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

July 23, 2012 updated by: Gilead Sciences

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

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

Study Overview

Status

Completed

Conditions

Study Type

Interventional

Enrollment (Actual)

82

Phase

  • Phase 1

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Masking: Single

Arms and Interventions

Participant Group / 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.
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.

through 24 weeks of off-treatment follow-up
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.
through 24 weeks of off-treatment follow-up

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Through 17 days of therapy
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.
Through 17 days of therapy
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
through 24 weeks of off-treatment follow-up

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Investigators

  • Study Director: Stephen Rossi, PharmD, Gilead Sciences

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2011

Primary Completion (Actual)

December 1, 2011

Study Completion (Actual)

May 1, 2012

Study Registration Dates

First Submitted

September 1, 2011

First Submitted That Met QC Criteria

September 9, 2011

First Posted (Estimate)

September 12, 2011

Study Record Updates

Last Update Posted (Estimate)

July 25, 2012

Last Update Submitted That Met QC Criteria

July 23, 2012

Last Verified

March 1, 2012

More Information

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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