Clinical trial NCT00743795: Safety, Tolerability, and Antiviral Activity of 24 or 48 Weeks of GS-9190 in Combination With Peginterferon Alfa 2a and Ribavirin for the Treatment of Genotype-1 Chronic HCV Infection
Official title: A Phase 2b, Randomized, Double-Blind, Placebo-Controlled Trial Comparing 24 or 48 Weeks of GS 9190, in Combination With Peginterferon Alfa 2a and Ribavirin, to 48 Weeks of Peginterferon Alfa 2a and Ribavirin for the Treatment of Genotype-1 Chronic Hepatitis C Virus (HCV) Infection (GS-US-196-0103)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HCV Infection
Keywords: Hepatitis C
HCV
Rapid Virologic Response
Sustained Virologic Response
HCV RNA
Polymerase inhibitor
GS-9190
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2008-08-29
Enrollment: 252
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to compare the safety, tolerability and effectiveness of the experimental drug GS-9190 when administered for 24 or 48 weeks with peginterferon alfa 2a and ribavirin for the treatment of genotype-1 chronic hepatitis C infection.

Detailed description: The safety, tolerability and antiviral efficacy GS-9190, administered orally twice daily at 40 mg, will be compared to placebo when used in combination with peginterferon alfa 2a (PEG) and ribavirin (RIBA) in treatment-naïve subjects chronically infected with HCV genotype 1 infection. Two-hundred forty-eight (248) subjects will be randomized (ratio: 1:2:1) to one of three treatment arms:

Arm 1: PEG/RIBA + placebo BID for 48 weeks + 24 weeks treatment-free follow-up (n = 62)

Arm 2: PEG/RIBA + GS 9190 40 mg BID for 48 weeks + 24 weeks treatment-free follow-up (n = 124)

Arm 3: PEG/RIBA + GS 9190 40 mg BID for 48 weeks + 24 weeks treatment-free follow-up. However, subjects who achieve RVR (HCV RNA undetectable at Week 4) and maintain that response through Week 24 will stop all study drugs at Week 24 and be followed for an additional 48 weeks (n = 62).

Randomization will be stratified by plasma HCV RNA level (\< or ≥ 400,000 IU/mL) at screening and race (of African descent or other).

In order to ensure adequate representation of subjects with genotypes 1a and 1b in this trial, enrollment for either genotype will be capped at 120 subjects. Once 120 subjects of either genotype (e.g., genotype 1a) have been randomized, subsequent enrollment will only be allowed for subjects with the other genotype (e.g., genotype 1b).

The duration of double-blind treatment is 48 weeks plus 24 weeks of treatment-free follow-up; however subjects in Arm 3 will stop all medication at Week 24 if they have achieved an RVR (defined by undetectable HCV RNA following 4 weeks on therapy) and have maintained that response thereafter. Subjects will only learn that they have been randomized to Arm 3 if, at Week 24, having achieved criteria for stopping therapy, they are instructed to stop. All other subjects will remain blinded to their treatment status throughout the course of the study.

The standard of care treatment stopping criterion used in clinical practice when treating HCV with PEG/RIBA, failure to achieve EVR, will be utilized in this trial. Additionally, subjects with detectable plasma HCV RNA at Week 24 will discontinue all study medications no later than the Week 28 visit and will be followed off-treatment for 24 weeks.

Eligibility criteria: Inclusion Criteria:

* Adult subjects (18 - 70 years of age)
* Chronic HCV infection for at least 6 months prior to Baseline (Day 1) (anti-HCV antibody positive; positive for plasma HCV RNA; medical history consistent with chronicity accepted by the investigator)
* Liver biopsy results within the past 2 years prior to Baseline (Day 1) indicating the absence of cirrhosis
* HCV treatment-naive, defined as no prior exposure to PEG, RIBA, or experimental HCV therapy
* Mono-infection with HCV genotype 1a or 1b
* Detectable plasma HCV RNA at Screening
* BMI between 19 and 36 kg/m2
* Willing and able to provide written informed consent and to comply with all study requirements
* Of generally good health as determined by the Investigator
* Subject agrees to use adequate skin protection (e.g., sunblocking agent) when exposed to the sun.
* Women of childbearing potential (i.e., a non-menopausal female or a female with menopausal \< 2 years, who has not had a hysterectomy, bilateral oophorectomy or medically documented ovarian failure) must have negative serum β-human chorionic gonadotropin (hCG) at screening and negative urine pregnancy test prior to the first study drug administration.
* All subjects (male and female) must agree to utilize highly effective contraception methods (two separate forms of contraception, one of which must be an effective barrier method, or be non-heterosexually active, practice sexual abstinence or have a vasectomized partner) from screening throughout the duration of study treatment and for 24 weeks after the last dose of RIBA.
* Female subjects who utilize hormonal contraceptive as one of their birth control methods must have used the same method for at least three months prior to study dosing.
* Female subjects who are postmenopausal for less than two years are required to have FSH \> 40 mIU/mL. If the FSH is ≤ 40 mIU/mL, the subject must agree to use highly effective method of birth control (as described above) to participate in the study.
* Male subjects who are sexually active must be willing to use effective barrier contraception (e.g., condom with spermicide) during heterosexual intercourse from screening through completion of the study and continue for 24 weeks after the last dose of RIBA

Exclusion Criteria:

* Pregnant or breast feeding women or women who may wish to become pregnant during the course of the study
* Males who have partners planning to become pregnant
* Males and females of reproductive potential who are unwilling to use two forms of effective birth control through Study Week 72. One method should include a condom with spermicide for males
* Infection with non-genotype 1 HCV
* Poorly controlled diabetes mellitus (hemoglobin A1c \> 7) unless treatment intervention has been reviewed with the Medical Monitor and improved glucose control is anticipated
* History of sarcoidosis
* History of hemoglobinopathy (e.g., thalassemia)
* History of known retinal disease
* History of invasive malignancy diagnosed or treated within 5 years (recent localized treatment of squamous or non-invasive basal cell skin cancers is permitted; cervical carcinoma in situ is allowed if appropriately treated prior to screen)
* Evidence of hepatocellular carcinoma
* Chronic liver disease of a non-HCV etiology
* Untreated or significant psychiatric illnesses including severe depression, schizophrenia, psychosis, or a history of a suicide attempt
* Co-infection with HIV, HBV, or multiple HCV genotypes
* Chronic use of systemic immunosuppressive agents
* Presence of autoimmune disorders. Subjects with treated hypothyroidism with normal TSH may be enrolled.
* Severe chronic obstructive pulmonary disease
* History of clinically significant cardiac disease, including a family history of Long QT Syndrome, and/or evidence of the following ECG abnormalities at screening: QTcF (QT corrected using Fridericia's formula) of \> 450 msec; complete or incomplete left or right bundle branch block; intraventricular conduction delay with QRS duration of \> 120 msec; bradycardia (\< 45 beats per minute); pathologic Q-waves (Q wave of \> 40 msec or depth of \> 0.4 to 0.5 V); arrhythmia (an isolated premature ventricular contraction on screening/Day 1 is not exclusionary) ; ventricular pre excitation; second or third degree heart block
* Positive urine screen for amphetamines or cocaine
* Known, current heroin, morphine, or methadone use
* Ongoing alcohol abuse in the judgment of the investigator (in no case intake of more than 28 units of alcohol per week \[1 unit = ½ pint of beer, 1 glass of wine, 1 shot of spirits\])
* Receiving a known potent CYP 3A4 inhibitor within 2 weeks of study drug dosing or are expected to receive such therapy during the course of study drug dosing
* Known hypersensitivity to the study drugs, their metabolites or formulation excipients
* In the judgment of the Investigator, should not participate in the study due to potential clinical or compliance issues

Primary outcomes:
measure: Undetectable HCV RNA level
timeFrame: At Week 12 for Early Virologic Response (EVR)
Secondary outcomes:
measure: Safety and tolerability
timeFrame: Throughout 72 week study period
measure: Undetectable HCV RNA level
timeFrame: Week 4, Week 24 and Week 48
measure: GS-9190 plasma concentrations
timeFrame: Through Week 48
measure: Undetectable HCV RNA
timeFrame: At Week 72 for sustained virologic response (SVR)
Other outcomes:
Locations:
city: Anaheim
country: United States
state: California
city: Los Angeles
country: United States
state: California
city: Newport Beach
country: United States
state: California
city: San Clemente
country: United States
state: California
city: San Diego
country: United States
state: California
city: San Diego
country: United States
state: California
city: San Francisco
country: United States
state: California
city: Englewood
country: United States
state: Colorado
city: Miami
country: United States
state: Florida
city: North Miami Beach
country: United States
state: Florida
city: Orlando
country: United States
state: Florida
city: Sarasota
country: United States
state: Florida
city: Tampa
country: United States
state: Florida
city: Atlanta
country: United States
state: Georgia
city: Decatur
country: United States
state: Georgia
city: Chicago
country: United States
state: Illinois
city: Bowling Green
country: United States
state: Kentucky
city: Baton Rouge
country: United States
state: Louisiana
city: Baltimore
country: United States
state: Maryland
city: Baltimore
country: United States
state: Maryland
city: Baltimore
country: United States
state: Maryland
city: Boston
country: United States
state: Massachusetts
city: Detroit
country: United States
state: Michigan
city: St. Louis
country: United States
state: Missouri
city: Cedar Knolls
country: United States
state: New Jersey
city: Johnson City
country: United States
state: New York
city: New York
country: United States
state: New York
city: New York
country: United States
state: New York
city: New York
country: United States
state: New York
city: New York
country: United States
state: New York
city: Plainview
country: United States
state: New York
city: Syracuse
country: United States
state: New York
city: Asheville
country: United States
state: North Carolina
city: Durham
country: United States
state: North Carolina
city: High Point
country: United States
state: North Carolina
city: Cincinatti
country: United States
state: Ohio
city: Cincinnati
country: United States
state: Ohio
city: Tulsa
country: United States
state: Oklahoma
city: Philadelphia
country: United States
state: Pennsylvania
city: Philadelphia
country: United States
state: Pennsylvania
city: Germantown
country: United States
state: Tennessee
city: Dallas
country: United States
state: Texas
city: Houston
country: United States
state: Texas
city: San Antonio
country: United States
state: Texas
city: Annandale
country: United States
state: Virginia
city: Fairfax
country: United States
state: Virginia
city: Norfolk
country: United States
state: Virginia
city: Richmond
country: United States
state: Virginia
city: Bruxelles
country: Belgium
city: Bruxelles
country: Belgium
city: Ghent
country: Belgium
city: Leuven
country: Belgium
city: Liege
country: Belgium
city: Berlin
country: Germany
city: Frankfurt
country: Germany
city: Hamburg
country: Germany
city: Hannover
country: Germany
city: Koln
country: Germany
city: Munchen
country: Germany
city: Dublin
country: Ireland
city: Dublin
country: Ireland
city: Dublin
country: Ireland
city: Bialystok
country: Poland
city: Bydgoszcz
country: Poland
city: Chorzow
country: Poland
city: Czeladz
country: Poland
city: Krakow
country: Poland
city: Warszawa
country: Poland
city: Santurce
country: Puerto Rico
city: Birmingham
country: United Kingdom
city: London
country: United Kingdom
city: London
country: United Kingdom
Study officials:
affiliation: Gilead Sciences
name: Steven Knox
role: STUDY_CHAIR
References: