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

Primary Purpose

Hepatitis C

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
GS-9669 tablets
Placebo to Match GS-9669 tablet
Sponsored by
Gilead Sciences
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Hepatitis C focused on measuring HCV RNA, Polymerase inhibitor, Treatment naïve and Treatment experienced, GS-9669, Hepatitis C, HCV

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept 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

Sites / Locations

  • Impact Clinical Trials
  • Avail Clinical Research, LLC
  • Orlando Clinical Research Center
  • Impact Clinical Trials
  • CRI Worldwide
  • CRI Worldwide
  • Alamo Medical Research
  • Lifetree Clinical Research, LC
  • University of Utah Health Sciences Center
  • Charles River Clinical Services Northwest
  • Fundacion de Investigacion de Diego

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

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

Arm Description

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.

Outcomes

Primary Outcome Measures

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.
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.

Secondary Outcome Measures

Viral Dynamics and Pharmacodynamics
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
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
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

Full Information

First Posted
September 1, 2011
Last Updated
July 23, 2012
Sponsor
Gilead Sciences
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1. Study Identification

Unique Protocol Identification Number
NCT01431898
Brief Title
Safety, Tolerability, Pharmacokinetics and Antiviral Activity of GS-9669 in Subjects With Chronic Hepatitis C Virus Infection
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 Type
Interventional

2. Study Status

Record Verification Date
March 2012
Overall Recruitment Status
Completed
Study Start Date
September 2011 (undefined)
Primary Completion Date
December 2011 (Actual)
Study Completion Date
May 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Gilead Sciences

4. Oversight

5. 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Hepatitis C
Keywords
HCV RNA, Polymerase inhibitor, Treatment naïve and Treatment experienced, GS-9669, Hepatitis C, HCV

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Masking
Participant
Enrollment
82 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Multiple-dose, dose-escalation study of GS-9669
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
GS-9669 tablets
Other Intervention Name(s)
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.
Intervention Type
Drug
Intervention Name(s)
Placebo to Match GS-9669 tablet
Primary Outcome Measure Information:
Title
Safety and Tolerability
Description
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.
Time Frame
through 24 weeks of off-treatment follow-up
Title
Antiviral Activity
Description
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.
Time Frame
through 24 weeks of off-treatment follow-up
Secondary Outcome Measure Information:
Title
Viral Dynamics and Pharmacodynamics
Description
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.
Time Frame
Through 17 days of therapy
Title
composite of Pharmacokinetics
Description
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.
Time Frame
Through 17 days of therapy
Title
Genotypic Changes
Description
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
Time Frame
through 24 weeks of off-treatment follow-up

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
65 Years
Accepts Healthy Volunteers
No
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Stephen Rossi, PharmD
Organizational Affiliation
Gilead Sciences
Official's Role
Study Director
Facility Information:
Facility Name
Impact Clinical Trials
City
Los Angeles
State/Province
California
ZIP/Postal Code
90036
Country
United States
Facility Name
Avail Clinical Research, LLC
City
Deland
State/Province
Florida
ZIP/Postal Code
32720
Country
United States
Facility Name
Orlando Clinical Research Center
City
Orlando
State/Province
Florida
ZIP/Postal Code
32809
Country
United States
Facility Name
Impact Clinical Trials
City
Las Vegas
State/Province
Nevada
ZIP/Postal Code
89106
Country
United States
Facility Name
CRI Worldwide
City
Willingboro
State/Province
New Jersey
ZIP/Postal Code
08046
Country
United States
Facility Name
CRI Worldwide
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19139
Country
United States
Facility Name
Alamo Medical Research
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78215
Country
United States
Facility Name
Lifetree Clinical Research, LC
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84106
Country
United States
Facility Name
University of Utah Health Sciences Center
City
Salt Lake City
State/Province
Utah
ZIP/Postal Code
84132
Country
United States
Facility Name
Charles River Clinical Services Northwest
City
Tacoma
State/Province
Washington
ZIP/Postal Code
98418
Country
United States
Facility Name
Fundacion de Investigacion de Diego
City
San Juan
ZIP/Postal Code
00927
Country
Puerto Rico

12. IPD Sharing Statement

Citations:
PubMed Identifier
25155588
Citation
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.
Results Reference
derived
PubMed Identifier
23183437
Citation
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.
Results Reference
derived

Learn more about this trial

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

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