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

Hepatitis C, Chronic Clinical Trial

Official title:

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 Infection (Protocol GS US 256 0124)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01371578
• Other study ID #: GS-US-256-0124
• Status: Completed
• Phase: Phase 2
• First received: June 9, 2011
• Last updated: January 14, 2014
• Start date: July 2011
• Est. completion date: March 2013

Study information

• Verified date: January 2014
• Source: Gilead Sciences
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 163
• Est. completion date: March 2013
• Est. primary completion date: March 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

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

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Hepatitis
• Hepatitis A
• Hepatitis C
• Hepatitis C, Chronic
• Virus Diseases

Intervention

Drug:
• GS-5885 tablet
30 mg active tablet
• GS-9451 tablet
two active 100 mg tablets

Biological:
• peginterferon alfa-2a
peginterferon alfa-2a (solution for injection) 180 µg/week

Drug:
• ribavirin tablet
ribavirin tablet (weight based: 1000 mg/day <75 kg; 1200 mg/day = 75 kg) divided twice daily (BID); tablet

Locations

Country	Name	City	State
Puerto Rico	Fundacion de Investigacion de Diego	San Juan
United States	The North Texas Research Institute	Arlington	Texas
United States	Asheville Gastroenterology Associates, P.A.	Asheville	North Carolina
United States	Digestive Healthcare of Georgia	Atlanta	Georgia
United States	Emory University, Infectious Disease Clinic	Atlanta	Georgia
United States	University of Colorado Denver	Aurora	Colorado
United States	Digestive Disease Associates, PA	Baltimore	Maryland
United States	Gastroenterology Associates, LLC	Baton Rouge	Louisiana
United States	California Liver Institute	Beverly Hills	California
United States	Binghamton Gastroenterology	Binghamton	New York
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Graves Gilbert Clinic	Bowling Green	Kentucky
United States	Bach and Godofsky Infectious Diseases	Bradenton	Florida
United States	University of Cincinnati	Cincinnati	Ohio
United States	Baylor University Medical Center	Dallas	Texas
United States	Dekalb Gastroenterology	Decatur	Georgia
United States	Henry Ford Health System	Detroit	Michigan
United States	Digestive Health Specialists of the Southeast	Dothan	Alabama
United States	Duke University Medical Center	Durham	North Carolina
United States	South Denver Gastroenterology	Englewood	Colorado
United States	Metropolitan Research	Fairfax	Virginia
United States	Cumberland Research Associates, LLC	Fayetteville	North Carolina
United States	University of Florida	Gainesville	Florida
United States	Memphis Gastroenterology Group	Germantown	Tennessee
United States	ID Care 105	Hillsborough	New Jersey
United States	Kelsey Research Foundation	Houston	Texas
United States	Research Specialists of Texas	Houston	Texas
United States	Indiana University	Indianapolis	Indiana
United States	Indianapolis Gastroenterology Research Foundation	Indianapolis	Indiana
United States	Gastrointestinal Associates, PA	Jackson	Mississippi
United States	Scripps Clinic	La Jolla	California
United States	North Shore University Hospital	Manhasset	New York
United States	Gastrointestinal Specialists of Georgia PC	Marietta	Georgia
United States	University of Miami	Miami	Florida
United States	Alabama Liver and Digestive Specialists	Montgomery	Alabama
United States	Atlantic Research Affiliates, LLC	Morristown	New Jersey
United States	Columbia Medical Group, The Frist Clinic	Nashville	Tennessee
United States	Nashville Gastrointestinal Specialists, Inc	Nashville	Tennessee
United States	Nashville Medical Research Institute	Nashville	Tennessee
United States	Concorde Medical Group	New York	New York
United States	Cornell University Gastroenterology & Hepatology	New York	New York
United States	Digestive and Liver Disease Specialists	Norfolk	Virginia
United States	Orlando Immunology Center	Orlando	Florida
United States	University Gastroenterology	Providence	Rhode Island
United States	Liver Institute of Virginia	Richmond	Virginia
United States	University of California Davis Medical Center	Sacramento	California
United States	Kaiser Permanente	San Diego	California
United States	Medical Associates Research Group	San Diego	California
United States	RESEARCH and EDUCATION, INC	San Diego	California
United States	Southwest CARE Center	Santa Fe	New Mexico
United States	Virginia Mason Medical Center, Digestive Disease Institute	Seattle	Washington
United States	Options Health Research, LLC	Tulsa	Oklahoma
United States	Digestive Health Specialists, PA	Tupelo	Mississippi
United States	South Florida Center of Gastroenterology, LLC	Wellington	Florida
United States	Partners in Internal Medicine, P.C.	Worcester	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Gilead Sciences

Countries where clinical trial is conducted

United States,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Sustained Virologic Response (SVR)	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.	through 24 weeks of off-treatment follow-up	No
Secondary	Sustained Virologic Response(SVR) of each regimen administered for 24 to 48 weeks	To evaluate antiviral efficacy as measured by SVR for 24 or 48 weeks of treatment with GS-5885, GS-9451, PEG, RBV.	Weeks 1, 2, 4, 8, 12, 16, 20, 24, 36, 48 and at 4 and 12 weeks off-treatment	No
Secondary	Safety and Tolerability	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.	through 24 to 48 week treatment period and up to 24 weeks of off-treatment follow-up	No
Secondary	Characterize the viral dynamics of GS-5885, GS-9451 when administered in combination with PEG and RBV	HCV RNA levels, pharmacokinetics, and viral sequencing	Through Week 2 of therapy	No
Secondary	Characterize the pharmacokinetics of GS-5885 and GS-9451 when administered in combination with PEG and RBV	Plasma concentrations of the study drug over time will be summarized using descriptive statistics. Pharmacokinetic parameters (Cmax, Tmax, Clast, Tlast, Ctau, ?z, 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).	Through Week 2 of therapy	No
Secondary	Emergence of Viral Resistance	To characterize the viral resistance to GS-5885 and GS 9451tegobuvir when administered in combination with PEG and RBV.	through 24 to 48 week treatment period and up to 24 weeks of off-treatment follow-up	No