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

Phase 2

Completed

Conditions: Hepatitis C, Chronic

Interventions: Drug: GS-5885 tablet
Drug: GS-9451 tablet
Biological: peginterferon alfa-2a
Drug: ribavirin tablet

Registration Number: NCT01371578

Lead Sponsor: Gilead Sciences

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 163

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Arm 2	GS-5885 tablet	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.
Arm 2	GS-9451 tablet	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.
Arm 2	peginterferon alfa-2a	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.
Arm 2	ribavirin tablet	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.

Primary Outcome Measures

Name	Time	Method
Sustained Virologic Response (SVR)	through 24 weeks of off-treatment follow-up	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.

Secondary Outcome Measures

Name	Time	Method
Sustained Virologic Response(SVR) of each regimen administered for 24 to 48 weeks	Weeks 1, 2, 4, 8, 12, 16, 20, 24, 36, 48 and at 4 and 12 weeks off-treatment	To evaluate antiviral efficacy as measured by SVR for 24 or 48 weeks of treatment with GS-5885, GS-9451, PEG, RBV.
Safety and Tolerability	through 24 to 48 week treatment period and up to 24 weeks of off-treatment follow-up	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.
Characterize the viral dynamics of GS-5885, GS-9451 when administered in combination with PEG and RBV	Through Week 2 of therapy	HCV RNA levels, pharmacokinetics, and viral sequencing
Characterize the pharmacokinetics of GS-5885 and GS-9451 when administered in combination with PEG and RBV	Through Week 2 of therapy	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).
Emergence of Viral Resistance	through 24 to 48 week treatment period and up to 24 weeks of off-treatment follow-up	To characterize the viral resistance to GS-5885 and GS 9451tegobuvir when administered in combination with PEG and RBV.

Trial Locations

Locations (55): Digestive Health Specialists of the Southeast
🇺🇸
Dothan, Alabama, United States
Alabama Liver and Digestive Specialists
🇺🇸
Montgomery, Alabama, United States
California Liver Institute
🇺🇸
Beverly Hills, California, United States
Scripps Clinic
🇺🇸
La Jolla, California, United States
University of California Davis Medical Center
🇺🇸
Sacramento, California, United States
RESEARCH and EDUCATION, INC
🇺🇸
San Diego, California, United States
Medical Associates Research Group
🇺🇸
San Diego, California, United States
Kaiser Permanente
🇺🇸
San Diego, California, United States
University of Colorado Denver
🇺🇸
Aurora, Colorado, United States
South Denver Gastroenterology
🇺🇸
Englewood, Colorado, United States
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Digestive Health Specialists of the Southeast
🇺🇸Dothan, Alabama, United States