Chronic Hepatitis C
Conditions
Keywords
HCV genotype 2 (GT-2), HCV genotype 3 (GT-3), HCV, Sustained Virologic Response, Direct Acting Antiviral, Combination Therapy, Interferon intolerant, Interferon ineligible, GS-7977, Ribavirin
Brief summary
This multicenter study was to evaluate subjects with chronic genotype 2 or 3 HCV infection who were interferon (IFN) ineligible, IFN intolerant or unwilling to take IFN. Participants were randomized in a 3:1 ratio to receive sofosbuvir (SOF)+ribavirin (RBV), or placebo to match SOF+placebo to match RBV. Randomization was stratified by presence/absence of cirrhosis. Approximately 20% of participants may have had evidence of cirrhosis at screening.
Detailed description
Participants who were randomized to the placebo arm and completed all scheduled study procedures were eligible to receive active SOF+RBV in open-label Study GS-US-334-0109. Participants who do not achieve sustained virologic response (SVR) were eligible for enrollment in the Sequence Registry Study GS-US-248-0123. The purpose of the Sequence Registry Study is to monitor the persistence of resistant mutations for up to 3 years. Participants who achieved SVR were eligible for enrollment in the SVR Registry Study GS-US-248-0122. The purpose of the SVR Registry Study is to evaluate durability of SVR for up to 3 years after treatment.
Interventions
DRUGSOF
Sofosbuvir (SOF) 400 mg tablet administered orally once daily
DRUGRBV
Ribavirin (RBV) was administered as a tablet orally 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 * Cirrhosis determination * Subject meets one of the following classifications: 1. IFN unwilling 2. IFN ineligible 3. IFN intolerant * Screening laboratory values within defined thresholds * Subject has 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 interfere 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 | Post-treatment Week 12 | SVR12 was defined as HCV RNA \< the lower limit of quantitation (LLOQ, ie, \< 25 IU/mL) 12 weeks after cessation of therapy |
| Number of Participants Experiencing Adverse Events Leading to Permanent Discontinuation of Study Drug | Baseline to Week 12 | The number of subjects experiencing adverse events leading to permanent discontinuation of study drug was summarized. Adverse events may or may not have been related to study treatment. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Achieving SVR4 | Post-treatment Week 4 | SVR4 was defined as HCV RNA \< LLOQ 4 weeks after cessation of therapy |
| Percentage of Participants Achieving SVR24 | Post-treatment Week 24 | SVR24 was defined as HCV RNA \< LLOQ 24 weeks after cessation of therapy |
| Percentage of Participants Experiencing Viral Breakthrough | Baseline to Week 12 | 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 |
| Percentage of Participants Experiencing Viral Relapse | End of treatment to post-treatment 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 |
Countries
Australia, Canada, New Zealand, Puerto Rico, United States
Participant flow
Recruitment details
Participants were enrolled at 54 sites in the North America, Australia, and New Zealand. The first participant was screened on 07 March 2012. The last participant observation was on 04 February 2013.
Pre-assignment details
410 participants were screened and 280 were randomized. Of those participants randomized, 278 received at least one dose of study drug, and comprise the Safety Analysis Set and the Full Analysis Set.
Participants by arm
| Arm | Count |
|---|---|
| SOF+RBV Participants were randomized to receive SOF+RBV for 12 weeks. SOF was administered as a 400 mg tablet orally once daily. RBV was administered as 200 mg tablets (1000-1200 mg daily based on weight) according to package insert recommendations. | 207 |
| Placebo Participants were randomized to receive placebo to match SOF plus placebo to match RBV for 12 weeks. Placebos were administered in the same manner as their active counterparts. | 71 |
| Total | 278 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 3 | 0 |
| Overall Study | Lack of Efficacy | 41 | 71 |
| Overall Study | Lost to Follow-up | 5 | 0 |
| Overall Study | Physician Decision | 1 | 0 |
| Overall Study | Protocol Violation | 2 | 0 |
| Overall Study | Randomized but Not Treated | 2 | 0 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | SOF+RBV | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 52 years STANDARD_DEVIATION 9.9 | 52 years STANDARD_DEVIATION 9.5 | 52 years STANDARD_DEVIATION 8.2 |
| Cirrhosis No | 176 participants | 234 participants | 58 participants |
| Cirrhosis Yes | 31 participants | 44 participants | 13 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 19 Participants | 30 Participants | 11 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 188 Participants | 248 Participants | 60 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| HCV Genotype Genotype 2 | 109 participants | 143 participants | 34 participants |
| HCV Genotype Genotype 3 | 98 participants | 135 participants | 37 participants |
| HCV RNA | 6.3 log10 IU/mL STANDARD_DEVIATION 0.77 | 6.3 log10 IU/mL STANDARD_DEVIATION 0.77 | 6.3 log10 IU/mL STANDARD_DEVIATION 0.76 |
| HCV RNA Category < 6 log10 IU/mL | 67 participants | 84 participants | 17 participants |
| HCV RNA Category ≥ 6 log10 IU/mL | 140 participants | 194 participants | 54 participants |
| IL28 Genotype CC | 97 participants | 126 participants | 29 participants |
| IL28 Genotype CT | 84 participants | 120 participants | 36 participants |
| IL28 Genotype TT | 26 participants | 32 participants | 6 participants |
| Interferon Classification Ineligible | 88 participants | 121 participants | 33 participants |
| Interferon Classification Intolerant | 17 participants | 25 participants | 8 participants |
| Interferon Classification Unwilling | 102 participants | 132 participants | 30 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 2 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 7 Participants | 8 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 13 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 188 Participants | 254 Participants | 66 Participants |
| Region of Enrollment Australia | 18 participants | 21 participants | 3 participants |
| Region of Enrollment Canada | 15 participants | 23 participants | 8 participants |
| Region of Enrollment New Zealand | 6 participants | 6 participants | 0 participants |
| Region of Enrollment United States | 168 participants | 228 participants | 60 participants |
| Sex: Female, Male Female | 90 Participants | 127 Participants | 37 Participants |
| Sex: Female, Male Male | 117 Participants | 151 Participants | 34 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 184 / 207 | 55 / 71 |
| serious Total, serious adverse events | 11 / 207 | 2 / 71 |
Outcome results
Primary
Number of Participants Experiencing Adverse Events Leading to Permanent Discontinuation of Study Drug
The number of subjects experiencing adverse events leading to permanent discontinuation of study drug was summarized. Adverse events may or may not have been related to study treatment.
Time frame: Baseline to Week 12
Population: Safety Analysis Set: participants were randomized and received at least 1 dose of study drug
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| SOF+RBV | Number of Participants Experiencing Adverse Events Leading to Permanent Discontinuation of Study Drug | Muscle spasms | 1 participants |
| SOF+RBV | Number of Participants Experiencing Adverse Events Leading to Permanent Discontinuation of Study Drug | Oedema peripheral | 0 participants |
| SOF+RBV | Number of Participants Experiencing Adverse Events Leading to Permanent Discontinuation of Study Drug | No adverse event leading to discontinuation | 202 participants |
| SOF+RBV | Number of Participants Experiencing Adverse Events Leading to Permanent Discontinuation of Study Drug | Abdominal pain upper | 1 participants |
| SOF+RBV | Number of Participants Experiencing Adverse Events Leading to Permanent Discontinuation of Study Drug | Alanine aminotransferase increased | 0 participants |
| SOF+RBV | Number of Participants Experiencing Adverse Events Leading to Permanent Discontinuation of Study Drug | Anaemia | 1 participants |
| SOF+RBV | Number of Participants Experiencing Adverse Events Leading to Permanent Discontinuation of Study Drug | Anxiety | 1 participants |
| SOF+RBV | Number of Participants Experiencing Adverse Events Leading to Permanent Discontinuation of Study Drug | Chest discomfort | 1 participants |
| SOF+RBV | Number of Participants Experiencing Adverse Events Leading to Permanent Discontinuation of Study Drug | Injury | 1 participants |
| SOF+RBV | Number of Participants Experiencing Adverse Events Leading to Permanent Discontinuation of Study Drug | Insomnia | 1 participants |
| SOF+RBV | Number of Participants Experiencing Adverse Events Leading to Permanent Discontinuation of Study Drug | Pancreatitis | 0 participants |
| SOF+RBV | Number of Participants Experiencing Adverse Events Leading to Permanent Discontinuation of Study Drug | Rash | 0 participants |
| SOF+RBV | Number of Participants Experiencing Adverse Events Leading to Permanent Discontinuation of Study Drug | Road traffic accident | 1 participants |
| Placebo | Number of Participants Experiencing Adverse Events Leading to Permanent Discontinuation of Study Drug | Rash | 1 participants |
| Placebo | Number of Participants Experiencing Adverse Events Leading to Permanent Discontinuation of Study Drug | Muscle spasms | 0 participants |
| Placebo | Number of Participants Experiencing Adverse Events Leading to Permanent Discontinuation of Study Drug | Chest discomfort | 0 participants |
| Placebo | Number of Participants Experiencing Adverse Events Leading to Permanent Discontinuation of Study Drug | Pancreatitis | 1 participants |
| Placebo | Number of Participants Experiencing Adverse Events Leading to Permanent Discontinuation of Study Drug | No adverse event leading to discontinuation | 68 participants |
| Placebo | Number of Participants Experiencing Adverse Events Leading to Permanent Discontinuation of Study Drug | Injury | 0 participants |
| Placebo | Number of Participants Experiencing Adverse Events Leading to Permanent Discontinuation of Study Drug | Abdominal pain upper | 0 participants |
| Placebo | Number of Participants Experiencing Adverse Events Leading to Permanent Discontinuation of Study Drug | Road traffic accident | 0 participants |
| Placebo | Number of Participants Experiencing Adverse Events Leading to Permanent Discontinuation of Study Drug | Alanine aminotransferase increased | 1 participants |
| Placebo | Number of Participants Experiencing Adverse Events Leading to Permanent Discontinuation of Study Drug | Insomnia | 0 participants |
| Placebo | Number of Participants Experiencing Adverse Events Leading to Permanent Discontinuation of Study Drug | Anaemia | 0 participants |
| Placebo | Number of Participants Experiencing Adverse Events Leading to Permanent Discontinuation of Study Drug | Oedema peripheral | 1 participants |
| Placebo | Number of Participants Experiencing Adverse Events Leading to Permanent Discontinuation of Study Drug | Anxiety | 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
Time frame: Post-treatment Week 12
Population: Full Analysis Set: participants with genotype 2 or 3 HCV infection who were randomized into the study and received at least 1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SOF+RBV | Percentage of Participants Achieving SVR12 | 78 percentage of participants |
| Placebo | Percentage of Participants Achieving SVR12 | 0 percentage of participants |
Comparison: A sample size of 180 subjects in the active group and 60 in the placebo group would provide 99% power to detect a difference between group SVR12 rates of 40% using a 2-sided continuity-corrected chi-square test at significance level of 0.05.p-value: <0.00195% CI: [71, 83.6]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Achieving SVR24
SVR24 was defined as HCV RNA \< LLOQ 24 weeks after cessation of therapy
Time frame: Post-treatment Week 24
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SOF+RBV | Percentage of Participants Achieving SVR24 | 77.8 percentage of participants |
| Placebo | Percentage of Participants Achieving SVR24 | 0.0 percentage of participants |
p-value: <0.00195% CI: [71, 83.6]Cochran-Mantel-Haenszel
Secondary
Percentage of Participants Achieving SVR4
SVR4 was defined as HCV RNA \< LLOQ 4 weeks after cessation of therapy
Time frame: Post-treatment Week 4
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SOF+RBV | Percentage of Participants Achieving SVR4 | 83.1 percentage of participants |
| Placebo | Percentage of Participants Achieving SVR4 | 0.0 percentage of participants |
95% CI: [76.8, 88.5]
Secondary
Percentage of Participants Experiencing 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
Time frame: Baseline to Week 12
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SOF+RBV | Percentage of Participants Experiencing Viral Breakthrough | 0.0 percentage of participants |
| Placebo | Percentage of Participants Experiencing Viral Breakthrough | 0.0 percentage of participants |
Secondary
Percentage of Participants Experiencing 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
Time frame: End of treatment to post-treatment Week 24
Population: Participants in the Full Analysis Set who had an end-of-treatment response (HCV RNA \< LLOQ as the last observed on-treatment value) were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SOF+RBV | Percentage of Participants Experiencing Viral Relapse | 20.5 percentage of participants |