University of Texas H.S.C. San Antonio Pioglitazone in Non-Alcoholic Steatohepatitis Trial (UTHSCSA NASH Trial)
Condition: Nonalcoholic Steatohepatitis; Nonalcoholic Fatty Liver Disease; Type 2 Diabetes Mellitus
MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease; Diabetes Mellitus; Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 4

Summary: 
      Obesity and Type 2 diabetes are creating a silent epidemic, Non-alcoholic fatty liver
      disease, which is a chronic liver disease associated with insulin resistance, impaired
      glucose intolerance, and hepatic fat accumulation. The thiazolidinedione pioglitazone
      improves glucose/lipid metabolism and histology in NASH by improving insulin resistance in
      the liver/peripheral/adipose tissues and reducing subclinical inflammation. 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).
    

Detailed description: 
      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 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.
    

Intervention name(s): Pioglitazone study drug; Placebo; Pioglitazone Open Label
Intervention type(s): Drug; Drug; Drug
Intervention description(s): 30 mg per day orally for 8 weeks, and if well tolerated, titrated to 45 mg per day until the end of 18 months; An oral tablet identical to pioglitazone will be given once daily but without active drug for 18 months.; Patients in both arms were placed open label pioglitazone for an additional 18 months after successfully completing the double-blind, placebo-controlled portion of the study design.
Other intervention name(s): Actos (brand name), manufactured by Takeda Pharmaceuticals.; Actos (brand name), manufactured by Takeda Pharmaceuticals.
Intervention MeSH terms: Pioglitazone
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Additional relevant MeSH terms:; Hypoglycemic Agents; Physiological Effects of Drugs; Pharmacologic Actions; Pioglitazone