Hepatitis C
Conditions
Keywords
HCV genotype 2 (GT-2), HCV genotype 3 (GT-3)
Brief summary
This study was to assess the safety and efficacy of sofosbuvir (GS-7977; PSI-7977) in combination with ribavirin (RBV) administered for 12 weeks compared with pegylated interferon (PEG)/RBV administered for 24 weeks in treatment-naive patients with Hepatitis C (HCV) genotype 2 or 3. Efficacy was assessed by the rate of sustained viral response (SVR) 12 weeks after the discontinuation of therapy (SVR12). This was a non-inferiority study, and if non-inferiority was demonstrated, the study was then allowed to test for superiority.
Interventions
DRUGSofosbuvir
Sofosbuvir 400 mg (2 × 200 mg tablets) administered orally once daily
DRUGPEG
Pegylated interferon alfa-2a (PEG) 180 μg administered once weekly by subcutaneous injection
DRUGRBV
Ribavirin (RBV) administered as 200 mg tablets up to 1200 mg in a divided daily dose * Dose of sofosbuvir+RBV group based on baseline weight: \< 75kg = 1000 mg and ≥ 75 kg = 1200 mg * Dose of PEG+RBV group: 800 mg
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Chronic Genotype 2 or 3 HCV-infection * Naive to all HCV antiviral treatment(s)
Exclusion criteria
* Positive test at Screening for HBsAg, anti-hepatitis B core immunoglobulin M antibody (anti-HBc IgM Ab), or anti-HIV Ab * History of any other clinically significant chronic liver disease * A history consistent with decompensated liver disease * History or current evidence of psychiatric illness, immunologic disorder, hemoglobinopathy, pulmonary or cardiac disease, seizure disorder or anticonvulsant use, poorly controlled diabetes, cancer, or a history of malignancy, that makes the subject unsuitable for the study. * Participation in a clinical study within 3 months prior to first dose
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Sustained Virologic Response 12 Weeks After Stopping All Study Drugs (SVR12) | Post-treatment Week 12 | SVR12 was defined as HCV RNA \< the lower limit of quantitation (LLOQ; \< 25 IU/mL) 12 weeks after study drug cessation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With HCV RNA < LLOQ on Treatment | Up to 12 Weeks | — |
| Number of Participants Who Experienced Adverse Events (AEs) and Graded Laboratory Abnormalities | Up to 24 weeks plus 30 days following the last dose of study drug | — |
| Percentage of Participants With Sustained Virologic Response 24 Weeks After Stopping All Study Drugs (SVR24) | Post-treatment Week 24 | SVR24 was defined as HCV RNA \< LLOQ 24 weeks after study drug cessation. |
| Percentage of Participants With Virologic Failure During Treatment | Baseline up to Week 24 | Virologic failure was defined as either * Viral breakthrough: HCV RNA ≥ 25 IU/mL after having previously had HCV RNA \< 25 IU/mL while on treatment, confirmed with 2 consecutive values or last available measurement * Viral rebound: \> 1 log10 IU/mL increase in HCV RNA from nadir while on treatment, confirmed with 2 consecutive values or last available measurement * Non-response: HCV RNA persistently ≥ 25 IU/ml while on treatment (through Week 12) |
| Percentage of Participants With Viral Relapse Following Treatment | Up to Post-treatment Week 24 | Viral relapse was defined as HCV RNA ≥ 25 IU/mL in post-treatment after having achieved \< LLOQ at last on-treatment measurement, confirmed with 2 consecutive values or last available measurement. |
| Change From Baseline in HCV RNA | Baseline to Week 12 | — |
Countries
Australia, Canada, Italy, Netherlands, New Zealand, Puerto Rico, Sweden, United States
Participant flow
Recruitment details
Subjects were enrolled in a total of 90 study sites in the United States, Australia, New Zealand, Canada, Sweden, Italy, and the Netherlands. The first participant was screened on 19 December 2011. The last participant observation was on 08 April 2013.
Pre-assignment details
666 participants were screened and 527 were randomized; 499 participants received at least 1 dose of study drug, and comprise the Safety Analysis Set. The 496 participants with genotype 2 or 3 HCV infection who were randomized and received at least 1 dose of study drug comprise the Full Analysis Set.
Participants by arm
| Arm | Count |
|---|---|
| Sofosbuvir+RBV Participants were randomized to receive sofosbuvir+RBV for 12 weeks. | 256 |
| PEG+RBV Participants were randomized to receive PEG+RBV for 24 weeks. | 243 |
| Total | 499 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 1 |
| Overall Study | Initiated Non-protocol HCV Treatment | 7 | 0 |
| Overall Study | Lost to Follow-up | 11 | 10 |
| Overall Study | Other | 5 | 0 |
| Overall Study | Randomized but not treated | 7 | 21 |
| Overall Study | Virologic failure | 2 | 50 |
| Overall Study | Withdrawal by Subject | 6 | 6 |
Baseline characteristics
| Characteristic | Total | PEG+RBV | Sofosbuvir+RBV |
|---|---|---|---|
| Age, Continuous | 48 years STANDARD_DEVIATION 11 | 48 years STANDARD_DEVIATION 11.4 | 48 years STANDARD_DEVIATION 10.8 |
| Baseline HCV RNA | 6.0 log10 IU/mL STANDARD_DEVIATION 0.8 | 6.0 log10 IU/mL STANDARD_DEVIATION 0.78 | 6.0 log10 IU/mL STANDARD_DEVIATION 0.82 |
| Baseline HCV RNA Category < 6 log10 IU/mL | 214 participants | 106 participants | 108 participants |
| Baseline HCV RNA Category ≥ 6 log10 IU/mL | 285 participants | 137 participants | 148 participants |
| Cirrhosis Missing | 5 participants | 4 participants | 1 participants |
| Cirrhosis No | 394 participants | 189 participants | 205 participants |
| Cirrhosis Yes | 100 participants | 50 participants | 50 participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 72 Participants | 31 Participants | 41 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 427 Participants | 212 Participants | 215 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Hepatitis C Virus (HCV) genotype Genotype 1 | 3 participants | 0 participants | 3 participants |
| Hepatitis C Virus (HCV) genotype Genotype 2 | 137 participants | 67 participants | 70 participants |
| Hepatitis C Virus (HCV) genotype Genotype 3 | 359 participants | 176 participants | 183 participants |
| IL28b genotype CC | 214 participants | 106 participants | 108 participants |
| IL28b genotype CT | 219 participants | 98 participants | 121 participants |
| IL28b genotype Missing | 3 participants | 1 participants | 2 participants |
| IL28b genotype TT | 63 participants | 38 participants | 25 participants |
| Race/Ethnicity, Customized American Indian/Alaska Native/First Nations | 8 participants | 4 participants | 4 participants |
| Race/Ethnicity, Customized Asian | 29 participants | 15 participants | 14 participants |
| Race/Ethnicity, Customized Black and White | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Black or African American | 17 participants | 5 participants | 12 participants |
| Race/Ethnicity, Customized Hawaiian or Pacific Islander | 8 participants | 6 participants | 2 participants |
| Race/Ethnicity, Customized South American | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized White | 435 participants | 212 participants | 223 participants |
| Region of Enrollment Australia | 61 participants | 29 participants | 32 participants |
| Region of Enrollment Canada | 39 participants | 24 participants | 15 participants |
| Region of Enrollment Italy | 12 participants | 4 participants | 8 participants |
| Region of Enrollment Netherlands | 4 participants | 1 participants | 3 participants |
| Region of Enrollment New Zealand | 59 participants | 30 participants | 29 participants |
| Region of Enrollment Sweden | 8 participants | 4 participants | 4 participants |
| Region of Enrollment United States | 316 participants | 151 participants | 165 participants |
| Sex: Female, Male Female | 172 Participants | 87 Participants | 85 Participants |
| Sex: Female, Male Male | 327 Participants | 156 Participants | 171 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 219 / 256 | 233 / 243 |
| serious Total, serious adverse events | 7 / 256 | 3 / 243 |
Outcome results
Primary
Percentage of Participants With Sustained Virologic Response 12 Weeks After Stopping All Study Drugs (SVR12)
SVR12 was defined as HCV RNA \< the lower limit of quantitation (LLOQ; \< 25 IU/mL) 12 weeks after study drug cessation.
Time frame: Post-treatment Week 12
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sofosbuvir+RBV | Percentage of Participants With Sustained Virologic Response 12 Weeks After Stopping All Study Drugs (SVR12) | 67 percentage of participants |
| PEG+RBV | Percentage of Participants With Sustained Virologic Response 12 Weeks After Stopping All Study Drugs (SVR12) | 67 percentage of participants |
95% CI: [-7.5, 8]
Secondary
Change From Baseline in HCV RNA
Time frame: Baseline to Week 12
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Sofosbuvir+RBV | Change From Baseline in HCV RNA | Week 2 (SOF+RBV, n = 246; PEG+RBV, n = 233) | -4.60 log10 IU/mL | Standard Deviation 0.82 |
| Sofosbuvir+RBV | Change From Baseline in HCV RNA | Week 8 (SOF+RBV, n = 248; PEG+RBV, n = 228) | -4.63 log10 IU/mL | Standard Deviation 0.85 |
| Sofosbuvir+RBV | Change From Baseline in HCV RNA | Week 4 (SOF+RBV, n = 250; PEG+RBV, n = 235) | -4.64 log10 IU/mL | Standard Deviation 0.816 |
| Sofosbuvir+RBV | Change From Baseline in HCV RNA | Week 12 (SOF+RBV, n = 243; PEG+RBV, n = 222) | -4.65 log10 IU/mL | Standard Deviation 0.82 |
| Sofosbuvir+RBV | Change From Baseline in HCV RNA | Week 1 (SOF+RBV, n = 239; PEG+RBV, n = 236) | -4.26 log10 IU/mL | Standard Deviation 0.689 |
| PEG+RBV | Change From Baseline in HCV RNA | Week 12 (SOF+RBV, n = 243; PEG+RBV, n = 222) | -4.45 log10 IU/mL | Standard Deviation 1.226 |
| PEG+RBV | Change From Baseline in HCV RNA | Week 1 (SOF+RBV, n = 239; PEG+RBV, n = 236) | -2.19 log10 IU/mL | Standard Deviation 1.287 |
| PEG+RBV | Change From Baseline in HCV RNA | Week 2 (SOF+RBV, n = 246; PEG+RBV, n = 233) | -3.19 log10 IU/mL | Standard Deviation 1.572 |
| PEG+RBV | Change From Baseline in HCV RNA | Week 4 (SOF+RBV, n = 250; PEG+RBV, n = 235) | -4.04 log10 IU/mL | Standard Deviation 1.389 |
| PEG+RBV | Change From Baseline in HCV RNA | Week 8 (SOF+RBV, n = 248; PEG+RBV, n = 228) | -4.42 log10 IU/mL | Standard Deviation 1.163 |
Secondary
Number of Participants Who Experienced Adverse Events (AEs) and Graded Laboratory Abnormalities
Time frame: Up to 24 weeks plus 30 days following the last dose of study drug
Population: Safety Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sofosbuvir+RBV | Number of Participants Who Experienced Adverse Events (AEs) and Graded Laboratory Abnormalities | Serious AEs | 7 participants |
| Sofosbuvir+RBV | Number of Participants Who Experienced Adverse Events (AEs) and Graded Laboratory Abnormalities | Grade 4 laboratory abnormalities | 3 participants |
| Sofosbuvir+RBV | Number of Participants Who Experienced Adverse Events (AEs) and Graded Laboratory Abnormalities | Grade 3 laboratory abnormalities | 33 participants |
| Sofosbuvir+RBV | Number of Participants Who Experienced Adverse Events (AEs) and Graded Laboratory Abnormalities | Deaths | 1 participants |
| Sofosbuvir+RBV | Number of Participants Who Experienced Adverse Events (AEs) and Graded Laboratory Abnormalities | AEs leading to discontinuation of any study drug | 3 participants |
| PEG+RBV | Number of Participants Who Experienced Adverse Events (AEs) and Graded Laboratory Abnormalities | Deaths | 0 participants |
| PEG+RBV | Number of Participants Who Experienced Adverse Events (AEs) and Graded Laboratory Abnormalities | AEs leading to discontinuation of any study drug | 29 participants |
| PEG+RBV | Number of Participants Who Experienced Adverse Events (AEs) and Graded Laboratory Abnormalities | Serious AEs | 3 participants |
| PEG+RBV | Number of Participants Who Experienced Adverse Events (AEs) and Graded Laboratory Abnormalities | Grade 3 laboratory abnormalities | 80 participants |
| PEG+RBV | Number of Participants Who Experienced Adverse Events (AEs) and Graded Laboratory Abnormalities | Grade 4 laboratory abnormalities | 21 participants |
Secondary
Percentage of Participants With HCV RNA < LLOQ on Treatment
Time frame: Up to 12 Weeks
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Sofosbuvir+RBV | Percentage of Participants With HCV RNA < LLOQ on Treatment | Week 2 (SOF+RBV, n = 251; PEG+RBV, n = 241) | 92.0 percentage of participants |
| Sofosbuvir+RBV | Percentage of Participants With HCV RNA < LLOQ on Treatment | Week 8 (SOF+RBV, n = 248; PEG+RBV, n = 231) | 99.6 percentage of participants |
| Sofosbuvir+RBV | Percentage of Participants With HCV RNA < LLOQ on Treatment | Week 4 (SOF+RBV, n = 250; PEG+RBV, n = 236) | 99.6 percentage of participants |
| Sofosbuvir+RBV | Percentage of Participants With HCV RNA < LLOQ on Treatment | Week 12 (SOF+RBV, n = 244; PEG+RBV, n = 224) | 99.2 percentage of participants |
| Sofosbuvir+RBV | Percentage of Participants With HCV RNA < LLOQ on Treatment | Week 1 (SOF+RBV, n = 252; PEG+RBV, n = 243) | 43.7 percentage of participants |
| PEG+RBV | Percentage of Participants With HCV RNA < LLOQ on Treatment | Week 12 (SOF+RBV, n = 244; PEG+RBV, n = 224) | 92.4 percentage of participants |
| PEG+RBV | Percentage of Participants With HCV RNA < LLOQ on Treatment | Week 1 (SOF+RBV, n = 252; PEG+RBV, n = 243) | 6.6 percentage of participants |
| PEG+RBV | Percentage of Participants With HCV RNA < LLOQ on Treatment | Week 2 (SOF+RBV, n = 251; PEG+RBV, n = 241) | 31.5 percentage of participants |
| PEG+RBV | Percentage of Participants With HCV RNA < LLOQ on Treatment | Week 4 (SOF+RBV, n = 250; PEG+RBV, n = 236) | 66.9 percentage of participants |
| PEG+RBV | Percentage of Participants With HCV RNA < LLOQ on Treatment | Week 8 (SOF+RBV, n = 248; PEG+RBV, n = 231) | 85.7 percentage of participants |
Secondary
Percentage of Participants With Sustained Virologic Response 24 Weeks After Stopping All Study Drugs (SVR24)
SVR24 was defined as HCV RNA \< LLOQ 24 weeks after study drug cessation.
Time frame: Post-treatment Week 24
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sofosbuvir+RBV | Percentage of Participants With Sustained Virologic Response 24 Weeks After Stopping All Study Drugs (SVR24) | 66.8 percentage of participants |
| PEG+RBV | Percentage of Participants With Sustained Virologic Response 24 Weeks After Stopping All Study Drugs (SVR24) | 65.4 percentage of participants |
Secondary
Percentage of Participants With Viral Relapse Following Treatment
Viral relapse was defined as HCV RNA ≥ 25 IU/mL in post-treatment after having achieved \< LLOQ at last on-treatment measurement, confirmed with 2 consecutive values or last available measurement.
Time frame: Up to Post-treatment Week 24
Population: Participants in the Full Analysis Set with available data were analyzed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sofosbuvir+RBV | Percentage of Participants With Viral Relapse Following Treatment | 30.5 percentage of participants |
| PEG+RBV | Percentage of Participants With Viral Relapse Following Treatment | 22.6 percentage of participants |
Secondary
Percentage of Participants With Virologic Failure During Treatment
Virologic failure was defined as either * Viral breakthrough: HCV RNA ≥ 25 IU/mL after having previously had HCV RNA \< 25 IU/mL while on treatment, confirmed with 2 consecutive values or last available measurement * Viral rebound: \> 1 log10 IU/mL increase in HCV RNA from nadir while on treatment, confirmed with 2 consecutive values or last available measurement * Non-response: HCV RNA persistently ≥ 25 IU/ml while on treatment (through Week 12)
Time frame: Baseline up to Week 24
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Sofosbuvir+RBV | Percentage of Participants With Virologic Failure During Treatment | 0.4 percentage of participants |
| PEG+RBV | Percentage of Participants With Virologic Failure During Treatment | 7.4 percentage of participants |