Oral Antivirals (GS-5885, Tegobuvir, and/or GS-9451) With Peginterferon Alfa 2a and Ribavirin in Treatment Experienced Subjects With Chronic Genotype 1 Hepatitis C Virus Infection

Study Overview
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Brief Summary
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This is a Phase 2b, Randomized, Double-Blind, Placebo-Controlled Trial Evaluating Response Guided Therapy using Combinations of Oral Antivirals (GS-5885, tegobuvir, and/or GS-9451) with Peginterferon Alfa 2a and Ribavirin in Treatment Experienced Subjects with Chronic Genotype 1 Hepatitis C Virus (HCV) Infection.

Detailed Description
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In September 2011, the FDA requested that Gilead make several major changes to this study because of side effects experienced by two patients in other Gilead studies. In 2 HCV-infected people that were given tegobuvir with another experimental medication plus interferon and ribavirin, big reductions in the number of white blood cells, red blood cells and platelets were seen. Because these cases might have been related to tegobuvir when given with interferon, ribavirin and another direct antiviral agent, tegobuvir is no longer being given to people with these other medications in this study. As a result, the study is now open label which means both you and your study doctor will know the medication you will be receiving and Arms 1 and 3 have been discontinued from the study. All subjects enrolled in the study as of September 2nd 2011 will receive Response Guided Therapy (RGT) with both GS-5885 and GS-9451 plus PEG and RBV.

Official Title
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A Phase 2b, Randomized, Double-Blind, Placebo-Controlled Trial Evaluating Response Guided Therapy Using Combinations of Oral Antivirals (GS-5885, Tegobuvir, and/or GS-9451) With Peginterferon Alfa 2a and Ribavirin in Treatment Experienced Subjects With Chronic Genotype 1 Hepatitis C Virus Infection (Protocol GS US 256 0124)

Conditions
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Hepatitis C, Chronic

Intervention / Treatment
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* Drug: GS-5885 tablet
* Drug: GS-9451 tablet
* Biological: peginterferon alfa-2a
* Drug: ribavirin tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male or female, aged from 18 to 70 years old, inclusive Chronic HCV infection for at least 6 months prior to Baseline Subjects must have liver biopsy results (≤ 3 years prior to screening) indicating the absence of cirrhosis. Monoinfection with HCV genotype 1 HCV RNA > 10^4 IU/mL at Screening Prior treatment and adherence (as defined by receiving at least 80% of the prescribed treatment) with one course of a pegylated interferon-alfa (Pegasys or Peg-Intron) and RBV The subject's medical records must include sufficient detail of prior treatment with pegylated interferon-alfa and RBV (start/stop dates and viral response) to allow for categorization of prior response as either Non-Responder: Subject did not achieve undetectable HCV RNA levels during or at the end of a treatment period of at least 12 weeks duration. Within Nonresponders, subjects will be further defined as Null or Partial Responders if they had < 2 log10 or ≥ 2 log10 reduction, respectively, in HCV RNA during the first 12 weeks of treatment Responder: Subject achieved undetectable HCV RNA during treatment. Within Responders, subjects will be further defined as Relapsers if they had undetectable HCV RNA at the end of at least 42 weeks of treatment but detectable HCV RNA levels observed within 1 year of the end of treatment and Breakthrough subjects if they achieved undetectable HCV RNA levels during the treatment period but detectable HCV RNA at the end of treatment. No prior treatment with an oral HCV antiviral (exclusive of RBV). Body mass index (BMI) 18-36 kg/m2, inclusive. Screening ECG without clinically significant abnormalities and with QTcF interval (QT corrected using Fridericia's formula) ≤ 450 msec for males and ≤ 470 msec for females Creatinine clearance ≥ 50 mL/min. Agree to use two forms of highly effective contraception for the duration of the study and for 6 months after the last dose of study medication. Females of childbearing potential must have a negative pregnancy test at Screening and Baseline Exclusion Criteria: Discontinued prior treatment with pegylated interferon-alfa and RBV due to an adverse event, toxicity reasons or were lost to follow-up. Exceed defined thresholds for leukopenia, neutropenia, anemia, thrombocytopenia, thyroid stimulating hormone (TSH) Diagnosis of autoimmune disease, decompensated liver disease, poorly controlled diabetes mellitus, significant psychiatric illness, severe chronic obstructive pulmonary disease (COPD), HIV, hepatitis B virus (HBV), or another HCV genotype, hepatocellular carcinoma or other malignancy (with exception of certain skin cancers), hemoglobinopathy, retinal disease, or are immunosuppressed. Current use of amphetamines, cocaine, opiates (e.g., morphine, heroin), or ongoing alcohol abuse are excluded. Subjects on stable methadone are excluded, however stable buprenorphine maintenance treatment for at least 6 months is not exclusionary Receiving any of the prohibited concomitant medications.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 2<br>AM Dosing: One GS-5885 30 mg tablet, two GS-9451 100 mg tablets, orally with RBV and with food. PM Dosing: RBV with food. PEG, 180 µg, will be administered weekly by subcutaneous injection for the specified period of time (see Study Design). Pegasys® prefilled syringes (Hoffman-La Roche) will be supplied by Gilead Sciences. | Drug: GS-5885 tablet<br>* 30 mg active tablet<br>Drug: GS-9451 tablet<br>* two active 100 mg tablets<br>Biological: peginterferon alfa-2a<br>* peginterferon alfa-2a (solution for injection) 180 µg/week<br>Drug: ribavirin tablet<br>* ribavirin tablet (weight based: 1000 mg/day <75 kg; 1200 mg/day ≥ 75 kg) divided twice daily (BID); tablet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained Virologic Response (SVR) | To evaluate antiviral efficacy as measured by sustained virologic response (SVR, defined as HCV RNA < Lower Limit of Quantification (LLoQ) 24 weeks post-treatment) of response guided therapy (RGT) with GS-9451 + GS-5885, with peginterferon alfa-2a (PEG) and ribavirin (RBV) in treatment-experienced subjects. | through 24 weeks of off-treatment follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sustained Virologic Response(SVR) of each regimen administered for 24 to 48 weeks | To evaluate antiviral efficacy as measured by SVR for 24 or 48 weeks of treatment with GS-5885, GS-9451, PEG, RBV. | Weeks 1, 2, 4, 8, 12, 16, 20, 24, 36, 48 and at 4 and 12 weeks off-treatment | 
| Safety and Tolerability | To evaluate the safety and tolerability of treatment with GS-5885, GS-9451, PEG & RBV administered for 24 or 48 weeks. Safety endpoints will be summarized as the number (proportion) of subjects with events or abnormalities for categorical values or as an 8-number summary (n, mean, standard deviation, median, Q1, Q3, minimum, maximum) for continuous data by treatment arm. | through 24 to 48 week treatment period and up to 24 weeks of off-treatment follow-up | 
| Characterize the viral dynamics of GS-5885, GS-9451 when administered in combination with PEG and RBV | HCV RNA levels, pharmacokinetics, and viral sequencing | Through Week 2 of therapy | 
| Characterize the pharmacokinetics of GS-5885 and GS-9451 when administered in combination with PEG and RBV | Plasma concentrations of the study drug over time will be summarized using descriptive statistics. Pharmacokinetic parameters (Cmax, Tmax, Clast, Tlast, Ctau, λz, AUCtau, and T½) will be listed and summarized for GS-5885 and GS-9451, using descriptive statistics (eg, sample size, arithmetic mean, geometric mean, % coefficient of variation, standard deviation, median, minimum, and maximum). | Through Week 2 of therapy | 
| Emergence of Viral Resistance | To characterize the viral resistance to GS-5885 and GS 9451tegobuvir when administered in combination with PEG and RBV. | through 24 to 48 week treatment period and up to 24 weeks of off-treatment follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hepatitis C, HCV, Rapid Virologic Response, Sustained Virologic Response, Direct Acting Antiviral, Combination Therapy HCV RNA, Polymerase inhibitor, Protease inhibitor, Treatment naïve, GS-5885, GS-9190, Tegobuvir, GS-9451