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

Purpose

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

Condition	Intervention	Phase
Hepatitis C	Drug: GS-9669 tablets Drug: Placebo to Match GS-9669 tablet	Phase 1

Study Type:	Interventional
Study Design:	Masking: Single Blind (Subject) Primary Purpose: Treatment
Official Title:	A Phase 1b, Randomized, Single-Blind, Multiple-Dose Ranging Study Evaluating the Safety, Tolerability, Pharmacokinetics and Antiviral Activity of GS-9669 in Subjects With Chronic Hepatitis C Virus Infection

Resource links provided by NLM:

MedlinePlus related topics: Hepatitis Hepatitis A Hepatitis C

Drug Information available for: Hepatitis A Vaccines

U.S. FDA Resources

Further study details as provided by Gilead Sciences:

Primary Outcome Measures:

Safety and Tolerability [ Time Frame: through 24 weeks of off-treatment follow-up ]
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.
Antiviral Activity [ Time Frame: through 24 weeks of off-treatment follow-up ]
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.

Secondary Outcome Measures:

Viral Dynamics and Pharmacodynamics [ Time Frame: Through 17 days of therapy ]
To characterize the viral dynamics of GS-9669. The median change from baseline in HCV RNA and time-weighted average change from baseline through Day 3 will be assessed based on plasma HCV RNA sampling times to characterize the viral dynamics of GS-9669.
composite of Pharmacokinetics [ Time Frame: Through 17 days of therapy ]
To characterize the plasma PK parameters of GS-9669. The secondary PK endpoints will be evaluated using standard non-compartmental methods. Relevant PK parameters will be determined using standard non-compartmental methods with the linear-logarithmic trapezoidal rule utilizing a PK data analysis program (e.g., WinNonlin®) for GS-9669 as appropriate: Cmax, Tmax, Clast, Tlast, Ctau, λz, AUC0-last, AUCtau, , CL/F, and T½.
Genotypic Changes [ Time Frame: through 24 weeks of off-treatment follow-up ]
To characterize genotypic changes from baseline in the NS5B coding region of HCV following multiple dose administration of GS-9669 and for up to 24 weeks thereafter

Enrollment:	82
Study Start Date:	September 2011
Study Completion Date:	May 2012
Primary Completion Date:	December 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: 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.	Drug: GS-9669 tablets Other 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. Drug: Placebo to Match GS-9669 tablet

Arms

Assigned Interventions

Experimental: 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.

Drug: GS-9669 tablets

Other 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.

Drug: Placebo to Match GS-9669 tablet

Eligibility

Ages Eligible for Study:	18 Years to 65 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01431898

Locations

United States, California
Impact Clinical Trials
Los Angeles, California, United States, 90036
United States, Florida
Avail Clinical Research, LLC
Deland, Florida, United States, 32720
Orlando Clinical Research Center
Orlando, Florida, United States, 32809
United States, Nevada
Impact Clinical Trials
Las Vegas, Nevada, United States, 89106
United States, New Jersey
CRI Worldwide
Willingboro, New Jersey, United States, 08046
United States, Pennsylvania
CRI Worldwide
Philadelphia, Pennsylvania, United States, 19139
United States, Texas
Alamo Medical Research
San Antonio, Texas, United States, 78215
United States, Utah
Lifetree Clinical Research, LC
Salt Lake City, Utah, United States, 84106
University of Utah Health Sciences Center
Salt Lake City, Utah, United States, 84132
United States, Washington
Charles River Clinical Services Northwest
Tacoma, Washington, United States, 98418
Puerto Rico
Fundacion de Investigacion de Diego
San Juan, Puerto Rico, 00927

Sponsors and Collaborators

Gilead Sciences

Investigators

Study Director:

Stephen Rossi, PharmD

Gilead Sciences

More Information

No publications provided by Gilead Sciences

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

Responsible Party:	Gilead Sciences
ClinicalTrials.gov Identifier:	NCT01431898 History of Changes
Other Study ID Numbers:	GS-US-257-0102
Study First Received:	September 1, 2011
Last Updated:	July 23, 2012
Health Authority:	United States: Food and Drug Administration

Keywords provided by Gilead Sciences:

HCV RNA
Polymerase inhibitor
Treatment naïve and Treatment experienced

GS-9669
Hepatitis C
HCV

Additional relevant MeSH terms:

Hepatitis
Hepatitis A
Hepatitis, Chronic
Hepatitis C
Virus Diseases
Hepatitis C, Chronic
Liver Diseases
Digestive System Diseases
Hepatitis, Viral, Human

Enterovirus Infections
Picornaviridae Infections
RNA Virus Infections
Flaviviridae Infections
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on May 19, 2013