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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Nonalcoholic Steatohepatitis, Nonalcoholic Fatty Liver Disease, Type 2 Diabetes Mellitus

Intervention / Treatment
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* Drug: Pioglitazone study drug
* Drug: Placebo
* Drug: Pioglitazone Open Label


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Be able to communicate meaningfully with the investigators and be legally competent to provide written informed consent. Age range between 18 to 70 years (inclusive). 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). 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 A diagnosis of NASH by liver biopsy performed within the past 6 months, Exclusion Criteria: 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). Any clinical evidence or history of ascitis, bleeding varices, or spontaneous encephalopathy. Current history of alcohol abuse (alcohol consumption greater than 20 grams of ethanol per day). Prior surgical procedures to include gastroplasty, jejuno-ileal or jejunocolic bypass. Prior exposure to organic solvents such as carbon tetrachloride. Total parenteral nutrition (TPN) within the past 6 months. Subjects with type 1 diabetes mellitus. 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. 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). Patients with severe osteoporosis.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pioglitazone<br>After all patients receive dietary counseling at the research unit (CTSA), patients with prediabetes or 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). | Drug: Pioglitazone study drug<br>* 30 mg per day orally for 8 weeks, and if well tolerated, titrated to 45 mg per day until the end of 18 months<br>* Other names: Actos (brand name), manufactured by Takeda Pharmaceuticals.;Drug: Pioglitazone Open Label<br>* 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.<br>* Other names: Actos (brand name), manufactured by Takeda Pharmaceuticals.;|
| Placebo Comparator: Placebo<br>After dietary counseling to all patients at the research unit (CTSA), patients with prediabetes or 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). | Drug: Placebo<br>* An oral tablet identical to pioglitazone will be given once daily but without active drug for 18 months.<br>Drug: Pioglitazone Open Label<br>* 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.<br>* Other names: Actos (brand name), manufactured by Takeda Pharmaceuticals.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Liver Histology (Using Kleiner et al Criteria, Hepatology 2005) | Number of patients with reduction of at least 2 points in the nonalcoholic fatty liver disease activity score (NAS) (with reduction in at least 2 different histological categories) without worsening of fibrosis. NAS is the sum of the separate scores for steatosis (0-3), hepatocellular ballooning (0-2) and lobular inflammation (0-3), and ranges from 0-8 . The scoring system is based on the following grading: Steatosis: 0 = <5%; 1 = 5-33%; 2 = >33-66%; 3 = >66%. Lobular Inflammation: 0 = No foci 1 = <2 foci/200x; 2 = 2-4 foci/200x, 3 = >4 foci/200x. Hepatocyte Ballooning: 0 = None; 1 = Few balloon cells; 2 = Many cells/prominent ballooning. Fibrosis: 0 = None; 1 = Perisinusoidal or periportal; 2 = Perisinusoidal and portal/periportal; 3 = Bridging fibrosis, 4 = Cirrhosis. | At 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Resolution of NASH | Resolution of NASH was defined as absence of NASH after 18 months of therapy in patients with definite NASH (presence of zone 3 accentuation of macrovesicular steatosis of any grade, hepatocellular ballooning of any degree, and lobular inflammatory infiltrates of any amount) at baseline. | Month 18 | 
| Mean Individual Histological Scores | Mean change in individual scores compared to baseline. Steatosis: 0 = <5%; 1 = 5-33%; 2 = >33-66%; 3 = >66%. Lobular Inflammation: 0 = No foci 1 = <2 foci/200x; 2 = 2-4 foci/200x, 3 = >4 foci/200x. Hepatocyte Ballooning: 0 = None; 1 = Few balloon cells; 2 = Many cells/prominent ballooning. Fibrosis: 0 = None; 1 = Perisinusoidal or periportal; 2 = Perisinusoidal and portal/periportal; 3 = Bridging fibrosis, 4 = Cirrhosis | Baseline and Month 18 | 
| Individual Histological Scores | Number of patients with improvement of at least 1 grade in each of the histological parameters. Steatosis: 0 = <5%; 1 = 5-33%; 2 = >33-66%; 3 = >66%. Lobular Inflammation: 0 = No foci 1 = <2 foci/200x; 2 = 2-4 foci/200x, 3 = >4 foci/200x. Hepatocyte Ballooning: 0 = None; 1 = Few balloon cells; 2 = Many cells/prominent ballooning. Fibrosis: 0 = None; 1 = Perisinusoidal or periportal, 1A = Mild, zone 3, perisinusoidal delicate fibrosis; 1B = Moderate, zone 3, perisinusoidal dense fibrosis; 1C = Portal/periportal; 2 = Perisinusoidal and portal/periportal; 3 = Bridging fibrosis, 4 = Cirrhosis | Month 18 | 
| Mean Individual Histological Scores | Steatosis: 0 = <5%; 1 = 5-33%; 2 = >33-66%; 3 = >66%. Lobular Inflammation: 0 = No foci 1 = <2 foci/200x; 2 = 2-4 foci/200x, 3 = >4 foci/200x. Hepatocyte Ballooning: 0 = None; 1 = Few balloon cells; 2 = Many cells/prominent ballooning. Fibrosis: 0 = None; 1 = Perisinusoidal or periportal; 2 = Perisinusoidal and portal/periportal; 3 = Bridging fibrosis, 4 = Cirrhosis | Month 36 | 
| Liver Transaminases (AST and ALT). |  | 18 and 36 months | 
| Liver Fat by Magnetic Resonance and Spectroscopy (MRS). | Liver fat content was calculated as the fat fraction: 100*(area under the curve [AUC] of fat peak / [AUC of fat peak + AUC of water peak]). | 18 months | 
| Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) | Homeostatic model assessment of insulin resistance (HOMA-IR) is a method for assessing insulin resistance (IR) from basal fasting plasma glucose (FPG) and fasting plasma insulin (FPI). It is calculated as (FPG x FPI)/405. | 18 and 36 months | 
| Hepatic Insulin Sensitivity | Suppression of endogenous glucose production (Supp EGP) by low dose insulin (i.e., percentage of reduction of EGP with low dose insulin infusion compared to the baseline state). This was calculated as: 100*((EGP without insulin - EGP with insulin infusion)/EGP without insulin). All measurements are obtained at the same time point during an euglycemic insulin clamp. | 18 months | 
| Adipose Tissue Insulin Sensitivity | Suppression of free fatty acids by low dose insulin (i.e., percentage of reduction of plasma FFA with low dose insulin infusion compared to the baseline state). This was calculated as: 100*((plasma FFA without insulin - plasma FFA with insulin infusion)/plasma FFA without insulin). All measurements are obtained at the same time point during an euglycemic insulin clamp. | 18 months | 
| Skeletal Muscle Insulin Sensitivity | Rate of glucose disappearance (Rd) during high-dose insulin infusion. The rate of plasma glucose disappearance was calculated using Steele's non-steady-state equation. | 18 months | 
| Body Mass Index (BMI) |  | Months 18 and 36 | 
| Total Body Fat | Total body fat measured by dual-energy x-ray absorptiometry (DXA) | Months 18 | 
| Plasma Biomarkers Relevant to Hepatic Inflammation, Apoptosis and Fibrosis (Adiponectin). |  | 18 and 36 months | 
| Plasma Biomarkers Relevant to Hepatic Inflammation, Apoptosis and Fibrosis (CK-18). |  | 18 and 36 months | 
| Prevention of the Onset of T2DM and/or Reversal From IFG/IGT to NGT in Non-diabetics. | Number of patients developing T2DM and number of patients regressing to NGT among patients with prediabetes (IFG/IGT). | 18 months | 
| Osteoporotic Fractures | Number of patients with osteoporotic fractures | 18 and 36 months | 
| Molecular Pathways of Liver Glucose and Lipid Signaling; Inflammatory Pathways; Oxidative Stress; Other. |  | At 18 (2nd liver biopsy) and 36 (3rd liver biopsy) months. | 
| Bone Mineral Density | Bone mineral density measured at the levels of spine, femoral neck, hip, and wrist by DXA. | 18 and 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Additional relevant MeSH terms:, Hypoglycemic Agents, Physiological Effects of Drugs, Pharmacologic Actions, Pioglitazone