Ezetimibe Versus Placebo in the Treatment of Non-alcoholic Steatohepatitis

This is an interventional treatment trial for Non Alcoholic Steatohepatitis Read More

Inclusion Criteria:

1. Age at entry at least 18 years.
2. Serum alanine (ALT) or aspartate (AST) aminotransferase activities that are above the upper limits of normal. 19 or more in women and 30 or more in men.
3. Evidence of hepatic steatosis or liver fat (>5%) by MRI.

4. Evidence of definite or suspected NASH

   1. Evidence of (definite) steatohepatitis on liver biopsy done within the previous 12 months with a NASH activity score of at least 4 (of a total possible score of 8) including a score of at least 1 each for steatosis, hepatocellular injury and parenchymal inflammation. Histological criteria of steatohepatitis include: (1) macrovesicular steatosis, (2) acinar zone 3 hepatocellular injury (ballooning degeneration), (3) parenchymal and (4) portal inflammation. Additionally helpful, but not required, features include the presence of (5) Mallory's hyaline and (6) pericellular and/or sinusoidal fibrosis that predominantly involves zone 3. If a liver biopsy is available within the last 12 months, then a repeat biopsy may not be conducted unless there has been a considerable change in body weight that may change liver histologic parameters associated with NASH
   2. Those who are suspected of having NASH and have not undergone a liver biopsy within the last 12 months may undergo a liver biopsy as a screening liver biopsy but would qualify for randomization into either ezetimibe or placebo arms only if they meet histologic criteria of NASH.
5. Written informed consent.

Exclusion Criteria:

1. Evidence of another form of liver disease.

   1. Hepatitis B as defined as presence of hepatitis B surface antigen (HBsAg).
   2. Hepatitis C as defined by presence of hepatitis C virus (HCV) RNA in serum.
   3. Autoimmune hepatitis as defined by anti-nuclear antibody (ANA) of 1:160 or greater and liver histology consistent with autoimmune hepatitis or previous response to immunosuppressive therapy.
   4. Autoimmune cholestatic liver disorders as defined by elevation of alkaline phosphatase and anti-mitochondrial antibody of greater than 1:80 or liver histology consistent with primary biliary cirrhosis or elevation of alkaline phosphatase and liver histology consistent with sclerosing cholangitis.
   5. Wilson disease as defined by ceruloplasmin below the limits of normal and liver histology consistent with Wilson disease.
   6. Alpha-1-antitrypsin deficiency as defined by alpha-1-antitrypsin level less than normal and liver histology consistent with alpha-1-antitrypsin deficiency.
   7. Hemochromatosis as defined by presence of 3+ or 4+ stainable iron on liver biopsy and homozygosity for C282Y or compound heterozygosity for C282Y/H63D.
   8. Drug-induced liver disease as defined on the basis of typical exposure and history.
   9. Bile duct obstruction as shown by imaging studies.
2. History of excess alcohol ingestion, averaging more than 30 gm/day (3 drinks per day) in the previous 10 years, or history of alcohol intake averaging greater than 10 gm/day (1 drink per day: 7 drinks per week) in the previous one year.
3. Contraindications to liver biopsy: platelet counts < 75,000/mm3 or prothrombin time >16 seconds or history of bleeding disorders
4. Decompensated liver disease, Child-Pugh score greater than or equal to 7 points
5. History of gastrointestinal bypass surgery or ingestion of drugs known to produce hepatic steatosis including corticosteroids, high-dose estrogens, methotrexate, tetracycline or amiodarone in the previous 6 months.
6. Recent initiation or change of anti-diabetic drugs, including insulin, sulfonylureas, or thiazolidinediones in the previous 90 days.
7. Use of ezetimibe or other agents in the same class within the 90 days prior to randomization and/or liver biopsy.
8. Significant systemic or major illnesses other than liver disease, including congestive heart failure, coronary artery disease, cerebrovascular disease, pulmonary disease with hypoxia, renal failure, organ transplantation, serious psychiatric disease, malignancy that, in the opinion of the investigator would preclude treatment with ezetimibe and adequate follow up.
9. Positive test for anti-HIV.
10. Active substance abuse, such as alcohol, inhaled or injection drugs within the previous one year.
11. Pregnancy or inability to practice adequate contraception in women of childbearing potential.
12. Evidence of hepatocellular carcinoma: alpha-fetoprotein levels greater than 200 ng/ml and/or liver mass on imaging study that is suggestive of liver cancer.
13. Any other condition, which, in the opinion of the investigators would impede competence or compliance or possibility hinder completion of the study.
14. Serum creatinine >1.5 mg/dl.

15. Contraindications to ezetimibe use :

    1. History of allergic reaction to ezetimibe
    2. patients with acute liver injury or unexplained persistent elevations in ALT > 500 U/L
    3. Women who are pregnant or may become pregnant
    4. Nursing mothers

16. Contraindications to MRI:

    1. The subject has any contraindication to MR imaging, such as patients with pacemakers, metallic cardiac valves, magnetic material such as surgical clips, implanted electronic infusion pumps or other conditions that would preclude proximity to a strong magnetic field.
    2. The subject has a history of extreme claustrophobia
    3. The subject cannot fit inside the MR scanner cavity