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

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Hepatitis C, Chronic	Drug: GS-5885; Drug: GS-9451; Drug: tegobuvir; Drug: placebo to match tegobuvir; Drug: placebo to match RBV; Drug: Ribavirin	Phase 2

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	170 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Treatment
Official Title:	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
Study Start Date :	September 2011
Actual Primary Completion Date :	January 2013
Actual Study Completion Date :	July 2013

Arms and Interventions

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

Outcome Measures

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Primary Outcome Measures :

1. Safety and Tolerability [ Time Frame: 24 weeks ]

   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.

2. Antiviral Activity [ Time Frame: 24 weeks ]
   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

Secondary Outcome Measures :

1. Viral Dynamics [ Time Frame: 10 days ]
   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.
2. Composite (or Profile) of Pharmacokinetics Composite (or Profile) of Pharmacokinetics [ Time Frame: predose, 1, 2, 3, 4, 6, 8, 10, 12 and 24 hours post-dose ]
   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
3. Antiviral Efficacy [ Time Frame: 24-48 weeks ]
   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

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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Sponsors and Collaborators

Gilead Sciences

Investigators

Study Director:	John McNally, PhD	Gilead Sciences

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Gilead Sciences
ClinicalTrials.gov Identifier:	NCT01435226 History of Changes
Other Study ID Numbers:	GS-US-248-0131
First Posted:	September 16, 2011
Last Update Posted:	December 17, 2013
Last Verified:	November 2013

Keywords provided by Gilead Sciences:

Hepatitis C; HCV; Rapid Virologic Response; Sustained Virologic Response; Direct Acting Antiviral; Combination Therapy; Tegobuvir; Treatment Experienced; HCV RNA	Polymerase inhibitor; Protease inhibitor; Interferon intolerant; Interferon ineligible; GS-9190; GS-9451; GS-5885; Chronic Genotype 1a or 1b

Additional relevant MeSH terms:

Hepatitis; Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Liver Diseases; Digestive System Diseases; Hepatitis, Viral, Human; Virus Diseases; Enterovirus Infections; Picornaviridae Infections; RNA Virus Infections	Flaviviridae Infections; Hepatitis, Chronic; Interferons; Ribavirin; Ledipasvir; Antineoplastic Agents; Antiviral Agents; Anti-Infective Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action