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

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. 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, the investigators 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 will be liver
histologic response assessed by liver biopsy performed at 18 and at 36 months of treatment.

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, raloxifene, 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.