Clinical trial NCT00740610: Safety, Tolerability, Pharmacokinetics and Activity of GS-9450 in Adults With Non-Alcoholic Steatohepatitis (NASH)
Official title: A Phase 2, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study to Investigate the Safety, Tolerability, Pharmacokinetics and Activity of GS 9450 in Adults With Non-Alcoholic Steatohepatitis (NASH)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Nonalcoholic Steatohepatitis
Lead sponsor: Gilead Sciences
Sponsor class: INDUSTRY
First posted: 2008-08-25
Enrollment: 124
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The overall purpose of this study is to examine the safety, tolerability, pharmacokinetics (how the body processes a drug), and activity of GS-9450 in preventing liver damage due to scarring, or fibrosis, caused by Non-Alcoholic Steatohepatitis (also known as NASH).

Detailed description: This is a Phase 2, randomized, double-blind, parallel group, placebo controlled, multicenter study investigating the safety, tolerability, pharmacokinetics and activity of multiple oral doses of GS 9450 in adults with NASH. Approximately 110 subjects 18 75 years of age with elevated ALT (\> 60 U/L at screening), fatty liver on screening ultrasound, and biopsy-proven NASH will be randomized (1:1:1:1:1) to one of five parallel treatment groups (22 subjects per treatment group) as follows:

GS-9450 1mg by mouth (PO) once daily, GS-9450 5 mg PO once daily, GS-9450 10 mg PO once daily, GS-9450 40 mg PO once daily, or Matching placebo PO once daily Qualifying subjects will be stratified by the presence/absence of type 2 diabetes (i.e., on/off oral diabetic medication at entry) and by geographic region (US and France). Following randomization, subjects will return within five business days later for a baseline visit, at which time they will be dispensed study medication and enter a 4-week treatment phase. Upon completion of the treatment phase, subjects will enter a 4 week off-treatment follow-up period. Each subject's participation in the study will last up to approximately 12 weeks (inclusive of screening, treatment phase, and off-treatment follow-up period).

Eligibility criteria: Inclusion Criteria:

* 18-75 years of age
* ALT \> 60 U/L
* fatty liver on screening ultrasound
* and biopsy-confirmed NASH
* platelet count \>/= 75,000/mm3 and adequate hematologic function (absolute neutrophil count \>/= 1,500/mm3, hemoglobin \>/= 11.0 g/dL)
* calculated creatinine clearance \>/= 70 mL/min
* non-insulin dependent diabetes for \< 10 years is allowed if stably managed for at least 6 months prior to screening
* stable weight (no weight loss \> 4%) for 8 weeks prior to screening and should maintain consistent diet, food intake, and physical exercise during the study
* must have been on stable therapy for at least 3 months prior to screening if receiving 3-hydroxy-3-methylglutaryl-coenzyme (HMG-CoA) reductase inhibitors, niacin, fibrates, vitamin E or angiotensin receptor blockers
* must have been on a stable treatment regimen for at least 3 months prior to screening if receiving other drugs possibly associated with hepatic adverse events (e.g., isoniazid, itraconazole, ketoconazole, rifabutin, rifampin, and other agents with significant hepatotoxic potential)

Exclusion Criteria:

* Insulin dependent diabetes mellitus, treatment with sulfonylureas (may be allowed pending results from a drug-drug interaction study), subjects receiving glitazones at screening or within 6 months of screening, presence of diabetic peripheral neuropathy or gastroparesis
* A \> 4% decrease in weight within 8 weeks of screening
* cirrhosis or decompensated liver disease (defined as conjugated bilirubin \> 1.5 x the upper limit of the normal range (ULN), prothrombin time \> 1.5 x ULN, serum albumin \< 3.0 g/dL, or prior history of clinical hepatic decompensation
* presence of other form of liver disease other than NASH
* history of excess alcohol ingestion, averaging \> 3 drinks/day in the previous 2 years; or current alcohol intake averaging \> 2 drinks/day for females and \> 3 drinks per day for males; history of or current binge drinking
* serological evidence of co-infection with hepatitis B virus (HBV), hepatitis C virus (HCV), or HIV
* evidence of hepatocellular carcinoma (i.e., α-fetoprotein \> 50 ng/mL)
* history of ingesting drugs possibly associated with hepatic steatosis within the past year
* history of total parenteral nutrition within the past 6 months
* prior history of gastroplasty, jejunoileal, or jejunocolonic bypass surgery
* history of ingesting drugs within the past 3 months that may improve NASH and associated fibrosis
* significant gastrointestinal disease that would interfere with absorption of oral medications; inflammatory bowel disease
* major surgery within the past year
* clinically significant abnormalities on ECG or other ECG findings that the investigator considers a safety risk
* significant systemic or major illnesses other than liver disease that, in the opinion of the investigator, would preclude treatment and adequate follow up
* prior or current malignancy involving any organ system and skin cancer (previously excised basal cell carcinoma allowed)
* acute ongoing infection, or symptoms of infection
* pregnant or breastfeeding females
* acute substance abuse within the past year.
* history of ingesting anti-TNFα drugs or immunomodulators within the past 3 months

Primary outcomes:
measure: Percentage of Participants Who Experienced Adverse Events (AEs) and Graded Laboratory Abnormalities
timeFrame: Baseline to Post-treatment Week 24
Secondary outcomes:
measure: Pharmacokinetics of GS-9450 and its metabolites
timeFrame: Weeks 2 and 4
measure: Change from baseline in alanine aminotransferase (ALT)
timeFrame: Baseline to Week 4
Other outcomes:
Locations:
city: Tucson
country: United States
state: Arizona
city: Fresno
country: United States
state: California
city: Fullerton
country: United States
state: California
city: San Diego
country: United States
state: California
city: San Mateo
country: United States
state: California
city: Lakewood
country: United States
state: Colorado
city: Washington
country: United States
state: District of Columbia
city: Jacksonville
country: United States
state: Florida
city: Atlanta
country: United States
state: Georgia
city: Marietta
country: United States
state: Georgia
city: Chicago
country: United States
state: Illinois
city: Des Moines
country: United States
state: Iowa
city: Kansas City
country: United States
state: Kansas
city: Monroe
country: United States
state: Louisiana
city: New Orleans
country: United States
state: Louisiana
city: Ann Arbor
country: United States
state: Michigan
city: Troy
country: United States
state: Michigan
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: Raleigh
country: United States
state: North Carolina
city: Clevleand
country: United States
state: Ohio
city: Providence
country: United States
state: Rhode Island
city: Dallas
country: United States
state: Texas
city: Galveston
country: United States
state: Texas
city: Irving
country: United States
state: Texas
city: Charlottesville
country: United States
state: Virginia
city: Falls Church
country: United States
state: Virginia
city: Richmond
country: United States
state: Virginia
city: Paris
country: France
city: Vandoeuvre les Nancy
country: France
Study officials:
affiliation: Gilead Sciences
name: Elsa Mondou, MD
role: STUDY_DIRECTOR
References: