Safety, Tolerability, Pharmacokinetics and Activity of GS-9450 in Adults With Non-Alcoholic Steatohepatitis (NASH)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Gilead Sciences
ClinicalTrials.gov Identifier:
NCT00740610
First received: August 21, 2008
Last updated: January 3, 2014
Last verified: January 2014
  Purpose

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).


Condition Intervention Phase
Nonalcoholic Steatohepatitis
Drug: GS-9450
Drug: GS-9450 Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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)

Resource links provided by NLM:


Further study details as provided by Gilead Sciences:

Primary Outcome Measures:
  • Percentage of Participants Who Experienced Adverse Events (AEs) and Graded Laboratory Abnormalities [ Time Frame: Baseline to Post-treatment Week 24 ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Pharmacokinetics of GS-9450 and its metabolites [ Time Frame: Weeks 2 and 4 ] [ Designated as safety issue: No ]
    Pharmacokinetics (Cmax, Tmax, Cmin, λz, t1/2, AUCtau, Vdss/F, and CL/F) measured by plasma sampling

  • Change from baseline in alanine aminotransferase (ALT) [ Time Frame: Baseline to Week 4 ] [ Designated as safety issue: No ]

Enrollment: 124
Study Start Date: August 2008
Study Completion Date: September 2009
Primary Completion Date: August 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort 1
22 subjects to receive 1 mg GS-9450 for 4 weeks
Drug: GS-9450
GS-9450 capsules at a dose of 1, 5, 10, and 40 mg administered orally once daily
Experimental: Cohort 2
22 subjects to receive 5 mg GS-9450 for 4 weeks
Drug: GS-9450
GS-9450 capsules at a dose of 1, 5, 10, and 40 mg administered orally once daily
Experimental: Cohort 3
22 subjects to receive 10 mg GS-9450 for 4 weeks
Drug: GS-9450
GS-9450 capsules at a dose of 1, 5, 10, and 40 mg administered orally once daily
Experimental: Cohort 4
22 subjects to receive 40 mg GS-9450 for 4 weeks
Drug: GS-9450
GS-9450 capsules at a dose of 1, 5, 10, and 40 mg administered orally once daily
Placebo Comparator: Cohort 5
22 subjects to receive placebo to match GS-9450 for 4 weeks
Drug: GS-9450 Placebo
Placebo to match GS-9450 administered orally once daily

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

Ages Eligible for Study:   18 Years to 75 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00740610

  Show 33 Study Locations
Sponsors and Collaborators
Gilead Sciences
Investigators
Study Director: Elsa Mondou, MD Gilead Sciences
  More Information

No publications provided

Responsible Party: Gilead Sciences
ClinicalTrials.gov Identifier: NCT00740610     History of Changes
Other Study ID Numbers: GS-US-228-0101
Study First Received: August 21, 2008
Last Updated: January 3, 2014
Health Authority: United States: Food and Drug Administration
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)

Additional relevant MeSH terms:
Fatty Liver
Liver Diseases
Digestive System Diseases

ClinicalTrials.gov processed this record on October 16, 2014