Hepatitis C
Conditions
Keywords
HCV, Genotype 2, Genotype 3
Brief summary
This study will evaluate the safety, tolerability, and antiviral efficacy of GS-7977 with ribavirin (RBV) in participants with genotype 2 or 3 hepatitis C virus (HCV) infection.
Interventions
DRUGSOF
Sofosbuvir (SOF) 400 mg tablet administered orally once daily
DRUGRBV
Ribavirin (RBV) 200 mg tablets administered orally in a divided daily dose according to package insert weight-based dosing recommendations (\< 75 kg = 1000 mg and ≥ 75 kg = 1200 mg)
Placebo to match SOF administered orally once daily
Placebo to match RBV administered orally in a divided daily dose
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age \> 18 with chronic genotype 2 or 3 HCV infection * HCV RNA \> 10,000 IU/mL at screening * Subjects must be treatment naive or treatment experienced * Presence or absence of cirrhosis; a liver biopsy may be required * Healthy according to medical history and physical examination with the exception of HCV diagnosis * Agree to use two forms of highly effective contraception for the duration of the study and 6 months after the last dose of study medication
Exclusion criteria
* Prior use of any other inhibitor of the HCV NS5B Polymerase * History of any other clinically significant chronic liver disease * Evidence of or history of decompensated liver disease * HIV or chronic hepatitis B virus (HBV) infection * Hepatocellular carcinoma (HCC) or other malignancy (with exception of certain resolved skin cancers) * Chronic use of immunosuppressive agents or immunomodulatory agents * History or current evidence of any condition, therapy, laboratory abnormality or other circumstance that might confound the results of the study, or interfere with the subject's participation for the full duration of the study or not be in the best interest of the subject in the opinion of the investigator
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Sustained Virologic Response 12 Weeks After Discontinuation of Therapy (SVR12) | Posttreatment Week 12 | SVR12 was defined as HCV RNA \< the lower limit of quantitation (LLOQ, ie, \< 25 IU/mL) 12 weeks following the last dose of study drug. Data for this outcome measure was not collected for the Placebo 12 Weeks (GT2/3) group. |
| Adverse Events Leading to Permanent Discontinuation of Study Drug(s) | Up to 24 weeks | The percentage of participants experiencing an adverse event leading to permanent discontinuation of study drug(s) was analyzed. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Sustained Virologic Response at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | Posttreatment Weeks 4 and 24 | SVR4 and SVR24 was defined as HCV RNA \< LLOQ at 4 and 24 weeks following the last dose of study drug, respectively. Data for this outcome measure was not collected for the Placebo 12 Weeks (GT2/3) group. |
| Percentage of Participants Experiencing Viral Breakthrough or Viral Relapse | Up to Posttreatment Week 24 | Viral breakthrough was defined as having confirmed detectable HCV RNA levels (HCV RNA \> LLOQ) after having previously had undetectable HCV RNA levels (HCV RNA \< LLOQ) while on treatment. Viral relapse was defined as having achieved undetectable HCV RNA levels (HCV RNA \< LLOQ) at end of treatment, but did not achieve an SVR. Data for this outcome measure was not collected for the Placebo 12 Weeks (GT2/3) group. |
Countries
Austria, Estonia, France, Germany, Italy, Netherlands, Poland, Spain, Sweden, United Kingdom
Participant flow
Recruitment details
Participants were enrolled at a total of 77 study sites in Europe. The first participant was screened on 19 September 2012. The last participant observation occurred on 08 January 2014.
Pre-assignment details
* 475 participants were screened and 421 were randomized. * 419 participants were randomized and received at least 1 dose of study drug (Safety Analysis Set). * 334 participants with genotype 2 or 3 hepatitis C virus (HCV) infection were randomized and received at least 1 dose of sofosbuvir (Full Analysis Set).
Participants by arm
| Arm | Count |
|---|---|
| Placebo 12 Weeks (GT2/3) Placebo to match SOF + placebo to match RBV for 12 weeks in participants with genotype 2 or 3 HCV infection. | 85 |
| SOF 12 Weeks (GT2) SOF 400 mg tablet once daily + weight-based RBV (1000-1200 mg as 200 mg tablets in a divided daily dose) for 12 weeks in participants with genotype 2 HCV infection. | 73 |
| SOF 12 Weeks (GT3) SOF 400 mg tablet once daily + weight-based RBV (1000-1200 mg as 200 mg tablets in a divided daily dose) for 12 weeks in participants with genotype 3 HCV infection. | 11 |
| SOF 24 Weeks (GT3) SOF 400 mg tablet once daily + weight-based RBV (1000-1200 mg as 200 mg tablets in a divided daily dose) for 24 weeks in participants with genotype 3 HCV infection. | 250 |
| Total | 419 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 1 | 1 |
| Overall Study | Efficacy Failure | 0 | 3 | 3 | 30 |
| Overall Study | Lost to Follow-up | 1 | 1 | 0 | 6 |
| Overall Study | Randomized but Not Treated | 0 | 1 | 1 | 0 |
| Overall Study | Subject Withdrew Consent | 0 | 0 | 2 | 2 |
| Overall Study | Terminated by Sponsor | 83 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Total | Placebo 12 Weeks (GT2/3) | SOF 24 Weeks (GT3) | SOF 12 Weeks (GT3) | SOF 12 Weeks (GT2) |
|---|---|---|---|---|---|
| Age, Continuous | 50 years STANDARD_DEVIATION 10.8 | 49 years STANDARD_DEVIATION 10.5 | 48 years STANDARD_DEVIATION 10.1 | 46 years STANDARD_DEVIATION 8.8 | 58 years STANDARD_DEVIATION 10.1 |
| HCV Genotype Genotype 2 | 91 participants | 18 participants | 0 participants | 0 participants | 73 participants |
| HCV Genotype Genotype 3 | 328 participants | 67 participants | 250 participants | 11 participants | 0 participants |
| HCV RNA | 6.4 log10 IU/mL STANDARD_DEVIATION 0.72 | 6.5 log10 IU/mL STANDARD_DEVIATION 0.69 | 6.3 log10 IU/mL STANDARD_DEVIATION 0.74 | 6.2 log10 IU/mL STANDARD_DEVIATION 0.77 | 6.5 log10 IU/mL STANDARD_DEVIATION 0.7 |
| HCV RNA Category < 6 log10 IU/mL | 113 participants | 21 participants | 72 participants | 4 participants | 16 participants |
| HCV RNA Category ≥ 6 log10 IU/mL | 306 participants | 64 participants | 178 participants | 7 participants | 57 participants |
| IL28b Status CC | 136 participants | 22 participants | 86 participants | 4 participants | 24 participants |
| IL28b Status CT | 225 participants | 49 participants | 131 participants | 4 participants | 41 participants |
| IL28b Status TT | 58 participants | 14 participants | 33 participants | 3 participants | 8 participants |
| Interferon Eligibility Interferon eligible | 153 participants | 30 participants | 94 participants | 2 participants | 27 participants |
| Interferon Eligibility Interferon ineligible | 21 participants | 5 participants | 11 participants | 0 participants | 5 participants |
| Liver Cirrhosis No | 329 participants | 68 participants | 190 participants | 9 participants | 62 participants |
| Liver Cirrhosis Yes | 90 participants | 17 participants | 60 participants | 2 participants | 11 participants |
| Prior HCV Treatment Experience Experienced | 245 participants | 50 participants | 145 participants | 9 participants | 41 participants |
| Prior HCV Treatment Experience Naive | 174 participants | 35 participants | 105 participants | 2 participants | 32 participants |
| Race/Ethnicity, Customized Asian | 13 participants | 3 participants | 9 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Black or African American | 6 participants | 1 participants | 0 participants | 0 participants | 5 participants |
| Race/Ethnicity, Customized Hispanic or Latino | 53 participants | 10 participants | 36 participants | 1 participants | 6 participants |
| Race/Ethnicity, Customized Not Hispanic or Latino | 349 participants | 71 participants | 203 participants | 10 participants | 65 participants |
| Race/Ethnicity, Customized Not permitted | 7 participants | 0 participants | 5 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized Not Permitted | 17 participants | 4 participants | 11 participants | 0 participants | 2 participants |
| Race/Ethnicity, Customized White | 393 participants | 81 participants | 236 participants | 11 participants | 65 participants |
| Region of Enrollment Austria | 18 participants | 4 participants | 12 participants | 0 participants | 2 participants |
| Region of Enrollment Estonia | 15 participants | 3 participants | 6 participants | 4 participants | 2 participants |
| Region of Enrollment France | 81 participants | 13 participants | 53 participants | 0 participants | 15 participants |
| Region of Enrollment Germany | 69 participants | 14 participants | 46 participants | 1 participants | 8 participants |
| Region of Enrollment Italy | 62 participants | 9 participants | 27 participants | 1 participants | 25 participants |
| Region of Enrollment Netherlands | 25 participants | 5 participants | 14 participants | 0 participants | 6 participants |
| Region of Enrollment Poland | 22 participants | 4 participants | 18 participants | 0 participants | 0 participants |
| Region of Enrollment Spain | 48 participants | 11 participants | 31 participants | 1 participants | 5 participants |
| Region of Enrollment Sweden | 24 participants | 5 participants | 12 participants | 0 participants | 7 participants |
| Region of Enrollment United Kingdom | 55 participants | 17 participants | 31 participants | 4 participants | 3 participants |
| Response to prior HCV treatment Interferon intolerant | 13 participants | 0 participants | 10 participants | 0 participants | 3 participants |
| Response to prior HCV treatment Nonresponse | 73 participants | 18 participants | 41 participants | 4 participants | 10 participants |
| Response to prior HCV treatment Relapse/Breakthrough | 159 participants | 32 participants | 94 participants | 5 participants | 28 participants |
| Sex: Female, Male Female | 169 Participants | 36 Participants | 95 Participants | 5 Participants | 33 Participants |
| Sex: Female, Male Male | 250 Participants | 49 Participants | 155 Participants | 6 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 60 / 85 | 72 / 84 | 229 / 250 |
| serious Total, serious adverse events | 2 / 85 | 0 / 84 | 10 / 250 |
Outcome results
Primary
Adverse Events Leading to Permanent Discontinuation of Study Drug(s)
The percentage of participants experiencing an adverse event leading to permanent discontinuation of study drug(s) was analyzed.
Time frame: Up to 24 weeks
Population: Safety Analysis Set: participants were randomized and received at least 1 dose of study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SOF 12 Weeks (GT2) | Adverse Events Leading to Permanent Discontinuation of Study Drug(s) | 1.2 percentage of participants |
| SOF 12 Weeks (GT3) | Adverse Events Leading to Permanent Discontinuation of Study Drug(s) | 1.2 percentage of participants |
| SOF 24 Weeks (GT3) | Adverse Events Leading to Permanent Discontinuation of Study Drug(s) | 0.4 percentage of participants |
Primary
Percentage of Participants With Sustained Virologic Response 12 Weeks After Discontinuation of Therapy (SVR12)
SVR12 was defined as HCV RNA \< the lower limit of quantitation (LLOQ, ie, \< 25 IU/mL) 12 weeks following the last dose of study drug. Data for this outcome measure was not collected for the Placebo 12 Weeks (GT2/3) group.
Time frame: Posttreatment Week 12
Population: Full Analysis Set: participants with genotype 2 or 3 HCV infection were randomized and received at least 1 dose of SOF.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SOF 12 Weeks (GT2) | Percentage of Participants With Sustained Virologic Response 12 Weeks After Discontinuation of Therapy (SVR12) | 93.2 percentage of participants |
| SOF 12 Weeks (GT3) | Percentage of Participants With Sustained Virologic Response 12 Weeks After Discontinuation of Therapy (SVR12) | 27.3 percentage of participants |
| SOF 24 Weeks (GT3) | Percentage of Participants With Sustained Virologic Response 12 Weeks After Discontinuation of Therapy (SVR12) | 85.2 percentage of participants |
Secondary
Percentage of Participants Experiencing Viral Breakthrough or Viral Relapse
Viral breakthrough was defined as having confirmed detectable HCV RNA levels (HCV RNA \> LLOQ) after having previously had undetectable HCV RNA levels (HCV RNA \< LLOQ) while on treatment. Viral relapse was defined as having achieved undetectable HCV RNA levels (HCV RNA \< LLOQ) at end of treatment, but did not achieve an SVR. Data for this outcome measure was not collected for the Placebo 12 Weeks (GT2/3) group.
Time frame: Up to Posttreatment Week 24
Population: Full Analysis Set: participants with genotype 2 or 3 HCV infection were randomized and received at least 1 dose of SOF.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| SOF 12 Weeks (GT2) | Percentage of Participants Experiencing Viral Breakthrough or Viral Relapse | Viral breakthrough | 0 percentage of participants |
| SOF 12 Weeks (GT2) | Percentage of Participants Experiencing Viral Breakthrough or Viral Relapse | Viral relapse | 6.8 percentage of participants |
| SOF 12 Weeks (GT3) | Percentage of Participants Experiencing Viral Breakthrough or Viral Relapse | Viral breakthrough | 0 percentage of participants |
| SOF 12 Weeks (GT3) | Percentage of Participants Experiencing Viral Breakthrough or Viral Relapse | Viral relapse | 54.5 percentage of participants |
| SOF 24 Weeks (GT3) | Percentage of Participants Experiencing Viral Breakthrough or Viral Relapse | Viral breakthrough | 0.4 percentage of participants |
| SOF 24 Weeks (GT3) | Percentage of Participants Experiencing Viral Breakthrough or Viral Relapse | Viral relapse | 14.0 percentage of participants |
Secondary
Percentage of Participants With Sustained Virologic Response at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24)
SVR4 and SVR24 was defined as HCV RNA \< LLOQ at 4 and 24 weeks following the last dose of study drug, respectively. Data for this outcome measure was not collected for the Placebo 12 Weeks (GT2/3) group.
Time frame: Posttreatment Weeks 4 and 24
Population: Full Analysis Set: participants with genotype 2 or 3 HCV infection were randomized and received at least 1 dose of SOF.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| SOF 12 Weeks (GT2) | Percentage of Participants With Sustained Virologic Response at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR24 | 93.2 percentage of participants |
| SOF 12 Weeks (GT2) | Percentage of Participants With Sustained Virologic Response at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR4 | 93.2 percentage of participants |
| SOF 12 Weeks (GT3) | Percentage of Participants With Sustained Virologic Response at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR24 | 27.3 percentage of participants |
| SOF 12 Weeks (GT3) | Percentage of Participants With Sustained Virologic Response at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR4 | 45.5 percentage of participants |
| SOF 24 Weeks (GT3) | Percentage of Participants With Sustained Virologic Response at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR24 | 84.4 percentage of participants |
| SOF 24 Weeks (GT3) | Percentage of Participants With Sustained Virologic Response at 4 and 24 Weeks After Discontinuation of Therapy (SVR4 and SVR24) | SVR4 | 87.2 percentage of participants |