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

Sponsor

Gilead Sciences (Industry)

Overall Status

Completed

CT.gov ID

NCT01431898

Collaborator

(none)

Enrollment

Locations

Arm

Duration (Months)

7.5

Patients Per Site

0.9

Patients Per Site Per Month

Study Details

Study Description

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.

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

Study Design

Study Type:

Interventional

Actual Enrollment :

82 participants

Masking:

Single (Participant)

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

Study Start Date :

Sep 1, 2011

Actual Primary Completion Date :

Dec 1, 2011

Actual Study Completion Date :

May 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
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

Arm

Intervention/Treatment

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

Outcome Measures

Primary Outcome Measures

Safety and Tolerability [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 [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 [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 [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 [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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

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