University of Texas H.S.C. San Antonio Pioglitazone in Non-Alcoholic Steatohepatitis Trial (UTHSCSA NASH Trial)

• Liver fat by magnetic resonance and spectroscopy (MRS). [ Time Frame: At 18 (2nd MRS) and 36 (3rd MRS) months. ] [ Designated as safety issue: No ]
• Liver transaminases. [ Time Frame: For up to 36 months (at 1-2 month intervals during the study). ] [ Designated as safety issue: Yes ]
• Plasma biomarkers relevant to hepatic inflammation, apoptosis and fibrosis. [ Time Frame: Up to 36 months ] [ Designated as safety issue: No ]
• Assessment of hepatic, muscle and adipose tissue insulin sensitivity. [ Time Frame: At 18 (2nd insulin clamp) and 36 (3rd insulin clamp) months. ] [ Designated as safety issue: No ]
• Evaluation of insulin secretion and glucose tolerance during an oral glucose tolerance test (OGTT). [ Time Frame: At 18 (2nd OGTT) and 36 (3rd OGTT) months. ] [ Designated as safety issue: No ]
• Prevention of the onset of T2DM and/or reversal from IGT to NGT in non-diabetics. [ Time Frame: At 18 (2nd OGTT) and 36 (3rd OGTT) months. ] [ Designated as safety issue: No ]
• Anthropometric measurements (body weight, W/H ratio, total body fat by DXA, visceral fat by MRI). [ Time Frame: At 18 (2nd DXA, MRI) and 36 months (3rd DXA, MRI). ] [ Designated as safety issue: No ]
• Fractures, bone density (DXA) and plasma measurements of bone metabolism. [ Time Frame: At 18 (2nd DXA, bone metabolism measurements) and 36 (3rd DXA, bone metabolism measurements) months ] [ Designated as safety issue: Yes ]
• Molecular pathways of liver glucose and lipid signaling; inflammatory pathways; oxidative stress; other. [ Time Frame: At 18 (2nd liver biopsy) and 36 (3rd liver biopsy) months. ] [ Designated as safety issue: No ]

Obesity and Type 2 diabetes are creating a silent epidemic, Non-alcoholic fatty liver disease, which is a chronic liver disease associated with insulin resistence, impaired glucose intolerance, and hepatic fat accumulation. The thiazolidinedione pioglitazone improves glucose/lipid metabolism and histology in NASH by improving insulin resistence in the liver/peripheral/adipose tissues and reducing subclinical inflammation (Belfort et al, NEJM 355:2297-2307, 2006). The aim of this study is to assess the underlying mechanisms at the clinical and molecular level and the long-term efficacy and safety of pioglitazone in NASH in a multiethnic cohort of subjects (predominantly Hispanics, Caucasians and African-Americans - the most common ethnic groups locally) and examine the response including patients with normal glucose tolerance, impaired glucose tolerance or established type 2 diabetes mellitus (T2DM).

1. PURPOSE/SPECIFIC AIMS: NASH is a disease characterized by elevated plasma aminotransferases and histopathological changes in liver characterized by hepatocellular steatosis, chronic inflammation and perisinusoidal fibrosis. NASH affects (~30-40%) of obese and type 2 diabetic subjects. While the pathogenesis of NASH is poorly understood, there is consensus that insulin resistance and its associated abnormalities in lipid metabolism play a key role in the development of liver fat accumulation. Insulin resistance in nonalcoholic steatohepatitis is frequently associated with chronic hyperinsulinemia, hyperglycemia, and an excessive supply of plasma free fatty acids to the liver. This in turn promotes hepatic lipogenesis. Pioglitazone, a thiazolidinedione (TZD), reverses these abnormalities by ameliorating insulin resistance in adipose tissue, liver and muscle. TZDs decrease excessive ectopic triglyceride accumulation in liver and muscle, reduce visceral fat, and redistribute fat to subcutaneous adipose stores. We have shown in a proof-of-concept 6-month study that pioglitazone is safe and effective for the treatment of T2DM (Belfort et al, NEJM 355:2297-2307, 2006). Patients with nonalcoholic steatohepatitis are also characterized by a low plasma adiponectin level. Thiazolidinediones increase plasma adiponectin levels, may activate AMP-activated protein kinase, stimulate hepatic/muscle fatty acid oxidation, and inhibit hepatic fatty acid synthesis in NASH nonalcoholic steatohepatitis. Thiazolidinediones also have antiinflammatory effects which are believed to be of value for therapy for NASH.

In order to evaluate this hypothesis, we will treat for up to 36 months a group of patients with normal (NGT) or impaired (IGT) glucose tolerance and T2DM patients recruited from the University Hospital and medical school clinics and by newspaper add targeting the San Antonio and South Texas geographical area, with pioglitazone in a randomized, double-blinded, placebo-controlled trial. The primary endpoint (see Methods for a detailed description) will be liver histologic response assessed by liver biopsy using criteria established by Kleiner et al (Hepatology 41, 1313-1321, 2005) with a liver biopsy perfromed before, at 18 and at 36 months of treatment.

• Nonalcoholic Steatohepatitis
• Nonalcoholic Fatty Liver Disease
• Type 2 Diabetes Mellitus

• Drug: Pioglitazone
  30 mg per day orally for 8 weeks, and if well tolerated, titrated to 45 mg per day until the end of the study.
  Other Name: Actos (brand name), manufactured by Takeda Pharmaceuticals.
• Drug: Placebo
  An oral tablet identical to pioglitazone will be given once daily.
• Drug: Placebo
  All subjects will take one placebo tablet per day that looks identical to pioglitazone but without active drug.

• Active Comparator: Pioglitazone (patients with T2DM)
  After all patients receive dietary counseling at the research unit (CTSA), patients with type 2 diabetes mellitus (T2DM) and NASH will be started on pioglitazone (or placebo) in a randomized, double-blind,placebo-controlled study design. Pioglitazone will be given at 30 mg/day for the first 2 months and titrated to 45 mg/day thereafter (if well tolerated).
  Intervention: Drug: Pioglitazone
• Placebo Comparator: Placebo (patients with T2DM)
  After all participants receive dietary counseling at the research unit (CTSA), patients WITHOUT type 2 diabetes mellitus (T2DM) and NASH will be started on placebo (or pioglitazone) in a randomized, double-blind,placebo-controlled study design by the research pharmacy.
  Intervention: Drug: Placebo
• Active Comparator: Pioglitazone (patients WITHOUT T2DM)
  After dietary counseling to all patients at the research unit (CTSA), NON-DIABETIC patients (NGT and IGT per pretreatment OGTT) with NASH will be started on pioglitazone (or placebo) in a randomized, double-blind,placebo-controlled study design. Pioglitazone will be given at 30 mg/day for the first 2 months and titrated to 45 mg/day thereafter (if well tolerated).
  Intervention: Drug: Pioglitazone
• Placebo Comparator: Placebo (patients WITHOUT T2DM).
  After dietary counseling to all patients at the research unit (CTSA), NON-DIABETIC patients (NGT and IGT per pretreatment OGTT) with NASH will be started on placebo (or pioglitazone) in a randomized, double-blind,placebo-controlled study design.
  Intervention: Drug: Placebo

Inclusion Criteria:

1. Be able to communicate meaningfully with the investigators and be legally competent to provide written informed consent.
2. Age range between 18 to 70 years (inclusive).
3. Female patients must be non-lactating and must either be at least one year post-menopausal, or be using adequate mechanical contraceptive precautions (i.e. intrauterine device, diaphragm with spermicide, condom with spermicide), or be surgically sterilized (i.e. bilateral tubal ligation, bilateral oophorectomy). Female patients who have undergone a hysterectomy are eligible for participation in the study. Female patients (except for those patients who have undergone a hysterectomy or a bilateral oophorectomy) are eligible only if they have a negative pregnancy test throughout the study period. Patients on oral contraceptives or an hormonal implant will be excluded (patches are acceptable as they deliver much lower estrogen systemically).

4. Participants must have the following laboratory values:

   • Hemoglobin ≥ 12 gm/dl in males, or ≥ 11 gm/dl in females,
   • WBC count ≥ 3,000/mm3
   • Neutrophil count ≥ 1,500/mm3
   • Platelets ≥ 100,000/mm3
   • Albumin ≥3.0 g/dl
   • Serum creatinine ≤ 1.8 mg/dl
   • Creatinine phosphokinase ≤ 2 times upper limit of normal
   • AST and ALT ≤ 3.0 times upper limit of normal
   • Alkaline phosphatase ≤ 2.5 times upper limit of normal
5. A diagnosis of NASH by liver biopsy performed within the past 6 months,

Exclusion Criteria:

1. Any cause of chronic liver disease other than NASH (such as -but not restricted to- alcohol or drug abuse, medication, chronic hepatitis B or C, autoimmune, hemochromatosis, Wilson's disease, alpha1-antitrypsin deficiency).
2. Any clinical evidence or history of ascitis, bleeding varices, or spontaneous encephalopathy.
3. Current history of alcohol abuse (alcohol consumption greater than 20 grams of ethanol per day).
4. Prior surgical procedures to include gastroplasty, jejuno-ileal or jejunocolic bypass.
5. Prior exposure to organic solvents such as carbon tetrachloride.
6. Total parenteral nutrition (TPN) within the past 6 months.
7. Subjects with type 1 diabetes mellitus.
8. Patients on chronic medications with known adverse effects on glucose tolerance levels unless the patient has been on a stable dose of such agents for 4 weeks before entry into the study. Patients on estrogens or other hormonal replacement therapy, tamoxifen, raloxifen, oral glucocorticoids or chloroquine will be excluded.
9. Patients with a history of clinically significant heart disease (New York Heart Classification greater than grade II), peripheral vascular disease (history of claudication), or diagnosed pulmonary disease (dyspnea on exertion of one flight or less; abnormal breath sounds on auscultation).
10. Patients with severe osteoporosis.