: ribavirin
    Change in AST: ribavirin
    Change in ALP: ribavirin
    Change in eGFR: ribavirin
    Change in bilirubin: ribavirin
    Statistical analysis title
    		 Change in haemoglobin: duration comparison
    Comparison groups
    Fixed duration v Variable duration
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 18 [29]
    Method
    		 GEE
    Confidence interval
    Notes
    [29] - Global p-value for change in Hb over time until EOT+24. Time point p-values: D14 p=0.35, D28 p=0.11, EOT=0.20, EOT+12 p=0.42, EOT+24 p=0.36
    Statistical analysis title
    		 Change in ALT: duration comparison
    Comparison groups
    Fixed duration v Variable duration
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [30]
    Method
    		 GEE
    Confidence interval
    Notes
    [30] - Global p-value for change in ALT over time until EOT+24. Time point p-values: D14: p=0.90, D28 p=0.15, EOT p=0.02, EOT+12 p=0.02, EOT+24 p=0.26
    Statistical analysis title
    		 Change in AST: duration comparison
    Comparison groups
    Variable duration v Fixed duration
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [31]
    Method
    		 GEE
    Confidence interval
    Notes
    [31] - Global p-value for change in AST over time until EOT+24. Time point p-values: D14 p=0.40, D28 p=0.01, EOT p=0.01, EOT+12 p=0.004, EOT+24 p=0.008
    Statistical analysis title
    		 Change in ALP: duration comparison
    Comparison groups
    Fixed duration v Variable duration
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.68 [32]
    Method
    		 GEE
    Confidence interval
    Notes
    [32] - Global p-value for change in ALP over time until EOT+24. Time point p-values: D14 p=0.87, D28 p=0.73, EOT p=0.11, EOT+12 p=0.94, EOT+24 p=0.995
    Statistical analysis title
    		 Change in eGFR: duration comparison
    Comparison groups
    Variable duration v Fixed duration
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.23 [33]
    Method
    		 GEE
    Confidence interval
    Notes
    [33] - Global p-value for change in eGFR over time until EOT+24. Time point p-values: D14 p=0.62, D28 p=0.92, EOT p=0.41, EOT+12 p=0.89 EOT+24 p=0.31
    Statistical analysis title
    		 Change in bilirubin: duration comparison
    Comparison groups
    Fixed duration v Variable duration
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.86 [34]
    Method
    		 GEE
    Confidence interval
    Notes
    [34] - Global p-value for change in bilirubin over time until EOT+24. Time point p-values: D14 p=0.31, D28 p=0.63, EOT p=0.32, EOT+12 p=0.96, EOT+24 p=0.38
    Statistical analysis title
    		 Change in haemoglobin: ribavirin comparison
    Comparison groups
    Ribavirin v No ribavirin
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [35]
    Method
    		 GEE
    Confidence interval
    Notes
    [35] - Global p-value for change in Hb over time until EOT+24. Time point p-values: D14 p<0.001, D28 p<0.001, EOT p<0.001, EOT+12 p=0.68, EOT+24 p=0.96
    Statistical analysis title
    		 Change in ALT: ribavirin comparison
    Comparison groups
    Ribavirin v No ribavirin
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.86 [36]
    Method
    		 GEE
    Confidence interval
    Notes
    [36] - Global p-value for change in ALT over time until EOT+24. Time point p-values: D14 p=0.56, D28 p=0.90, EOT p=0.84, EOT+12 p=0.62, EOT+24 p=0.35
    Statistical analysis title
    		 Change in AST: ribavirin comparison
    Comparison groups
    Ribavirin v No ribavirin
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.58 [37]
    Method
    		 GEE
    Confidence interval
    Notes
    [37] - Global p-value for change in AST over time until EOT+24. Time point p-values: D14 p=0.31, D28 p=0.85, EOT p=0.29, EOT+12 p=0.78, EOT+24 p=0.68
    Statistical analysis title
    		 Change in ALP: ribavirin comparison
    Comparison groups
    No ribavirin v Ribavirin
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.15 [38]
    Method
    		 GEE
    Confidence interval
    Notes
    [38] - Global p-value for change in ALP over time until EOT+24. Time point p-values: D14 p=0.75, D28 p=0.72, EOT p=0.12, EOT+12 p=0.13, EOT+24 p=0.73
    Statistical analysis title
    		 Change in eGFR: ribavirin comparison
    Comparison groups
    No ribavirin v Ribavirin
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.62 [39]
    Method
    		 GEE
    Confidence interval
    Notes
    [39] - Global p-value for change in eGFR over time until EOT+24. Time point p-values: D14 p=0.59, D28 p=0.25, EOT p=0.70, EOT+12 p=0.90, EOT+24 p=0.46
    Statistical analysis title
    		 Change in bilirubin: ribavirin comparison
    Comparison groups
    No ribavirin v Ribavirin
    Number of subjects included in analysis
    202
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001 [40]
    Method
    		 GEE
    Confidence interval
    Notes
    [40] - Global p-value for change in bilirubin over time until EOT+24. Time point p-values: D14 p<0.001, D28 p<0.001, EOT p<0.001, EOT+12 p=0.23, EOT+24 p=0.93

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    For an individual participant, the timeframe is from randomisation up to 24 weeks after completing their most recent treatment, either first-line or retreatment for those who started retreatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Variable duration
    Reporting group description
    		 All participants randomised to receive variable duration treatment

    Reporting group title
    Fixed duration
    Reporting group description
    		 All participants randomised to receive fixed duration

    Reporting group title
    Ribavirin group
    Reporting group description
    		 All participants randomised to receive ribavirin

    Reporting group title
    Without ribavirin group
    Reporting group description
    		 All participants randomised to not receive ribavirin

    Serious adverse events
    		 Variable duration Fixed duration Ribavirin group Without ribavirin group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 100 (5.00%)
    5 / 102 (4.90%)
    5 / 100 (5.00%)
    5 / 102 (4.90%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Oesophageal adenocarcinoma
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 102 (0.98%)
    0 / 100 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Thermal burn
    Additional description: Burn to foot, degree unknown
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Pericarditis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Loss of consciousness
    Additional description: Loss of consciousness due to (non-study) drug overdose
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
    Additional description: Musculoskeletal chest pain with radiation to left arm
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 102 (0.98%)
    0 / 100 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 102 (0.98%)
    0 / 100 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 102 (0.98%)
    0 / 100 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 102 (0.98%)
    0 / 100 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Variable duration Fixed duration Ribavirin group Without ribavirin group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 100 (15.00%)
    15 / 102 (14.71%)
    17 / 100 (17.00%)
    13 / 102 (12.75%)
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 102 (0.98%)
    2 / 100 (2.00%)
    0 / 102 (0.00%)
         occurrences all number
    1
    1
    2
    0
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 102 (0.98%)
    0 / 100 (0.00%)
    1 / 102 (0.98%)
         occurrences all number
    0
    1
    0
    1
    Vascular disorders
    Syncope
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 102 (0.98%)
    0 / 100 (0.00%)
    1 / 102 (0.98%)
         occurrences all number
    0
    1
    0
    1
    Nervous system disorders
    Disturbance in attention
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 102 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Lethargy
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 102 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 100 (6.00%)
    0 / 102 (0.00%)
    3 / 100 (3.00%)
    3 / 102 (2.94%)
         occurrences all number
    6
    0
    3
    3
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 102 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Gastrointestinal disorders
    Inguinal hernia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 102 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Mouth ulceration
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 102 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Stomatitis
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 102 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    1 / 102 (0.98%)
         occurrences all number
    1
    0
    0
    1
    Jaundice
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 102 (0.98%)
    0 / 100 (0.00%)
    1 / 102 (0.98%)
         occurrences all number
    0
    1
    0
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 102 (0.98%)
    1 / 100 (1.00%)
    0 / 102 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 102 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Insomnia
         subjects affected / exposed
    3 / 100 (3.00%)
    0 / 102 (0.00%)
    3 / 100 (3.00%)
    0 / 102 (0.00%)
         occurrences all number
    3
    0
    3
    0
    Suicidal ideation
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 102 (0.00%)
    1 / 100 (1.00%)
    0 / 102 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Infections and infestations
    Abscess limb
    Additional description: Abscess on leg
         subjects affected / exposed
    1 / 100 (1.00%)
    0 / 102 (0.00%)
    0 / 100 (0.00%)
    1 / 102 (0.98%)
         occurrences all number
    1
    0
    0
    1
    Cellulitis
         subjects affected / exposed
    1 / 100 (1.00%)
    1 / 102 (0.98%)
    1 / 100 (1.00%)
    1 / 102 (0.98%)
         occurrences all number
    1
    1
    1
    1
    Pyelonephritis
         subjects affected / exposed
    0 / 100 (0.00%)
    1 / 102 (0.98%)
    1 / 100 (1.00%)
    0 / 102 (0.00%)
         occurrences all number
    0
    1
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 May 2017
    After reviewing the data, the DMC recommended changing the duration of treatment for those receiving variable duration therapy from 4-6 weeks to 4-7 weeks.
    19 Oct 2017
    To help improve recruitment, genotype 4 patients were allowed to join the study (previously just 1a and 1b). The combination ombitasvir/paritaprevir/ritonavir was added to the protocol for genotype 4 patients. The combination glecaprevir/pibrentasvir was added to the protocol for all genotypes.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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