Role of Pioglitazone in the Treatment of Non-alcoholic Steatohepatitis (NASH)
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Role of Pioglitazone in the Treatment of Non-alcoholic Steatohepatitis (NASH)|
- Liver histology (Kleiner criteria, Hepatology 2005) [ Time Frame: 6 months. ] [ Designated as safety issue: No ]
- Liver fat content by MRS. [ Time Frame: 6 months. ] [ Designated as safety issue: No ]
- Double-tracer OGTT (EGP, glucose clearance). [ Time Frame: 6 months. ] [ Designated as safety issue: No ]
|Study Start Date:||October 2002|
|Study Completion Date:||January 2006|
|Primary Completion Date:||November 2005 (Final data collection date for primary outcome measure)|
Active Comparator: Pioglitazone
Pioglitazone 30 mg/d will be given for 8 weeks and titrated to 45 mg/d until the end of the 6-month study in a randomized, double-blind, study design.
30 mg/d for 8 weeks and titrated to 45 mg/d until completing 6 months of treatment.
Other Name: Actos (Takeda Pharmaceuticals).
Placebo Comparator: Placebo
Placebo once daily is given following a randomized, double-blind, placebo-controlled study design.
Placebo is given to match pioglitazone.
v. 4/1/2003 Role of Pioglitazone in the Treatment of Nonalcoholic Steatohepatitis
1. PURPOSE/SPECIFIC AIMS To determine the role of pioglitazone in the treatment of nonalcoholic steatohepatitis (NASH) in patients with glucose intolerance or type 2 diabetes mellitus (T2DM). NASH is a disease characterized by elevated plasma aminotransferases and histopathological changes in liver characterized by hepatocellular steatosis, chronic inflammation and fibrosis (1-3). Pioglitazone, a new thiazolidinedione (TZD), has proven to be safe and effective for the treatment of type 2 diabetes mellitus (T2DM) (4). NASH affects ~10-20% of obese and type 2 diabetic subjects (1-3, 5, 6). 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, and TNF-alpha is a major mediator in the progression of liver damage (7-9). Currently, there is no satisfactory therapy for NASH.
Pioglitazone improves insulin sensitivity and glycemic control in patients with T2DM (4, 10-12), but the mechanism of action of TZDs is unclear (13, 14). Pioglitazone activates genes involved in lipid synthesis, causing a reduction in plasma free fatty acid (FFA) and triglycerides (15). TZDs decrease excessive triglyceride accumulation in liver (16), muscle (17), and visceral fat (11, 16, 18), with a redistribution of fat to subcutaneous adipose stores (14). TZDs also antagonize the metabolic effects of TNF-alpha (19-22). Because pioglitazone ameliorates insulin resistance, reverses the metabolic abnormalities that contribute to hepatic fat infiltration (increased plasma glucose, FFA, and triglyceride concentrations), and antagonizes the effects of TNF-alpha, it follows that pioglitazone may prove useful for the treatment of patients with NASH.
In order to evaluate this hypothesis, we plan to treat for 6 months a group of patients with impaired glucose tolerance (IGT) or T2DM with pioglitazone in a randomized, double-blinded, placebo-controlled trial. Three major endpoints will be measured before and after treatment (see Methods for a detailed description):
- Liver histologic response; assessed by liver biopsy. Steatosis and inflammatory changes will be quantified using a standardized staging system.
- Liver fat content: measured by liver magnetic resonance spectroscopy (MRS).
- Hepatic insulin sensitivity and glucose metabolism: Because fat infiltration of liver and muscle causes insulin resistance and impairs glucose tolerance, we will measure parameters of metabolic control including fasting plasma glucose, free fatty acids, fructosamine, HbA1c and fasting lipid profile. To assess the effect of pioglitazone on hepatic insulin sensitivity, fasting (basal) and postprandial hepatic glucose production will be studied using a double-tracer technique (infusion of 3-3H glucose combined with an oral glucose load radiolabeled with 1-14C glucose) (23). Glucose and lipid oxidation will be measured by indirect calorimetry (24). In addition, an index of hepatic and peripheral insulin sensitivity will be derived from the oral glucose tolerance test (OGTT) (25).
Please refer to this study by its ClinicalTrials.gov identifier: NCT00227110
|United States, Texas|
|Audie L Murphy VA Hospital|
|San Antonio, Texas, United States, 78229|
|Principal Investigator:||Kenneth Cusi, MD||University of Texas|