The purpose of this study is to determine if orlistat (Xenical) therapy in overweight patients with NASH leads to enhanced weight loss over time, with subsequent improvement in the underlying necroinflammatory and fibrotic changes that are typical of NASH.

Condition	Intervention	Phase
Fatty Liver Hepatitis	Drug: Orlistat (Xenical)  Behavior: 1400 kcal diet (30% fat)	Phase IV

Further Study Details: 

Primary Outcomes: The primary endpoint is weight loss leading to improvement in the global necroinflammatory and fibrosis scores on liver biopsies. A change of one point in the necroinflammatory grade or fibrosis stage will be considered statistically significant.
Secondary Outcomes: 1. BMI; 2. ALT; 3. Serum free fatty acids; 4. HOMA-IR (fasting insulin x fasting glucose/22.4)
Expected Total Enrollment:  50

Previous studies have suggested that steady weight loss over time will result in improvement in aminotransferases, and more importantly, underlying histopathology in patients with NASH. A total of 50 biopsy-proven NASH patients will be enrolled in a prospective, randomized fashion. Twenty-five patients have been enrolled at the primary study site at Saint Louis University. Recruitment of the next 25 patients is taking place at a study subsite at Brooke Army Medical Center in San Antonio, Texas.

This will be an open-label study comparing an established weight loss program (1400-calorie diet with 30% fat) plus daily vitamin E (800 IU) and a daily multivitamin to the same weight loss program, daily vitamin E (800 IU) and multivitamin, plus orlistat (120 mg), three times daily for 36 weeks.

Data to be collected from prospective patients includes demographic information, such as age, sex, past medical history, medications, height and weight. Biochemical data to be collected from prospective patients includes liver enzymes, measures of insulin resistance to include, insulin levels, lipid panel, hemoglobin A1C, free fatty acids, complete blood count, coagulation studies, and vitamin E levels. Blood will also be collected and stored for markers of inflammation and fibrosis, such as C reactive protein and TNF-alpha. A liver biopsy will be obtained at the completion of the study for both histopathologic analysis and RNA analysis.

Ages Eligible for Study:  18 Years and above,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria:

• Liver biopsy obtained no more than 24 months before randomization with a pathology report confirming that the histological diagnosis is consistent with NASH

• Compensated liver disease with the following laboratory parameters at the entry visit:

  • Hemoglobin values of greater than or equal to 12 gm/dl for females or 13 gm/dl for males
  • WBC count > 3,000/mm3
  • Neutrophil count > 1,500/mm3
  • Platelets > 70,000/mm3
  • Albumin >3.0 g/dl
• Serum creatinine <1.4mg/dl
• Ability to give informed consent
• Alanine aminotransferase (ALT) greater than or equal to 40 U/L
• BMI > or equal to 27 kg/m2
• Patients who receive orlistat must agree to participate in Xenicare, a free dietary counseling program provided by Roche (sponsor)

Exclusion Criteria:

• Any cause for chronic liver disease other than NASH
• Evidence of decompensated liver disease such as a history of or presence of ascites, bleeding varices, or spontaneous encephalopathy
• History of alcohol consumption of greater than 20 grams per day in the past 2 years
• Prior surgical procedures to include gastroplasty, jejunoileal or jejunocolic bypass
• TPN within the past 6 months
• History of prior organ transplantation
• Concurrent enrollment in other experimental treatment protocols
• Use of ursodeoxycholic acid, rosiglitazone, pioglitazone, or metformin within the 6-month period before enrollment
• Women who are pregnant or breast-feeding

Please refer to this study by ClinicalTrials.gov identifier  NCT00160407

Brent A Tetri, MD      314-577-8764    tetriba@slu.edu
Stephen A Harrison, MD      210-916-4811    Stephen.Harrison@CEN.AMEDD.ARMY.MIL

Missouri
      Saint Louis University, St. Louis,  Missouri,  63110,  United States; No longer recruiting
Texas
      Brooke Army Medical Center, San Antonio,  Texas,  78234,  United States; Recruiting

Study chairs or principal investigators

Brent A Tetri, MD,  Principal Investigator,  St. Louis University   

Study ID Numbers:  12458; XEN185
Last Updated:  September 11, 2005
Record first received:  September 8, 2005
ClinicalTrials.gov Identifier:  NCT00160407
Health Authority: United States: Institutional Review Board
ClinicalTrials.gov processed this record on 2005-09-13