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

Condition(s) targeted: Nonalcoholic Steatohepatitis; Nonalcoholic Fatty Liver Disease; Type 2 Diabetes Mellitus

Intervention: Pioglitazone (Drug); Placebo (Drug); Pioglitazone (Drug); Placebo (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: The University of Texas Health Science Center at San Antonio

Official(s) and/or principal investigator(s):
Kenneth Cusi, M.D., Principal Investigator, Affiliation: The University of Texas H.S.C. at San Antonio and the San Antonio Audie L. Murphy VA Hospital

Overall contact:
Joan Finch, R.N., Phone: 210-617-5300, Ext: 14750, Email: Finchj@uthscsa.edu

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).

Official title: Long-term Role of Pioglitazone in Non-Alcoholic Fatty Liver Disease (NAFLD) in Type 2 Diabetes Mellitus (T2DM).

Study design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study

Primary outcome: Liver histology (using Kleiner et al criteria, Hepatology 2005)

Secondary outcome:

Liver fat by magnetic resonance and spectroscopy (MRS).

Liver transaminases.

Plasma biomarkers relevant to hepatic inflammation, apoptosis and fibrosis.

Assessment of hepatic, muscle and adipose tissue insulin sensitivity.

Evaluation of insulin secretion and glucose tolerance during an oral glucose tolerance test (OGTT).

Prevention of the onset of T2DM and/or reversal from IGT to NGT in non-diabetics.

Anthropometric measurements (body weight, W/H ratio, total body fat by DXA, visceral fat by MRI).

Fractures, bone density (DXA) and plasma measurements of bone metabolism.

Molecular pathways of liver glucose and lipid signaling; inflammatory pathways; oxidative stress; other.

Detailed description: 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.

Minimum age: 18 Years. Maximum age: 70 Years. Gender(s): Both.

Criteria:

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.

Joan Finch, R.N., Phone: 210-617-5300, Ext: 14750, Email: Finchj@uthscsa.edu

Bartter Research Unit, Audie L Murphy VA Hospital, San Antonio, Texas 78248, United States; Recruiting
Joan Finch, R.N., Phone: 210-617-5300, Ext: 14750

Starting date: December 2008
Ending date: July 2013
Last updated: October 13, 2009