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

• Sponsor: Gilead Sciences (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00740610
• Collaborator: (none)
• Enrollment: 124
• Locations: 33
• Arms: 5
• Duration (Months): 13
• Patients Per Site: 3.8
• Patients Per Site Per Month: 0.3

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Nonalcoholic Steatohepatitis	Drug: GS-9450; Drug: GS-9450 Placebo	Phase 2

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 124 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, 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)
• Study Start Date: Aug 1, 2008
• Actual Primary Completion Date: Aug 1, 2009
• Actual Study Completion Date: Sep 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
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

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Who Experienced Adverse Events (AEs) and Graded Laboratory Abnormalities [Baseline to Post-treatment Week 24]

Secondary Outcome Measures

1. Pharmacokinetics of GS-9450 and its metabolites [Weeks 2 and 4]

   Pharmacokinetics (Cmax, Tmax, Cmin, λz, t1/2, AUCtau, Vdss/F, and CL/F) measured by plasma sampling

2. Change from baseline in alanine aminotransferase (ALT) [Baseline to Week 4]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 75 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Locations

	Site	City	State	Country	Postal Code
1		Tucson	Arizona	United States
2		Fresno	California	United States
3		Fullerton	California	United States
4		San Diego	California	United States	92161
5		San Mateo	California	United States
6		Lakewood	Colorado	United States
7		Washington	District of Columbia	United States
8		Jacksonville	Florida	United States
9		Atlanta	Georgia	United States	30309
10		Marietta	Georgia	United States
11		Chicago	Illinois	United States
12		Des Moines	Iowa	United States
13		Kansas City	Kansas	United States	66160
14		Monroe	Louisiana	United States
15		New Orleans	Louisiana	United States
16		Ann Arbor	Michigan	United States	48109
17		Troy	Michigan	United States
18		New York	New York	United States
19		Plainview	New York	United States
20		Syracuse	New York	United States
21		Asheville	North Carolina	United States
22		Durham	North Carolina	United States
23		Raleigh	North Carolina	United States
24		Clevleand	Ohio	United States
25		Providence	Rhode Island	United States	02905
26		Dallas	Texas	United States	75203
27		Galveston	Texas	United States	77555
28		Irving	Texas	United States
29		Charlottesville	Virginia	United States
30		Falls Church	Virginia	United States
31		Richmond	Virginia	United States
32		Paris		France	75020
33		Vandoeuvre les Nancy		France	54511

Sponsors and Collaborators

• Gilead Sciences

Investigators

• Study Director: Elsa Mondou, MD, Gilead Sciences

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Gilead Sciences
• ClinicalTrials.gov Identifier: NCT00740610
• Other Study ID Numbers: GS-US-228-0101
• First Posted: Aug 25, 2008
• Last Update Posted: Feb 4, 2014
• Last Verified: Jan 1, 2014

• Additional relevant MeSH terms: Fatty Liver; Non-alcoholic Fatty Liver Disease

Study Results

No Results Posted as of Feb 4, 2014