GS-5885, GS-9451, Tegobuvir and Ribavirin (RBV) in Interferon Ineligible or Intolerant 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; GS-5885, GS-9451 and Tegobuvir; GS-5885, GS-9451 and Ribavirin in Interferon Ineligible or Intolerant Subjects with Chronic Genotype 1a or 1b 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; GS-5885, GS-9451 and Tegobuvir; GS-5885, GS-9451 and Ribavirin in Interferon Ineligible or Intolerant Subjects With Chronic Genotype 1a or 1b HCV Infection (Protocol No. GS US 248 0132)

Conditions
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Chronic Genotype 1a or 1b HCV Infection

Intervention / Treatment
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* Drug: GS-5885 tablet
* Drug: GS-9451 tablet
* Drug: tegobuvir capsule
* Drug: ribavirin tablet
* Drug: placebo matching ribavirin tablet
* Device: placebo matching tegobuvir capsule


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult subjects 18 and older with chronic HCV infection Liver biopsy results (performed no more than 3 years prior to Screening) indicating the absence of cirrhosis Monoinfection with HCV genotype 1a or 1b Interferon ineligible or intolerant Body mass index (BMI) between 18 and 40 kg/m2 Use of highly effective contraception methods if female of childbearing potential or sexually active male Screening laboratory values within defined thresholds Has not been exposed to any investigational drug or device within 30 days of the Screening visit Able to comply with the dosing instructions for study drug administration and able to complete the study schedule of assessments Exclusion Criteria: Prior treatment of HCV with any direct-acting antiviral (whether approved or experimental) Decompensated liver disease or cirrhosis Co-infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or another HCV genotype History of difficulty with blood collection and/or poor venous access Pregnant or nursing female or male with pregnant female partner Chronic liver disease of a non-HCV etiology Suspicion of hepatocellular carcinoma Clinically-relevant drug abuse

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, GS-9451, tegobuvir (GS-9190), and Copegus® for 24 weeks | Drug: GS-5885 tablet<br>* GS-5885 tablet, 90 mg, QD<br>Drug: GS-9451 tablet<br>* GS-9451 tablet, 200 mg QD<br>Drug: tegobuvir capsule<br>* tegobuvir capsule, 30 mg BID<br>Drug: ribavirin tablet<br>* ribavirin tablet (weight based: 1000 mg/day <75 kg; 1200 mg/day ≥ 75 kg) divided twice daily (BID)<br>|
| Active Comparator: Arm 2<br>GS-5885, GS-9451, tegobuvir (GS-9190), and a placebo matching ribavirin for 24 weeks | Drug: GS-5885 tablet<br>* GS-5885 tablet, 90 mg, QD<br>Drug: GS-9451 tablet<br>* GS-9451 tablet, 200 mg QD<br>Drug: tegobuvir capsule<br>* tegobuvir capsule, 30 mg BID<br>Drug: placebo matching ribavirin tablet<br>* placebo matching ribavirin tablet, BID<br>|
| Active Comparator: Arm 3<br>GS-5885, GS-9451, a placebo matching tegobuvir, and Copegus® for 24 weeks | Drug: GS-5885 tablet<br>* GS-5885 tablet, 90 mg, QD<br>Drug: GS-9451 tablet<br>* GS-9451 tablet, 200 mg QD<br>Drug: ribavirin tablet<br>* ribavirin tablet (weight based: 1000 mg/day <75 kg; 1200 mg/day ≥ 75 kg) divided twice daily (BID)<br>Device: placebo matching tegobuvir capsule<br>* placebo matching tegobuvir capsule, 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. | Through 24 weeks of off-treatment follow-up | 
| Antiviral Activity | To evaluate antiviral efficacy as measured by sustained virologic response (defined as HCV RNA < lower limit of quantitation 24-weeks post-treatment) 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. | Through 24 weeks of off-treatment follow-up | 

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. | Through 10 days of therapy | 
| 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 | 

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