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

NCT01431898 | Completed Phase 1

• 1 other identifier: GS-US-257-0102
• Study Type: interventional
• Target: 82
• Locations: 2 countries
• Sites: 11

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

Outcome Measures

Primary Outcomes (2)

• Safety and Tolerability

  To evaluate safety and tolerability of escalating multiple oral doses of GS 9669. 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.

  through 24 weeks of off-treatment follow-up

• Antiviral Activity

  To evaluate antiviral activity of GS-9669 against HCV in genotype-1a and 1b (GT1a/b) subjects. This will be evaluated using change from baseline in plasma HCV RNA. Reduction in HCV RNA will be summarized as categorical (as \< 1, ≥ 1 to \<2, ≥ 2 to \<3, or ≥ 3 log10 IU/mL) reduction from baseline.

  through 24 weeks of off-treatment follow-up

Secondary Outcomes (3)

• Viral Dynamics and Pharmacodynamics

  Through 17 days of therapy

• composite of Pharmacokinetics

  Through 17 days of therapy

• Genotypic Changes

  through 24 weeks of off-treatment follow-up

Study Arms (1)

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

EXPERIMENTAL

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.

Drug: GS-9669 tablets; Drug: Placebo to Match GS-9669 tablet

Interventions

GS-9669 tablets DRUG

Also known as: 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.

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

Placebo to Match GS-9669 tablet DRUG

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

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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 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

Sponsors & Collaborators

• Gilead Sciences: lead

Study Sites (11)

Impact Clinical Trials

Los Angeles, California, 90036, United States

Location

Avail Clinical Research, LLC

DeLand, Florida, 32720, United States

Location

Orlando Clinical Research Center

Orlando, Florida, 32809, United States

Location

Impact Clinical Trials

Las Vegas, Nevada, 89106, United States

Location

CRI Worldwide

Willingboro, New Jersey, 08046, United States

Location

CRI Worldwide

Philadelphia, Pennsylvania, 19139, United States

Location

Alamo Medical Research

San Antonio, Texas, 78215, United States

Location

Lifetree Clinical Research, LC

Salt Lake City, Utah, 84106, United States

Location

University of Utah Health Sciences Center

Salt Lake City, Utah, 84132, United States

Location

Charles River Clinical Services Northwest

Tacoma, Washington, 98418, United States

Location

Fundacion de Investigacion de Diego

San Juan, 00927, Puerto Rico

Location

Related Publications (2)

• 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.

  PMID: 25155588 DERIVED

• 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.

  PMID: 23183437 DERIVED

MeSH Terms

Conditions

Hepatitis C

Interventions

GS-9669; Food; Communication Devices for People with Disabilities; WW Domain-Containing Oxidoreductase

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Hepatitis, Viral, Human; Virus Diseases; Flaviviridae Infections; RNA Virus Infections; Hepatitis; Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Diet, Food, and Nutrition; Physiological Phenomena; Food and Beverages; Self-Help Devices; Equipment and Supplies; Short Chain Dehydrogenase-Reductases; NAD (+) and NADP (+) Dependent Alcohol Oxidoreductases; Alcohol Oxidoreductases; Oxidoreductases; Enzymes; Enzymes and Coenzymes; Tumor Suppressor Proteins; Neoplasm Proteins; Proteins; Amino Acids, Peptides, and Proteins

Study Officials

• Stephen Rossi, PharmD

  Gilead Sciences

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Masking: SINGLE
• Who Masked: PARTICIPANT
• Purpose: TREATMENT
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 1, 2011
• First Posted: September 12, 2011
• Study Start: September 1, 2011
• Primary Completion: December 1, 2011
• Study Completion: May 1, 2012
• Last Updated: July 25, 2012

Record last verified: 2012-03

Locations

US (10); PR (1)