Open-Labeled Study of PSI-7977 and RBV With and Without PEG-IFN in Treatment-Naïve Patients With HCV GT2 or GT3

Study Overview
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Brief Summary
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This study is to assess the safety and tolerability of sofosbuvir (SOF) 400 mg with and without ribavirin (RBV) and/or with and without pegylated interferon alfa-2a (PEG) in subjects with genotype 1, 2 or 3 hepatitis C (HCV) infection.

Detailed Description
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Part 1: HCV genotype 2 or 3: participants will receive SOF 400 mg once daily with weight-based RBV for 12 weeks. Participants will be randomized in equal proportions to: no PEG (Arm 1), PEG for 4 weeks (Arm 2), PEG for 8 weeks (Arm 3), or PEG for 12 weeks (Arm 4). Part 2: HCV genotype 2 or 3: participants will receive SOF 400 mg once daily (monotherapy) for 12 weeks (Arm 5), or SOF 400 mg once daily with PEG and weight-based RBV for 8 weeks (Arm 6); HCV genotype 1: null responders (did not respond to their prior treatment) will receive SOF 400 mg once daily with weight-based RBV for 12 weeks (Arm 7). Part 3: HCV genotype 1 treatment-naive (Arm 8) or HCV genotype 2 or 3 treatment-experienced participants (Arm 9) will receive SOF 400 mg once daily in combination with weight-based RBV for 12 weeks. Part 4: HCV genotype 2 or 3 treatment naive participants will receive SOF 400 mg once daily with weight-based RBV for 8 weeks (Arm 10) or SOF 400 mg once daily and 800 mg RBV for 12 weeks (Arm 11). HCV genotype 1 null responders will receive SOF 400 mg once daily, ledipasvir (LDV), and weight based RBV for 12 weeks (Arm 12). HCV genotype-1 treatment naive participants will receive SOF 400 mg once daily with weight-based RBV and LDV for 12 weeks (Arm 13). Part 5: HCV genotype 1 null responders will receive SOF 400 mg once daily with GS-9669 500 mg once daily and weight-based RBV for 12 weeks (Arm 14). HCV genotype-1 treatment naive participants receive SOF 400 mg once daily with GS-9669 500 mg once daily and weight-based RBV for 12 weeks (Arm 15). Part 6: HCV genotype 1 null responders with Stage F4 fibrosis will receive LDV/SOF FDC for 12 weeks (Arm 16) or LDV/SOF FDC with weight-based RBV for 12 weeks (Arm 17). HCV genotype 2 or 3 treatment-naive participants will receive LDV/SOF FDC for 12 weeks (Arm 18). HCV genotype 2 or 3 treatment-experienced participants will receive LDV/SOF FDC for 12 weeks (Arm 19). HCV genotype 1 hemophiliacs will receive LDV/SOF FDC with weight-based RBV for 12 weeks (Arm 20). HCV genotype 1 treatment-naive participants will receive LDV/SOF FDC with weight-based RBV for 6 weeks (Arm 21). HCV genotype 1 treatment-naive participants will receive LDV/SOF FDC for 6 weeks (Arm 22).

Official Title
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A Multi-center, Open-Labeled Exploratory Study to Investigate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Following Oral Administration of PSI-7977 400 mg and Ribavirin for 12 Weeks With and Without Pegylated Interferon in Treatment-Naïve Patients With Chronic HCV Infection Genotype 2 or Genotype 3

Conditions
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Chronic Hepatitis C Infection

Intervention / Treatment
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* Drug: SOF
* Drug: RBV
* Drug: PEG
* Drug: LDV
* Drug: GS-9669
* Drug: LDV/SOF


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Chronic Genotype 2 or 3 HCV-infection or Genotype 1, serum HCV RNA ≥ 50,000 IU/mL Not co-infected with HIV Use of highly effective contraception methods if female of childbearing potential or sexually active male Exclusion Criteria: History of any other clinically significant chronic liver disease Pregnant or nursing female or male with pregnant female partner History of significant drug allergy to nucleoside/nucleotide analogs. Participation in a clinical study within 3 months prior to first dose Positive result for significant drug use at Screening

Ages Eligible for Study
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Minimum Age: 18 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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group 1: SOF+RBV 12 wk: GT 2 or 3, TN<br>Treatment-naive (TN) participants with genotype (GT) 2 or 3 HCV infection will receive SOF 400 mg once daily plus weight-based RBV (1000-1200 in a divided daily dose) for 12 weeks. | Drug: SOF<br>* Sofosbuvir (SOF) tablets administered orally once daily<br>* Other names: PSI-7977;Drug: RBV<br>* Ribavirin (RBV) capsules administered orally in a divided daily dose<br>* Other names: Copegus®;|
| Experimental: Group 2: SOF+RBV 12 wk+PEG 4 wk: GT 2 or 3, TN<br>Treatment-naive participants with genotype 2 or 3 HCV infection will receive SOF 400 mg once daily plus weight-based RBV (1000-1200 in a divided daily dose) for 12 weeks plus PEG 180 µg once weekly for 4 weeks. | Drug: SOF<br>* Sofosbuvir (SOF) tablets administered orally once daily<br>* Other names: PSI-7977;Drug: RBV<br>* Ribavirin (RBV) capsules administered orally in a divided daily dose<br>* Other names: Copegus®;Drug: PEG<br>* Peginterferon alfa-2a (PEG) administered via subcutaneous injection once weekly<br>* Other names: Pegasys®;|
| Experimental: Group 3: SOF+RBV 12 wk+PEG 8 wk: GT 2 or 3, TN<br>Treatment-naive participants with genotype 2 or 3 HCV infection will receive SOF 400 mg once daily plus weight-based RBV (1000-1200 in a divided daily dose) for 12 weeks plus PEG 180 µg once weekly for 8 weeks. | Drug: SOF<br>* Sofosbuvir (SOF) tablets administered orally once daily<br>* Other names: PSI-7977;Drug: RBV<br>* Ribavirin (RBV) capsules administered orally in a divided daily dose<br>* Other names: Copegus®;Drug: PEG<br>* Peginterferon alfa-2a (PEG) administered via subcutaneous injection once weekly<br>* Other names: Pegasys®;|
| Experimental: Group 4: SOF+RBV+PEG 12 wk: GT 2 or 3, TN<br>Treatment-naive participants with genotype 2 or 3 HCV infection will receive SOF 400 mg once daily+weight-based RBV (1000-1200 in a divided daily dose) plus PEG 180 µg once weekly for 12 weeks. | Drug: SOF<br>* Sofosbuvir (SOF) tablets administered orally once daily<br>* Other names: PSI-7977;Drug: RBV<br>* Ribavirin (RBV) capsules administered orally in a divided daily dose<br>* Other names: Copegus®;Drug: PEG<br>* Peginterferon alfa-2a (PEG) administered via subcutaneous injection once weekly<br>* Other names: Pegasys®;|
| Experimental: Group 5: SOF 12 wk: GT 2 or 3, TN<br>Treatment-naive participants with genotype 2 or 3 HCV infection will receive SOF 400 mg once daily for 12 weeks. | Drug: SOF<br>* Sofosbuvir (SOF) tablets administered orally once daily<br>* Other names: PSI-7977;|
| Experimental: Group 6: SOF+RBV+PEG 8 wk: GT 2 or 3, TN<br>Treatment-naive participants with genotype 2 or 3 HCV infection will receive SOF 400 mg once daily plus weight-based RBV (1000-1200 in a divided daily dose) plus PEG 180 µg once weekly for 8 weeks. | Drug: SOF<br>* Sofosbuvir (SOF) tablets administered orally once daily<br>* Other names: PSI-7977;Drug: RBV<br>* Ribavirin (RBV) capsules administered orally in a divided daily dose<br>* Other names: Copegus®;Drug: PEG<br>* Peginterferon alfa-2a (PEG) administered via subcutaneous injection once weekly<br>* Other names: Pegasys®;|
| Experimental: Group 7: SOF+RBV 12 wk: GT 1, TE<br>Treatment-experienced (TE) participants with genotype 1 HCV infection who did not respond to prior treatment will receive SOF 400 mg once daily plus weight-based RBV (1000-1200 in a divided daily dose) for 12 weeks. | Drug: SOF<br>* Sofosbuvir (SOF) tablets administered orally once daily<br>* Other names: PSI-7977;Drug: RBV<br>* Ribavirin (RBV) capsules administered orally in a divided daily dose<br>* Other names: Copegus®;|
| Experimental: Group 8: SOF+RBV 12 wk: GT 1, TN<br>Treatment-naive participants with genotype 1 HCV infection will receive SOF 400 mg once daily plus weight-based RBV (1000-1200 in a divided daily dose) for 12 weeks. | Drug: SOF<br>* Sofosbuvir (SOF) tablets administered orally once daily<br>* Other names: PSI-7977;Drug: RBV<br>* Ribavirin (RBV) capsules administered orally in a divided daily dose<br>* Other names: Copegus®;|
| Experimental: Group 9: SOF+RBV 12 wk: GT 2 or 3, TE<br>Treatment-experienced participants with genotype 2 or 3 HCV infection will receive SOF 400 mg once daily plus weight-based RBV (1000-1200 in a divided daily dose) for 12 weeks. | Drug: SOF<br>* Sofosbuvir (SOF) tablets administered orally once daily<br>* Other names: PSI-7977;Drug: RBV<br>* Ribavirin (RBV) capsules administered orally in a divided daily dose<br>* Other names: Copegus®;|
| Experimental: Group 10: SOF+RBV 8 wk: GT 2 or 3, TN<br>Treatment-naive participants with genotype 2 or 3 HCV infection will receive SOF 400 mg once daily plus weight-based RBV (1000-1200 in a divided daily dose) for 8 weeks. | Drug: SOF<br>* Sofosbuvir (SOF) tablets administered orally once daily<br>* Other names: PSI-7977;Drug: RBV<br>* Ribavirin (RBV) capsules administered orally in a divided daily dose<br>* Other names: Copegus®;|
| Experimental: Group 11: SOF+RBV 12 wk: GT 2 or 3, TN<br>Treatment-naive participants with genotype 2 or 3 HCV infection will receive SOF 400 mg once daily plus split-dose RBV (800 mg in a divided daily dose) for 12 weeks. | Drug: SOF<br>* Sofosbuvir (SOF) tablets administered orally once daily<br>* Other names: PSI-7977;Drug: RBV<br>* Ribavirin (RBV) capsules administered orally in a divided daily dose<br>* Other names: Copegus®;|
| Experimental: Group 12: SOF+RBV+LDV 12 wk: GT 1, TE<br>Treatment-experienced participants with genotype 1 HCV infection who did not respond to prior treatment will receive SOF 400 mg once daily plus weight-based RBV (1000-1200 in a divided daily dose) plus LDV 90 mg once daily for 12 weeks. | Drug: SOF<br>* Sofosbuvir (SOF) tablets administered orally once daily<br>* Other names: PSI-7977;Drug: RBV<br>* Ribavirin (RBV) capsules administered orally in a divided daily dose<br>* Other names: Copegus®;Drug: LDV<br>* Ledipasvir (LDV) tablets administered orally once daily<br>* Other names: GS-5885;|
| Experimental: Group 13: SOF+RBV+LDV 12 wk: GT 1, TN<br>Treatment-naive participants with genotype 1 HCV infection will receive SOF 400 mg once daily plus weight-based RBV (1000-1200 in a divided daily dose) plus LDV 90 mg once daily for 12 weeks. | Drug: SOF<br>* Sofosbuvir (SOF) tablets administered orally once daily<br>* Other names: PSI-7977;Drug: RBV<br>* Ribavirin (RBV) capsules administered orally in a divided daily dose<br>* Other names: Copegus®;Drug: LDV<br>* Ledipasvir (LDV) tablets administered orally once daily<br>* Other names: GS-5885;|
| Experimental: Group 14: SOF+RBV+GS-9669 12 wk: GT 1, TE<br>Treatment-experienced participants with genotype 1 HCV infection who did not respond to prior treatment will receive SOF 400 mg once daily plus weight-based RBV (1000-1200 in a divided daily dose) plus GS-9669 500 mg once daily for 12 weeks. | Drug: SOF<br>* Sofosbuvir (SOF) tablets administered orally once daily<br>* Other names: PSI-7977;Drug: RBV<br>* Ribavirin (RBV) capsules administered orally in a divided daily dose<br>* Other names: Copegus®;Drug: GS-9669<br>* GS-9669 tablets administered orally once daily<br>|
| Experimental: Group 15: SOF+RBV+GS-9669 12 wk: GT 1, TN<br>Treatment-naive participants with genotype 1 HCV infection will receive SOF 400 mg once daily plus weight-based RBV (1000-1200 in a divided daily dose) plus GS-9669 500 mg once daily for 12 weeks. | Drug: SOF<br>* Sofosbuvir (SOF) tablets administered orally once daily<br>* Other names: PSI-7977;Drug: RBV<br>* Ribavirin (RBV) capsules administered orally in a divided daily dose<br>* Other names: Copegus®;Drug: GS-9669<br>* GS-9669 tablets administered orally once daily<br>|
| Experimental: Group 16: LDV/SOF FDC 12 wk: GT 1, fibrosis<br>Treatment-experienced participants with genotype 1 HCV infection and Stage F4 fibrosis who did not respond to prior treatment will receive LDV 90 mg/SOF 400 mg FDC once daily for 12 weeks. | Drug: LDV/SOF<br>* LDV/SOF fixed-dose combination (FDC) tablet administered once daily<br>* Other names: Harvoni®;|
| Experimental: Group 17: LDV/SOF FDC+RBV 12 wk: GT 1, fibrosis<br>Treatment-experienced participants with genotype 1 HCV infection with Stage F4 fibrosis who did not respond to prior treatment will receive LDV 90 mg/SOF 400 mg FDC once daily plus weight-based RBV (1000-1200 in a divided daily dose) for 12 weeks. | Drug: RBV<br>* Ribavirin (RBV) capsules administered orally in a divided daily dose<br>* Other names: Copegus®;Drug: LDV/SOF<br>* LDV/SOF fixed-dose combination (FDC) tablet administered once daily<br>* Other names: Harvoni®;|
| Experimental: Group 18: LDV/SOF FDC 12 wk: GT 2 or 3, TN<br>Treatment-naive participants with genotype 2 or 3 HCV infection will receive LDV 90 mg/SOF 400 mg FDC once daily for 12 weeks. | Drug: LDV/SOF<br>* LDV/SOF fixed-dose combination (FDC) tablet administered once daily<br>* Other names: Harvoni®;|
| Experimental: Group 19: LDV/SOF FDC 12 wk: GT 2 or 3, TE<br>Treatment-experienced participants with genotype 2 or 3 HCV infection will receive LDV 90 mg/SOF 400 mg FDC once daily for 12 weeks. | Drug: LDV/SOF<br>* LDV/SOF fixed-dose combination (FDC) tablet administered once daily<br>* Other names: Harvoni®;|
| Experimental: Group 20: LDV/SOF FDC+RBV 12 wk: GT 1, hemophiliac<br>Hemophiliac participants with genotype 1 HCV infection will receive LDV 90 mg/SOF 400 mg FDC once daily plus weight-based RBV (1000-1200 in a divided daily dose) for 12 weeks. | Drug: RBV<br>* Ribavirin (RBV) capsules administered orally in a divided daily dose<br>* Other names: Copegus®;Drug: LDV/SOF<br>* LDV/SOF fixed-dose combination (FDC) tablet administered once daily<br>* Other names: Harvoni®;|
| Experimental: Group 21: LDV/SOF FDC+RBV 6 wk: GT 1, TN<br>Treatment-naive participants with genotype 1 HCV infection will receive LDV 90 mg/SOF 400 mg FDC once daily plus weight-based RBV (1000-1200 in a divided daily dose) for 6 weeks. | Drug: RBV<br>* Ribavirin (RBV) capsules administered orally in a divided daily dose<br>* Other names: Copegus®;Drug: LDV/SOF<br>* LDV/SOF fixed-dose combination (FDC) tablet administered once daily<br>* Other names: Harvoni®;|
| Experimental: Group 22: LDV/SOF FDC 6 wk: GT 1, TN<br>Treatment-naive participants with genotype 1 HCV infection were randomized to receive LDV 90 mg/SOF 400 mg FDC once daily for 6 weeks. | Drug: LDV/SOF<br>* LDV/SOF fixed-dose combination (FDC) tablet administered once daily<br>* Other names: Harvoni®;|

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 | Adverse events (AEs) occurring from baseline (Day 1 for all groups) to 30 days following the last dose of study drug were summarized across the participant population. A participant was counted once if they had a qualifying event. | Up to 12 weeks plus 30 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Sustained Virologic Response 12 Weeks Following Completion of Treatment (SVR12) | SVR12 was defined as HCV RNA < the limit of detection (LOD; < 15 IU/mL) 12 weeks after the last dose of study drug. | Posttreatment Week 12 | 
| Percentage of Participants With HCV RNA < LOD at Week 6 |  | Week 6 | 
| Percentage of Participants With HCV RNA < LOD at Week 8 | Data are not presented for Group 21 which ended treatment after Week 6. | Week 8 | 
| Percentage of Participants With HCV RNA < LOD at Week 12 | Data are not presented for Groups 6, 10, and 21 which ended treatment after Week 8 or Week 6. | Week 12 | 
| Change From Baseline in HCV RNA at Week 6 |  | Baseline to Week 6 | 
| Change From Baseline in HCV RNA at Week 8 | Data are not presented for Group 21 which ended treatment after Week 6. | Baseline to Week 8 | 
| Change From Baseline in HCV RNA at Week 12 | Data are not presented for Groups 6, 10, and 21 which ended treatment after Week 8 or Week 6. Data are not presented for Groups 16, 17, 18, and 20 because participants with detectable HCV RNA discontinued due to protocol-specified stopping rules. | Baseline to Week 12 | 
| Percentage of Participants With Virologic Failure | The percentage of participants with on-treatment virologic failure (viral breakthrough, rebound, or nonresponse) or following treatment (viral relapse) was summarized. On-treatment virologic failure was defined as: Viral breakthrough (confirmed HCV RNA ≥ LOD after having previously had HCV RNA < LOD while on treatment), Viral rebound (confirmed > 1 log10 IU/mL increase in HCV RNA from nadir while on treatment, or Nonresponse (HCV RNA persistently ≥ LOD through 6 weeks of treatment) Viral relapse was defined as confirmed HCV RNA ≥ LOD during the posttreatment period having achieved HCV RNA < LOD at the last on-treatment visit. | Up to Posttreatment Week 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PSI-7977, Sofosbuvir, GS-7977, GS-5885, GS-9669, FDC, ribavirin, RBV, Pegylated Interferon, PEG-IFN, Chronic Hepatitis C Infection, HCV, Hepatitis, Genotype 1, Genotype 2, Genotype 3, GT 1, GT 2, GT 3, Hemophilia