Chronic Hepatitis C
Conditions
Keywords
HCV genotype 2 (GT-2), HCV genotype 3 (GT-3), HCV, Sustained Virologic Response, Direct Acting Antiviral, Combination Therapy, Treatment Experienced, GS-7977, Ribavirin
Brief summary
This study was to assess the safety and efficacy of sofosbuvir in combination with ribavirin (RBV) administered for 12 or 16 weeks in participants with genotypes 2 or 3 hepatitis C virus (HCV) infection as assessed by the proportion of participants with sustained virologic response (SVR) 12 weeks after discontinuation of therapy (SVR12).
Interventions
DRUGSOF
Sofosbuvir (SOF) 400 mg tablet was administered orally once daily.
DRUGRBV
Ribavirin (RBV) tablets was administered orally in a divided daily dose according to package insert weight-based dosing recommendations (\< 75kg = 1000 mg and ≥ 75 kg = 1200 mg).
Placebo to match SOF was administered orally once daily.
Placebo to match RBV was administered orally twice daily.
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Infection with HCV genotype 2 or 3 * Had cirrhosis determination * Prior treatment failure * Screening laboratory values within defined thresholds * Subject had not been treated with any investigational drug or device within 30 days of the screening visit * Use of highly effective contraception methods if female of childbearing potential or sexually active male
Exclusion criteria
* Prior exposure to an direct-acting antiviral targeting the HCV nonstructural protein (NS)5B polymerase * Pregnant or nursing female or male with pregnant female partner * Current or prior history of clinical hepatic decompensation * History of clinically significant illness or any other major medical disorder that may have interfered with subject treatment, assessment or compliance with the protocol * Excessive alcohol ingestion or significant drug abuse
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving SVR12 | Posttreatment Week 12 | SVR12 was defined as HCV RNA \< the lower limit of quantitation (LLOQ, ie, \< 25 IU/mL) 12 weeks after cessation of therapy. For the purposes of this efficacy analysis, the posttreatment period began after the end of active treatment (following Week 12 for the SOF+RBV+placebo arm, and Week 16 for the SOF+RBV arm). |
| Adverse Events Leading to Permanent Discontinuation of Study Drug | Baseline to Week 16 | Adverse events which led to permanent discontinuation of study drug may or may not have been related to study treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving SVR4 | Posttreatment Week 4 | SVR4 was defined as HCV RNA \< LLOQ 4 weeks after cessation of therapy. For the purposes of this efficacy analysis, the posttreatment period began after the end of active treatment (following Week 12 for the SOF+RBV+placebo arm, and Week 16 for the SOF+RBV arm). |
| Percentage of Participants Achieving SVR24 | Posttreatment Week 24 | SVR24 was defined as HCV RNA \< LLOQ 24 weeks after cessation of therapy. For the purposes of this efficacy analysis, the posttreatment period began after the end of active treatment (following Week 12 for the SOF+RBV+placebo arm, and Week 16 for the SOF+RBV arm). |
| Percentage of Participants With Viral Breakthrough | Up to 16 weeks | Viral breakthrough was defined as HCV RNA ≥ LLOQ after having previously had HCV RNA \< LLOQ while receiving treatment, confirmed with 2 consecutive values (second confirmation value could be posttreatment), or last available on-treatment measurement with no subsequent follow-up values. For the purposes of this efficacy analysis, assessments were made during active treatment (up to Week 12 for the SOF+RBV+placebo arm, and Week 16 for the SOF+RBV arm). |
| Percentage of Participants With Viral Relapse | End of treatment to posttreatment Week 24 | Viral relapse was defined as HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA \< LLOQ at end of treatment, confirmed with 2 consecutive values or last available posttreatment measurement. For the purposes of this efficacy analysis, the posttreatment period began after the end of active treatment (following Week 12 for the SOF+RBV+placebo arm, and Week 16 for the SOF+RBV arm). |
Countries
Canada, New Zealand, Puerto Rico, United States
Participant flow
Recruitment details
Subjects were enrolled in a total of 57 study sites in the United States, Canada, and New Zealand. The first participant was screened on 04 June 2012. The last participant observation was on 08 May 2013.
Pre-assignment details
277 participants were screened and 202 were randomized. Of those participants randomized, 201 received at least one dose of study drug, and comprise the Safety Analysis Set; 195 of those participants with genotypes 2 or 3 HCV infection were treated and comprise the Full Analysis Set.
Participants by arm
| Arm | Count |
|---|---|
| SOF+RBV+Placebo Participants were randomized to receive sofosbuvir+RBV for 12 weeks, followed by placebo to match sofosbuvir plus placebo to match RBV for 4 weeks.
Sofosbuvir (400 mg) was administered as an oral tablet and RBV (1000-1200 mg) as 200 mg oral tablets. Placebo to match sofosbuvir and placebo to match RBV were also administered as oral tablets. | 103 |
| SOF+RBV Participants were randomized to receive sofosbuvir+RBV for 16 weeks.
Sofosbuvir (400 mg) was administered as an oral tablet and RBV (1000-1200 mg) as 200 mg oral tablets. | 98 |
| Total | 201 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Efficacy Failure | 50 | 29 |
| Overall Study | Enrolled but never treated | 0 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Subject withdrew consent | 1 | 0 |
Baseline characteristics
| Characteristic | SOF+RBV+Placebo | SOF+RBV | Total |
|---|---|---|---|
| Age, Continuous | 54 years STANDARD_DEVIATION 7.7 | 54 years STANDARD_DEVIATION 7.8 | 54 years STANDARD_DEVIATION 7.8 |
| Cirrhosis (Y/N) Missing | 1 participants | 0 participants | 1 participants |
| Cirrhosis (Y/N) No | 66 participants | 66 participants | 132 participants |
| Cirrhosis (Y/N) Yes | 36 participants | 32 participants | 68 participants |
| HCV RNA | 6.5 log10 IU/mL STANDARD_DEVIATION 0.67 | 6.5 log10 IU/mL STANDARD_DEVIATION 0.63 | 6.5 log10 IU/mL STANDARD_DEVIATION 0.65 |
| HCV RNA Category < 6 log10 IU/mL | 26 participants | 29 participants | 55 participants |
| HCV RNA Category ≥ 6 log10 IU/mL | 77 participants | 69 participants | 146 participants |
| Hepatitis C Virus (HCV) genotype Genotype 1 | 3 participants | 3 participants | 6 participants |
| Hepatitis C Virus (HCV) genotype Genotype 2 | 36 participants | 32 participants | 68 participants |
| Hepatitis C Virus (HCV) genotype Genotype 3 | 64 participants | 63 participants | 127 participants |
| IL28 Genotype CC | 31 participants | 30 participants | 61 participants |
| IL28 Genotype CT | 53 participants | 56 participants | 109 participants |
| IL28 Genotype TT | 19 participants | 12 participants | 31 participants |
| Race/Ethnicity, Customized American Indian/ Alaska Native/ First Nations | 1 participants | 3 participants | 4 participants |
| Race/Ethnicity, Customized Asian | 7 participants | 5 participants | 12 participants |
| Race/Ethnicity, Customized Black or African American | 5 participants | 1 participants | 6 participants |
| Race/Ethnicity, Customized Hawaiian or Pacific Islander | 0 participants | 1 participants | 1 participants |
| Race/Ethnicity, Customized Other | 2 participants | 2 participants | 4 participants |
| Race/Ethnicity, Customized White | 88 participants | 86 participants | 174 participants |
| Region of Enrollment Canada | 26 participants | 17 participants | 43 participants |
| Region of Enrollment New Zealand | 3 participants | 5 participants | 8 participants |
| Region of Enrollment United States | 74 participants | 76 participants | 150 participants |
| Response to Prior HCV Treatment Nonresponse | 25 participants | 25 participants | 50 participants |
| Response to Prior HCV Treatment Relapse/Breakthrough | 78 participants | 73 participants | 151 participants |
| Sex: Female, Male Female | 30 Participants | 31 Participants | 61 Participants |
| Sex: Female, Male Male | 73 Participants | 67 Participants | 140 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 92 / 103 | 86 / 98 |
| serious Total, serious adverse events | 5 / 103 | 3 / 98 |
Outcome results
Primary
Adverse Events Leading to Permanent Discontinuation of Study Drug
Adverse events which led to permanent discontinuation of study drug may or may not have been related to study treatment.
Time frame: Baseline to Week 16
Population: The Safety Analysis Set included participants who were randomized and received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SOF+RBV+Placebo | Adverse Events Leading to Permanent Discontinuation of Study Drug | 1 participants |
| SOF+RBV | Adverse Events Leading to Permanent Discontinuation of Study Drug | 0 participants |
Primary
Percentage of Participants Achieving SVR12
SVR12 was defined as HCV RNA \< the lower limit of quantitation (LLOQ, ie, \< 25 IU/mL) 12 weeks after cessation of therapy. For the purposes of this efficacy analysis, the posttreatment period began after the end of active treatment (following Week 12 for the SOF+RBV+placebo arm, and Week 16 for the SOF+RBV arm).
Time frame: Posttreatment Week 12
Population: The Full Analysis Set included all participants with genotype 2 or 3 HCV infection who were randomized and received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SOF+RBV+Placebo | Percentage of Participants Achieving SVR12 | 51.0 percentage of participants |
| SOF+RBV | Percentage of Participants Achieving SVR12 | 72.6 percentage of participants |
Comparison: A sample size of 100 subjects in each group would provide over 97% power to detect at least 20% improvement in SVR12 rate from the assumed null rate of 25% using 2-sided exact 1-sample binomial test at significance level of 0.025.p-value: <0.00195% CI: [-34.4, -10.3]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Achieving SVR24
SVR24 was defined as HCV RNA \< LLOQ 24 weeks after cessation of therapy. For the purposes of this efficacy analysis, the posttreatment period began after the end of active treatment (following Week 12 for the SOF+RBV+placebo arm, and Week 16 for the SOF+RBV arm).
Time frame: Posttreatment Week 24
Population: The Full Analysis Set included all participants with genotype 2 or 3 HCV infection who were randomized and received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SOF+RBV+Placebo | Percentage of Participants Achieving SVR24 | 50.0 percentage of participants |
| SOF+RBV | Percentage of Participants Achieving SVR24 | 71.6 percentage of participants |
Secondary
Percentage of Participants Achieving SVR4
SVR4 was defined as HCV RNA \< LLOQ 4 weeks after cessation of therapy. For the purposes of this efficacy analysis, the posttreatment period began after the end of active treatment (following Week 12 for the SOF+RBV+placebo arm, and Week 16 for the SOF+RBV arm).
Time frame: Posttreatment Week 4
Population: The Full Analysis Set included all participants with genotype 2 or 3 HCV infection who were randomized and received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SOF+RBV+Placebo | Percentage of Participants Achieving SVR4 | 56.0 percentage of participants |
| SOF+RBV | Percentage of Participants Achieving SVR4 | 76.8 percentage of participants |
Secondary
Percentage of Participants With Viral Breakthrough
Viral breakthrough was defined as HCV RNA ≥ LLOQ after having previously had HCV RNA \< LLOQ while receiving treatment, confirmed with 2 consecutive values (second confirmation value could be posttreatment), or last available on-treatment measurement with no subsequent follow-up values. For the purposes of this efficacy analysis, assessments were made during active treatment (up to Week 12 for the SOF+RBV+placebo arm, and Week 16 for the SOF+RBV arm).
Time frame: Up to 16 weeks
Population: The Full Analysis Set included all participants with genotype 2 or 3 HCV infection who were randomized and received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SOF+RBV+Placebo | Percentage of Participants With Viral Breakthrough | 0.0 percentage of participants |
| SOF+RBV | Percentage of Participants With Viral Breakthrough | 0.0 percentage of participants |
Secondary
Percentage of Participants With Viral Relapse
Viral relapse was defined as HCV RNA ≥ LLOQ during the posttreatment period having achieved HCV RNA \< LLOQ at end of treatment, confirmed with 2 consecutive values or last available posttreatment measurement. For the purposes of this efficacy analysis, the posttreatment period began after the end of active treatment (following Week 12 for the SOF+RBV+placebo arm, and Week 16 for the SOF+RBV arm).
Time frame: End of treatment to posttreatment Week 24
Population: The Full Analysis Set included all participants with genotype 2 or 3 HCV infection who were randomized and received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SOF+RBV+Placebo | Percentage of Participants With Viral Relapse | 47 participants |
| SOF+RBV | Percentage of Participants With Viral Relapse | 26 participants |