Clinical trial NCT00994682: University of Texas H.S.C. San Antonio Pioglitazone in Non-Alcoholic Steatohepatitis Trial (UTHSCSA NASH Trial)
Official title: Long-term Role of Pioglitazone in Non-Alcoholic Fatty Liver Disease (NAFLD) in Type 2 Diabetes Mellitus (T2DM).
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Nonalcoholic Steatohepatitis
Nonalcoholic Fatty Liver Disease
Type 2 Diabetes Mellitus
Keywords: Additional relevant MeSH terms:
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions
Pioglitazone
Lead sponsor: University of Florida
Sponsor class: OTHER
Collaborators: name: The University of Texas at San Antonio
First posted: 2009-10-14
Enrollment: 176
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Eligibility 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, 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.

Primary outcomes:
measure: Liver Histology (Using Kleiner et al Criteria, Hepatology 2005)
timeFrame: At 18 months
Secondary outcomes:
measure: Number of Participants With Resolution of NASH
timeFrame: Month 18
measure: Mean Individual Histological Scores
timeFrame: Baseline and Month 18
measure: Individual Histological Scores
timeFrame: Month 18
measure: Mean Individual Histological Scores
timeFrame: Month 36
measure: Liver Transaminases (AST and ALT).
timeFrame: 18 and 36 months
measure: Liver Fat by Magnetic Resonance and Spectroscopy (MRS).
timeFrame: 18 months
measure: Homeostatic Model Assessment of Insulin Resistance (HOMA-IR)
timeFrame: 18 and 36 months
measure: Hepatic Insulin Sensitivity
timeFrame: 18 months
measure: Adipose Tissue Insulin Sensitivity
timeFrame: 18 months
measure: Skeletal Muscle Insulin Sensitivity
timeFrame: 18 months
measure: Body Mass Index (BMI)
timeFrame: Months 18 and 36
measure: Total Body Fat
timeFrame: Months 18
measure: Plasma Biomarkers Relevant to Hepatic Inflammation, Apoptosis and Fibrosis (Adiponectin).
timeFrame: 18 and 36 months
measure: Plasma Biomarkers Relevant to Hepatic Inflammation, Apoptosis and Fibrosis (CK-18).
timeFrame: 18 and 36 months
measure: Prevention of the Onset of T2DM and/or Reversal From IFG/IGT to NGT in Non-diabetics.
timeFrame: 18 months
measure: Osteoporotic Fractures
timeFrame: 18 and 36 months
measure: Molecular Pathways of Liver Glucose and Lipid Signaling; Inflammatory Pathways; Oxidative Stress; Other.
timeFrame: At 18 (2nd liver biopsy) and 36 (3rd liver biopsy) months.
measure: Bone Mineral Density
timeFrame: 18 and 36 months
Other outcomes:
Locations:
city: San Antonio
country: United States
facility: Bartter Research Unit, Audie L Murphy VA Hospital
state: Texas
Study officials:
affiliation: University of Florida
name: Kenneth Cusi, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ipsen EO, Madsen KS, Chi Y, Pedersen-Bjergaard U, Richter B, Metzendorf MI, Hemmingsen B. Pioglitazone for prevention or delay of type 2 diabetes mellitus and its associated complications in people at risk for the development of type 2 diabetes mellitus. Cochrane Database Syst Rev. 2020 Nov 19;11(11):CD013516. doi: 10.1002/14651858.CD013516.pub2.
citation: Bril F, Kalavalapalli S, Clark VC, Lomonaco R, Soldevila-Pico C, Liu IC, Orsak B, Tio F, Cusi K. Response to Pioglitazone in Patients With Nonalcoholic Steatohepatitis With vs Without Type 2 Diabetes. Clin Gastroenterol Hepatol. 2018 Apr;16(4):558-566.e2. doi: 10.1016/j.cgh.2017.12.001. Epub 2017 Dec 7.
citation: Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C, Tio F, Hardies J, Darland C, Musi N, Webb A, Portillo-Sanchez P. Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial. Ann Intern Med. 2016 Sep 6;165(5):305-15. doi: 10.7326/M15-1774. Epub 2016 Jun 21.