Efficacy and Safety Study of GS-9256 and GS-9190 Alone and in Combination With Ribavirin for 28 Days in Patients With Chronic Hepatitis C Virus Infection

Study Overview
=================
Brief Summary
-----------------
This a phase 2, randomized, open-label trial of GS-9256 plus GS-9190, two oral anti HCV drugs, for 28 days with and without ribavirin (RIBA) and with pegylated interferon (PEG)/RIBA in adults with chronic Hepatitis C virus (HCV). In Part A, approximately thirty (30) subjects 18-70 years of age who meet study entry criteria will be randomized (in other words, selected at random, like flipping a coin) to one of the two treatment groups (GS-9256 plus GS-9190 or GS-9256 plus GS-9190 plus RIBA). In Part B, an additional fifteen (15) subjects will receive 75 mg GS-9256 BID plus 40 mg GS-9190 BID in combination with PEG/RIBA. After the 28-day treatment period, subjects will receive PEG/RIBA as standard of care (SOC). Following randomization, subjects will return for a Baseline (Day 1) visit, at which time study medication will be dispensed and subjects will enter a 28 day treatment phase. During the treatment phase, subjects will receive oral study drugs twice daily for 28 days and PEG once weekly for Part B. Subjects then receive PEG/RIBA as local SOC starting on Day 28 (not provided as part of the study). Following completion of the 28-day treatment phase, subjects will be followed for approximately 72 weeks.

Detailed Description
-----------------
GS-9256 (an HCV NS3 protease inhibitor) plus GS-9190 (non-nucleoside HCV NS5B inhibitor) will be administered for 28 days with and without RIBA (weight-based dosing) and with PEG/RIBA in treatment-naïve subjects with chronic genotype 1 HCV infection. In Part A, thirty (30) subjects with genotype 1 will be randomized to 75 mg GS-9256 BID plus 40 mg GS-9190 BID or 75 mg GS-9256 BID plus 40 mg GS-9190 BID plus RIBA 1000-1200 mg/day for 28 days. In Part B, an additional fifteen (15) subjects with genotype 1 will receive 75 mg GS-9256 BID plus 40 mg GS-9190 BID in combination with PEG/RIBA for 28 days. After the 28-day treatment period, subjects will receive PEG/RIBA as standard of care (SOC). In Part A, for any subjects meeting pre-defined, individual, virologic criteria, PEG/RIBA standard of care will be started prior to Day 28. Both PEG and RIBA will be administered at their currently approved dosages for treatment of HCV infection in accordance with appropriate labeling. Subjects will be monitored for safety (including ECG monitoring), antiviral activity, pharmacokinetics, and resistance 2-3 times weekly through Day 28.

Official Title
-----------------
A Phase 2, Randomized, Open-Label Trial of GS-9256 Plus GS-9190 Alone and in Combination With Ribavirin for 28 Days in Treatment Naïve Subjects With Chronic Genotype 1 Hepatitis C Virus Infection (Protocol No. GS-US-196-0112)

Conditions
-----------------
HCV Infection

Intervention / Treatment
-----------------
* Drug: GS-9256
* Drug: GS-9190
* Drug: Ribavirin
* Drug: Peginterferon alfa-2a


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Adult subjects, ages 18-70 Willing able to provide informed consent BMI between 18 and 36 kg/m2 (inclusive) Chronic HCV infection, genotype 1 HCV RNA >/= 3 log, but < 7.2 log10 IU/ml at screen Liver biopsy, FibroTest, or FibroScan indicating absence of cirrhosis HCV treatment naïve with imminent plans to start treatment with PEG/RIBA QTcF </= 450 msec at screen ALT, AST, GGT < 5 X ULN at the screening visit Creatinine clearance >= 50 mL/min Absolute neutrophil count >= 1500/mm3 Hemoglobin >/= 12 g/dL (female), >/= 13 g/dL (male) Males agree to use of effective contraception and refrain from sperm donation Able to comply with dosing instructions and study visits Of generally good health Exclusion Criteria: Females of child-bearing potential or males with female partners who are pregnant or planning to become pregnant Infection with other HCV genotype or multiple HCV genotypes Poorly controlled diabetes Hemoglobinopathy or known retinal disease History of sarcoidosis or invasive malignancy Untreated or significant psychiatric illness Co-infection with hepatitis B virus or human immunodeficiency virus Chronic use of systemic immunosuppressive agents Autoimmune disorders Severe COPD History of significant cardiac disease Known cirrhosis Non-HCV chronic liver disease Transplantation Suspicion of hepatocellular carcinoma Bilirubin above the normal range or Gilbert's syndrome Decompensated liver disease Clinically significant illness GI disease that could interfere with absorption Acute porphyria Current excessive alcohol ingestion, averaging > 3 drinks/day for females and > 4 drinks/day for males or current binge drinking Positive urine drug screen History of difficult blood collection Significant recent blood loss Prohibited medications, including H2 antagonists, investigational agents Restricted fruits, fruit juices Hypersensitivity

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br> | Drug: GS-9256<br>* 75 mg BID x 28 days<br>Drug: GS-9190<br>* 40 mg BID x 28 days<br>|
| Experimental: Arm 2<br> | Drug: GS-9256<br>* 75 mg BID x 28 days<br>Drug: GS-9190<br>* 40 mg BID x 28 days<br>Drug: Ribavirin<br>* 1000-1200 mg/day given BID<br>* Other names: COPEGUS;|
| Experimental: Arm 3<br> | Drug: GS-9256<br>* 75 mg BID x 28 days<br>Drug: GS-9190<br>* 40 mg BID x 28 days<br>Drug: Ribavirin<br>* 1000-1200 mg/day given BID<br>* Other names: COPEGUS;Drug: Peginterferon alfa-2a<br>* 180 ug q week<br>* Other names: Pegasys;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of subjects achieving rapid virologic response (RVR) |  | Day 28 | 
| AEs, physical examination and clinical laboratory test findings, vital signs, ECGs |  | Throughout first six weeks of study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma pharmacokinetics |  | Throughout Day 28 | 
| Viral resistance |  | Throughout study | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Hepatitis C, HCV, GS-9256, GS-9190, Genotype 1