Dose-Ranging Study of Sofosbuvir in Combination With Pegylated Interferon and Ribavirin in Treatment Naïve GT 1 HCV Patients

Study Overview
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Brief Summary
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Participants with genotype 1 HCV infection were randomized to 1 of 3 sofosbuvir doses (100 mg, 200 mg, or 400 mg) or matching placebo once daily based upon stratification for IL28B status (CC or CT/TT). Placebo tablets were administered to participants receiving 100 mg active sofosbuvir (3 placebo tablets) and 200 mg active sofosbuvir (2 placebo tablets) in order to maintain the study blind. Participants received sofosbuvir/matching placebo from Day 0 to 27. Participants also received treatment with PEG+RBV starting on Day 0 of the study which continued for 48 weeks. Participants were evaluated for sustained virologic response (SVR) for an additional 24 weeks following completion of study treatment.

Official Title
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A Multi-center, Double-Blind, Parallel Group, Randomized, Placebo-Controlled, Dose Ranging Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Following Oral Administration of PSI-7977 in Combination With Standard of Care (Pegylated Interferon and Ribavirin) in Treatment-Naïve Patients With Chronic HCV Infection Genotype 1

Conditions
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Hepatitis C

Intervention / Treatment
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* Drug: Sofosbuvir
* Drug: Placebo
* Drug: PEG
* Drug: RBV


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Treatment-naive males and females, 18-65 years of age Genotype 1 HCV infection Negative pregnancy test for females of childbearing age Females of childbearing age and males with female partners of childbearing age must use two forms of contraception during treatment and following the last dose of ribavirin in accordance with locally approved label for ribavirin Exclusion Criteria: Hepatitis B or HIV infection Pregnant or breast feeding females or male partners of pregnant females Previous interferon or ribavirin-based therapy or investigational anti-HCV agent History or evidence of medical condition associated with chronic liver disease other than HCV

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sofosbuvir 100 mg+PEG+RBV<br>Participants received sofosbuvir 100 mg (1 x 100 mg tablet) and placebo to match sofosbuvir (3 tablets) for 28 days (baseline to Day 28), plus PEG+RBV (baseline to Week 48) | Drug: Sofosbuvir<br>* Sofosbuvir tablet(s) administered orally once daily<br>* Other names: PSI-7977;Drug: PEG<br>* Pegylated interferon alfa-2a (PEG) 180 μg was administered once weekly by subcutaneous injection.<br>* Other names: Pegasys®;Drug: RBV<br>* Ribavirin (RBV) tablets were administered orally in a divided daily dose according to package insert weight-based dosing recommendations (< 75kg = 1000 mg and ≥ 75 kg = 1200 mg).<br>* Other names: Copegus®;|
| Experimental: Sofosbuvir 200 mg+PEG+RBV<br>Participants received sofosbuvir 200 mg (2 x 100 mg tablets) and placebo to match sofosbuvir (2 tablets) for 28 days (baseline to Day 28), plus PEG+RBV (baseline to Week 48) | Drug: Sofosbuvir<br>* Sofosbuvir tablet(s) administered orally once daily<br>* Other names: PSI-7977;Drug: PEG<br>* Pegylated interferon alfa-2a (PEG) 180 μg was administered once weekly by subcutaneous injection.<br>* Other names: Pegasys®;Drug: RBV<br>* Ribavirin (RBV) tablets were administered orally in a divided daily dose according to package insert weight-based dosing recommendations (< 75kg = 1000 mg and ≥ 75 kg = 1200 mg).<br>* Other names: Copegus®;|
| Experimental: Sofosbuvir 400 mg+PEG+RBV<br>Participants received sofosbuvir 400 mg (4 x 100 mg tablets) for 28 days (baseline to Day 28), plus PEG+RBV (baseline to Week 48) | Drug: Sofosbuvir<br>* Sofosbuvir tablet(s) administered orally once daily<br>* Other names: PSI-7977;Drug: PEG<br>* Pegylated interferon alfa-2a (PEG) 180 μg was administered once weekly by subcutaneous injection.<br>* Other names: Pegasys®;Drug: RBV<br>* Ribavirin (RBV) tablets were administered orally in a divided daily dose according to package insert weight-based dosing recommendations (< 75kg = 1000 mg and ≥ 75 kg = 1200 mg).<br>* Other names: Copegus®;|
| Active Comparator: Placebo+PEG+RBV<br>Participants received placebo to match sofosbuvir (4 tablets) for 28 days (baseline to Day 28), plus PEG+RBV (baseline to Week 48) | Drug: Placebo<br>* Placebo to match sofosbuvir administered orally once daily<br>Drug: PEG<br>* Pegylated interferon alfa-2a (PEG) 180 μg was administered once weekly by subcutaneous injection.<br>* Other names: Pegasys®;Drug: RBV<br>* Ribavirin (RBV) tablets were administered orally in a divided daily dose according to package insert weight-based dosing recommendations (< 75kg = 1000 mg and ≥ 75 kg = 1200 mg).<br>* Other names: Copegus®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Experienced Adverse Events During the Sofosbuvir Treatment Period | Adverse events (AEs) occurring during the sofosbuvir treatment period were summarized across the participant population. A participant was counted once if they had a qualifying event. | Baseline to Week 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Circulating HCV RNA at Week 4 |  | Baseline to Week 4 | 
| Percentage of Participants With Rapid Virologic Response at Week 4 | Rapid virologic response (RVR) was defined as HCV RNA below the limit of detection (LOD [15 IU/mL]) at Week 4. | Week 4 | 
| Percentage of Participants With Sustained Virologic Response (SVR) at 12 and 24 Weeks After Last Dose of PEG+RBV Following Completion of 48 Weeks of Treatment | SVR at 12 weeks (SVR12) and 24 weeks (SVR24) was defined as HCV RNA < LOD 12 and 24 weeks after last dose of PEG+RBV, respectively, following completion of 48 weeks of treatment (4 weeks of sofosbuvir or matching placebo and PEG+RBV, followed by an additional 44 weeks of PEG+RBV). | Post-treatment Weeks 12 and 24 | 
| Plasma Pharmacokinetics of Sofosbuvir: Cmax at Day 0 | The Cmax of sofosbuvir was measured at Day 0 following a single dose of sofosbuvir. Cmax is defined as the maximum concentration of drug. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours postdose | 
| Plasma Pharmacokinetics of Sofosbuvir: Cmax at Day 27 | The Cmax of sofosbuvir was measured at Day 27 following continuous dosing of sofosbuvir. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose) | 
| Plasma Pharmacokinetics of Sofosbuvir: AUCinf at Day 0 | The AUCinf of sofosbuvir was analyzed at Day 0 (following a single dose of sofosbuvir). AUCinf is defined as the concentration of drug (area under the plasma concentration versus time curve) extrapolated to infinite time. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours postdose | 
| Plasma Pharmacokinetics of Sofosbuvir: AUCtau at Day 27 | The AUCtau of sofosbuvir was analyzed at Day 27 (following continuous dosing of sofosbuvir). AUCtau is defined as the concentration of drug (area under the plasma concentration versus time curve) over the dosing interval. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose) | 
| Plasma Pharmacokinetics of GS-331007: Cmax at Day 0 | The Cmax of GS-331007 was measured at Day 0 following a single dose of sofosbuvir. GS-331007 is the predominant circulating metabolite of sofosbuvir. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours postdose | 
| Plasma Pharmacokinetics of GS-331007: Cmax at Day 27 | The Cmax of GS-331007 was measured at Day 27 following continuous dosing of sofosbuvir. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose) | 
| Plasma Pharmacokinetics of GS-331007: AUCinf at Day 0 | The AUCinf of GS-331007 was analyzed at Day 0 (following a single dose of sofosbuvir). | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours postdose | 
| Plasma Pharmacokinetics of GS-331007: AUCtau at Day 27 | The AUCtau of GS-331007 was analyzed at Day 27 (following continuous dosing of sofosbuvir). | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose) | 
| Plasma Pharmacokinetics of GS-566500: Cmax at Day 0 | The Cmax of GS-566500 was measured at Day 0 following a single dose of sofosbuvir. GS-566500 is one of the major metabolites of sofosbuvir. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours postdose | 
| Plasma Pharmacokinetics of GS-566500: Cmax at Day 27 | The Cmax of GS-566500 was measured at Day 27 following continuous dosing of sofosbuvir. | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose) | 
| Plasma Pharmacokinetics of GS-566500: AUCinf at Day 0 | The AUCinf of GS-566500 was analyzed at Day 0 (following a single dose of sofosbuvir). | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 12 hours postdose | 
| Plasma Pharmacokinetics of GS-566500: AUCtau at Day 27 | The AUCtau of GS-566500 was analyzed at Day 27 (following continuous dosing of sofosbuvir). | Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12, and 24 hours postdose) | 
| Percentage of Participants Who Developed Resistance to Sofosbuvir |  | Baseline to Week 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HCV, Chronic Hepatitis C infection Genotype 1, GT1, GT 1