Treating Nonalcoholic Steatohepatitis With Pioglitazone
Condition: Hepatitis
MeSH terms: Hepatitis; Fatty Liver; Non-alcoholic Fatty Liver Disease
Intervention: Actos (Pioglitazone)
Intervention description: Pts receive drug in a dose of 15 mg daily for at least 1 year; the dose is escalated to 30 mg daily if serum ALT levels do not fall to normal by the 1 year pt; if pts have a biochemical response, drug is continued for 3 years,
Intervention MeSH terms: Pioglitazone
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 18.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Insulin Resistance; Obesity; Fatty Liver; Cirrhosis; Diabetes; Pioglitazone; Thiazolidinediones; Peroxisome Proliferator-Advanced Receptor Gamma; PPAR Gama; Nonalcoholic Steatohepatitis; Hepatitis; Non-Alcoholic Steatohepatitis; NASH

Summary:

      Nonalcoholic steatohepatitis (NASH) is a common liver disease that resembles alcoholic
      hepatitis but occurs in persons who drink little or no alcohol. The etiology of NASH is
      unclear, but it is commonly associated with diabetes, obesity, and insulin resistance.
      Several pilot studies, including a study of pioglitazone at the NIH Clinical Center
      (01-DK-0130), have shown that the insulin-sensitizing thiazolidinediones lead to decreases in
      serum alanine aminotransferase (ALT) levels and improved liver histology. Once therapy is
      stopped, however, ALT levels rapidly return to pre-treatment values. Inaddition we are
      currently enrolling patients with NASH in a pilot study of metformin therapy for 48-weeks,
      however our results in 3 patients thus far have not been very encouraging.

      In the current study, patients who have completed the pilot study of pioglitazone and have
      been off therapy for 48 weeks will be offered re-treatment for 3 years. We also propose to
      treat patients who have not had a satisfactory response to metformin with pioglitazone for
      the same duration. After a repeat medical and metabolic evaluation and liver biopsy, patients
      with moderate-to-severe NASH (activity score greater than or equal to 4) will restart
      pioglitazone at a dose of 15 mg daily. If after 48 weeks, ALT levels are not normal or
      improved to the degree identified during the pilot study, the dose will be increased to 30 mg
      daily at the end of 3 years, all patients will undergo repeat medical and metabolic
      evaluation and liver biopsy. The primary end point will be improvement in liver histology.
      Secondary end points will be improvements in insulin sensitivity, reduction in visceral fat,
      liver volume, and liver biochemistry. The aim of this study is to evaluate whether long-term
      pioglitazone therapy can safely achieve and maintain biochemical and histological
      improvements in NASH.

      ...
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

        Completion of a 48-week course of pioglitazone in protocol 01-DK-0130 or completion of
        48-weeks of metformin in protocol 03-DK-0233.

        At least 48 weeks of follow up on no thiazolidinedione therapy after completion of protocol
        01-DK-0130.

        At least 24-weeks follow up on no metformin theray after completion of protocol 03-DK-0233.

        Written informed consent.

        Patients who participated in protocol 01-DK-0130 will also have to meet the following
        inclusion criteria:

        Demonstrated improvements in liver histology and/or serum ALT levels during the 48-week
        course of pioglitazone therapy in protocol 01-DK-0130.

        Elevations in serum ALT levels.

        Liver biopsy showing NASH with a total NASH activity score of at least 4 (of a total
        possible score of 16) including a score of at least 1 each for parenchyma inflammation,
        cellular injury and steatosis on liver biopsy taken 48 weeks after stopping pioglitazone.

        Willingness to receive pioglitazone for 3 years.

        Patients who participated in protocol 03-DK-0233 will also have to me the following
        inclusion criteria:

        Demonstrated no significant improvement in liver histology and/or serum ALT levels during
        the 48-week course of metformin treatment in protocol 03-DK-0233.

        Elevations in serum ALT levels.

        Liver biopsy showing NASH with a total activity score of at least 4 (of a total possible
        score of 16) including a score of at least 1 each for parenchymal inflammation, cellular
        injury and steatosis on liver biopsy taken at the end of the 48-week course of metofrmin.

        EXCLUSION CRITERIA:

        Evidence of another form of liver disease (these largely will have been excluded based upon
        enrollment in the previous study, 01-DK-0130 and 03-DK-0233).

        Hepatitis B as defined as presence of hepatitis B surface antigen (HBsAg).

        Hepatitis C as defined by presence of hepatitis C virus (HCV) RNA in serum.

        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.

        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.

        e. Wilson disease as defined by ceruloplasmin below the limits of normal and liver
        histology consistent with Wilson disease.

        Alpha-1-antitrypsin deficiency as defined by alpha-1-antitrypsin level less than normal and
        liver histology consistent with alpha-1-antitrypsin deficiency.

        Hemochromatosis as defined by presence of 3+ or 4 iron on liver biopsy stain and
        homozygosity for C282Y or compound heterozygosity for C282Y/H63D.

        Drug-induced liver disease as defined on the basis of typical exposure and history.

        Bile duct obstruction as shown by imaging studies.

        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.

        Contraindications to liver biopsy: platelet counts less than 75,000/mm(3) or prothrombin
        time greater than 16 seconds.

        Decompensated liver disease, Child-Pugh score greater than or equal to 7 points.

        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.

        Preexistent diabetes mellitus or the development of diabetes mellitus during the study
        requiring the use of another drug in addition to pioglitazone for glycaemic control.
        Diabetes being as defined by: fasting plasma glucose of greater than or equal to 126 mg/dl
        on two separate occasions, or diabetic symptoms with a random plasma glucose of greater
        than or equal to 200 mg/dl.

        Use of anti-diabetic drugs, including insulin, biguanides, sulfonylureas, or
        thiazolidinediones at the time of enrollment or in the previous 48 weeks.

        Significant systemic or major illnesses other than liver disease, including congestive
        heart failure, coronary artery disease, cerebrovascular disease, pulmonary disease, renal
        failure, organ transplantation, serious psychiatric disease, malignancy that, in the
        opinion of the investigator would preclude treatment with pioglitazone and adequate follow
        up.

        Positive test for anti-HIV.

        Active substance abuse, such as alcohol, inhaled or injection drugs within the previous one
        year.

        Pregnancy or inability to practice adequate contraception in women of childbearing
        potential.

        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.

        Any other conditions, which, in the opinion of the investigators would impede competence or
        compliance or possibility, hinder completion of the study.