GS-5885, GS-9451, Tegobuvir and Ribovirin in Treatment-Experienced Subjects With Chronic Genotype 1a Or 1b Hepatitis C Virus (HCV) Infection

Study Overview
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Brief Summary
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This is a Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of GS-5885, GS-9451, Tegobuvir and Ribavirin (RBV) Compared with GS-5885, GS-9451 with Tegobuvir or RBV in Treatment-Experienced Subjects with Chronic Genotype 1a or 1b Hepatitis C Virus (HCV) Infection.

Official Title
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A Phase 2 Randomized, Double-Blind, Placebo-Controlled Study of GS-5885, GS-9451, Tegobuvir and Ribavirin (RBV) Compared With GS-5885, GS-9451 With Tegobuvir or RBV in Treatment-Experienced Subjects With Chronic Genotype 1a or 1b Hepatitis C Virus (HCV) Infection

Conditions
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Hepatitis C, Chronic

Intervention / Treatment
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* Drug: GS-5885
* Drug: GS-9451
* Drug: tegobuvir
* Drug: placebo to match tegobuvir
* Drug: placebo to match RBV
* Drug: Ribavirin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years with chronic HCV infection Liver biopsy results ≤ 3 years prior to screening indicating the absence of cirrhosis. Alternatively, a non-invasive procedure conducted within 6 months of screening is permitted in countries where allowed Monoinfection with HCV genotype (GT) 1a or 1b HCV RNA ≥ 104 IU/mL at screening Prior treatment and adherence with one course of pegylated interferon alfa 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 null, partial, breakthrough or relapse. Body mass index (BMI) 18-40 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. Agree to use two forms of highly effective contraception for the duration of the study and for 7 months after the last dose of study medication. Females of childbearing potential must have a negative pregnancy test at screening and baseline. Exclusion Criteria: Discontinuation of prior treatment with pegylated interferon alfa and RBV due to an adverse event, toxicity reasons or were lost to follow-up History of significant cardiac disease Exceed criteria delineated in Section 4.2 for laboratory measure thresholds related to leukopenia, neutropenia, anemia, thrombocytopenia, and 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), hepatocellular carcinoma or other malignancy (with exception of certain resolved skin cancers), hemoglobinopathy, retinal disease, or are immunosuppressed. Current abuse of amphetamines, cocaine, opiates, or alcohol. Methadone use is not allowed, however stable buprenorphine maintenance treatment for ≥ 6 months is permitted.

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Arm 1<br>GS-5885 90 mg QD + GS-9451 200 mg QD + tegobuvir 30 mg BID + RBV BID | Drug: GS-5885<br>* Drug: GS-5885 tablet GS-5885 tablet, 90 mg, QD<br>Drug: GS-9451<br>* Drug: GS-9451 tablet GS-9451 tablet, 200 mg QD<br>Drug: tegobuvir<br>* tegobuvir 30 mg BID<br>Drug: Ribavirin<br>* Ribavirin (Copegus®) BID (1000 mg for subjects weighing < 75 kg and 1200 mg for subjects weighing ≥ 75 kg) divided BID<br>|
| Active Comparator: Arm 2<br>GS-5885 90 mg QD + GS-9451 200 mg QD + tegobuvir 30 mg BID + RBV placebo BID | Drug: GS-5885<br>* Drug: GS-5885 tablet GS-5885 tablet, 90 mg, QD<br>Drug: GS-9451<br>* Drug: GS-9451 tablet GS-9451 tablet, 200 mg QD<br>Drug: tegobuvir<br>* tegobuvir 30 mg BID<br>Drug: placebo to match RBV<br>* Ribovirin placebo BID<br>|
| Active Comparator: Arm 3<br>GS-5885 90 mg QD + GS-9451 200 mg QD + tegobuvir placebo BID + RBV BID | Drug: GS-5885<br>* Drug: GS-5885 tablet GS-5885 tablet, 90 mg, QD<br>Drug: GS-9451<br>* Drug: GS-9451 tablet GS-9451 tablet, 200 mg QD<br>Drug: placebo to match tegobuvir<br>* tegobuvir placebo BID<br>Drug: Ribavirin<br>* Ribavirin (Copegus®) BID (1000 mg for subjects weighing < 75 kg and 1200 mg for subjects weighing ≥ 75 kg) divided BID<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety and Tolerability | To evaluate safety and tolerability of combination therapy with GS-5885, GS-9451, tegobuvir and ribavirin or GS-5885, GS-9451 and tegobuvir or GS-5885, GS-9451 and ribavirin. Safety will be assessed during the study through the reporting of adverse events, clinical laboratory tests, physical examinations, vital signs and 12-lead ECGs at various time points during the study. | 24 weeks | 
| Antiviral Activity | To evaluate the antiviral efficacy as measured by sustained virologic response (SVR, defined as HCV RNA < lower limit of quantitation [LLoQ] 24 weeks post-treatment) of combination therapy with GS-5885, GS-9451, tegobuvir and RBV compared with GS-5885, GS-9451 and tegobuvir or GS-5885, GS-9451 and RBV in treatment-experienced subjects with chronic genotype 1a or 1b HCV infection | 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Viral Dynamics | To characterize the viral dynamics of GS-5885, GS-9451 and tegobuvir. The median change from baseline in HCV RNA and time-weighted average change from baseline through Day 10 will be assessed based on plasma HCV RNA sampling times to characterize the viral dynamics of GS-5885, GS-9451 and tegobuvir. | 10 days | 
| Composite (or Profile) of Pharmacokinetics Composite (or Profile) of Pharmacokinetics | To characterize the steady state pharmacokinetics of GS-5885, GS-9451, tegobuvir and ribavirin (if appropriate). Cmax, Tmax, Clast, Tlast, Ctau, λz, AUCtau and T ½ | predose, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose | 
| Antiviral Efficacy | To evaluate the antiviral efficacy (as defined by SVR) of adding pegylated interferon alfa-2a (PEG) and RBV (Arm 2 only) for 24-48 weeks to the original treatment regimen in subjects who experience viral breakthrough or relapse and enter the Rescue Therapy Substudy | 24-48 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Interferon intolerant, Interferon ineligible, GS-9190, GS-9451, GS-5885, Chronic Genotype 1a or 1b, Hepatitis C, HCV, Rapid Virologic Response, Sustained Virologic Response, Direct Acting Antiviral, Combination Therapy, Tegobuvir, Treatment Experienced, HCV RNA, Polymerase inhibitor, Protease inhibitor