Safety, Tolerability, Pharmacokinetics and Antiviral Activity of GS-9669 in Subjects With Chronic Hepatitis C Virus Infection

NCT ID: NCT01431898

Last Updated: 2012-07-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1
• Total Enrollment: 82 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2011-09-30
• Study Completion Date: 2012-05-31

Brief Summary

This is a research study to evaluate the safety, tolerability and anti-viral activity of GS-9669 in patients with Hepatitis C infection.

Conditions

Hepatitis C

Keywords

HCV RNA; Polymerase inhibitor; Treatment naïve and Treatment experienced; GS-9669; Hepatitis C; HCV

Study Design

• Primary Study Purpose: TREATMENT
• Blinding Strategy: SINGLE

Study Groups

Multiple-dose, dose-escalation study of GS-9669

Multiple-dose, dose-escalation study of GS-9669, a nonnucleotide NS5B inhibitor of hepatitis C virus (HCV), in subjects with chronic HCV infection. Dosing is planned in up to 7 unique dosing cohorts. Each cohort will be comprised of 10 genotype 1a (Cohorts 1, 2, 3, 4, and 5) or genotype 1b (Cohort 6 and 7), with eight subjects randomized to receive active drug and two subjects randomized to receive placebo per cohort.

Group Type: EXPERIMENTAL

GS-9669 tablets

Intervention Type: DRUG

Placebo to Match GS-9669 tablet

Intervention Type: DRUG

Interventions

GS-9669 tablets

Intervention Type: DRUG

Placebo to Match GS-9669 tablet

Intervention Type: DRUG

Other Intervention Names

Cohort 1 (N = 10, genotype 1a): 100 mg GS-9669 or placebo BID with; food [total daily dose (TDD) = 200 mg] for 3 days; Cohort 2 (N = 10, genotype 1a): 400 mg GS-9669 or placebo BID with; food (TDD = 800 mg) for 3 days; Cohorts 1 and 2 may be conducted in parallel. Additional adaptive BID; and/or QD cohorts (Cohorts 3-5) in genotype 1a subjects may be; conducted depending on the safety, virology, and available; pharmacokinetics from the first two cohorts. Cohorts 3 -5 may be; conducted in parallel if the total daily dose is lower than the highest total; daily dose previously tested and determined to be safe and well tolerated.; Cohort 3 (N = 10, genotype 1a): up to 400 mg GS-9669 or placebo BID; with food (TDD = up to 800 mg) for 3 days; Cohort 4 (N = 10, genotype 1a): up to 400 mg GS-9669 or placebo BID; Cohort 5 (N=10, genotype 1a): up to 800 mg GS-9669 or placebo QD in; the morning with food (TDD = up to 800 mg) for 3 days; Based on the results of Cohorts 1 to 5, one or more regimens will be; selected for an evaluation in genotype 1b subjects to enable comparison; between genotypes. Cohorts 6 and 7 may proceed in parallel with other; Cohorts if the total daily dose is the same or lower than the highest total; Cohort 6 (N = 10, genotype 1b): up to 400 mg GS-9669 or placebo BID; with food (TDD = up to 800 mg) for 3 days; Cohort 7 (N = 10, genotype 1b): up to 800 mg GS-9669 or placebo QD in; the morning with food (TDD = up to 800 mg) for 3 days.

Eligibility Criteria

Inclusion Criteria

• Adult subjects 18-65 years of old, inclusive
• Documented chronic HCV infection to be of at least 6 months duration and plasma HCV RNA ≥ 5 log10 IU/mL at screening.
• HCV treatment naïve or PEG-IFN, IFN, and/or RBV experienced (treatment must have ceased at least 3 months prior to screening). Treatment experienced subjects should not exceed 40% of the subjects enrolled in each cohort
• Mono-infection with HCV genotype 1a for Cohorts 1, 2, 3, 4, and 5 and mono-infection with HCV genotype 1b for Cohort 6 and 7.
• Estimated creatinine clearance ≥ 70 mL/min,
• QTcF interval ≤ 450 msec for males and ≤ 470 msec for females, QRS duration < 120 msec, PR interval < 220 msec,
• Body mass index (BMI) of 19.0 to 34.0 kg/m^2, inclusive.

Exclusion Criteria

• Urine drug screen positive for illicit/illegal drugs
• ALT and AST levels > 5 times the upper limit of the normal range (ULN)
• Direct bilirubin > ULN, clinical or other laboratory evidence of hepatic decompensation (i.e., platelets < 90,000/mm^3, prothrombin time ≥ 1.5 × ULN and albumin < 3.5 g/dL) are not eligible for study participation.
• Subjects with an absolute neutrophil count (ANC) < 1,000 cells/mm^3 (< 750 cells/mm^3 for black or African-American subjects), hemoglobin (Hb) < 11 g/dL,
• Coinfected with hepatitis B virus (HBV), human immunodeficiency virus (HIV), or another HCV genotype other than genotype 1a/b are not eligible for study participation.
• Evidence of hepatocellular carcinoma (e.g., a-fetoprotein > 50 ng/mL or as indicated by recent ultrasound or other standard of care measure)
• History of significant cardiac disease. The following ECG abnormalities at screening are exclusionary: QTcF (QT corrected using Fridericia's formula=QT/RR^0.333) > 450 msec for males and > 470 for females; QRS > 120 msec (left or right hemiblock is not exclusionary); PR interval > 220 msec; bradycardia (< 45 beats per minute); second or third degree heart block.
• History of clinically-significant illness or any other major medical disorder that may interfere with subject treatment, assessment or compliance with the protocol
• History of a primary gastrointestinal disorder that could interfere with the absorption of the study drug or that could interfere with normal gastrointestinal anatomy or motility

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Gilead Sciences

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Stephen Rossi, PharmD

Role: STUDY_DIRECTOR

Gilead Sciences

Locations

Impact Clinical Trials

Los Angeles, California, United States

Avail Clinical Research, LLC

DeLand, Florida, United States

Orlando Clinical Research Center

Orlando, Florida, United States

Impact Clinical Trials

Las Vegas, Nevada, United States

CRI Worldwide

Willingboro, New Jersey, United States

CRI Worldwide

Philadelphia, Pennsylvania, United States

Alamo Medical Research

San Antonio, Texas, United States

Lifetree Clinical Research, LC

Salt Lake City, Utah, United States

University of Utah Health Sciences Center

Salt Lake City, Utah, United States

Charles River Clinical Services Northwest

Tacoma, Washington, United States

Fundacion de Investigacion de Diego

San Juan, , Puerto Rico

Countries

United States; Puerto Rico

References

Dvory-Sobol H, Voitenleitner C, Mabery E, Skurnac T, Lawitz EJ, McHutchison J, Svarovskaia ES, Delaney W, Miller MD, Mo H. Clinical and in vitro resistance to GS-9669, a thumb site II nonnucleoside inhibitor of the hepatitis C virus NS5B polymerase. Antimicrob Agents Chemother. 2014 Nov;58(11):6599-606. doi: 10.1128/AAC.02815-14. Epub 2014 Aug 25.

Reference Type: DERIVED

PMID: 25155588 (View on PubMed)

Fenaux M, Eng S, Leavitt SA, Lee YJ, Mabery EM, Tian Y, Byun D, Canales E, Clarke MO, Doerffler E, Lazerwith SE, Lew W, Liu Q, Mertzman M, Morganelli P, Xu L, Ye H, Zhang J, Matles M, Murray BP, Mwangi J, Zhang J, Hashash A, Krawczyk SH, Bidgood AM, Appleby TC, Watkins WJ. Preclinical characterization of GS-9669, a thumb site II inhibitor of the hepatitis C virus NS5B polymerase. Antimicrob Agents Chemother. 2013 Feb;57(2):804-10. doi: 10.1128/AAC.02052-12. Epub 2012 Nov 26.

Reference Type: DERIVED

PMID: 23183437 (View on PubMed)

Other Identifiers

GS-US-257-0102

Identifier Type: -

Identifier Source: org_study_id