Ignite Creation Date:
2024-05-05 @ 12:02 PM
Last Modification Date:
2024-10-26 @ 9:19 AM
Study NCT ID:
NCT00227110
Status:
COMPLETED
Last Update Posted:
2009-10-14
First Post:
2005-09-23
Brief Title:
Role of Pioglitazone in the Treatment of Non-alcoholic Steatohepatitis NASH
Sponsor:
The University of Texas Health Science Center at San Antonio
Organization:
The University of Texas Health Science Center at San Antonio
Study Overview
Official Title:
Role of Pioglitazone in the Treatment of Non-alcoholic Steatohepatitis NASH
Status:
COMPLETED
Status Verified Date:
2009-10
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
To determine the role of pioglitazone in the treatment of nonalcoholic steatohepatitis NASH in patients with glucose intolerance or type 2 diabetes mellitus T2DM
Detailed Description:
v 412003 Role of Pioglitazone in the Treatment of Nonalcoholic Steatohepatitis
1 PURPOSESPECIFIC 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
1 Liver histologic response assessed by liver biopsy Steatosis and inflammatory changes will be quantified using a standardized staging system
2 Liver fat content measured by liver magnetic resonance spectroscopy MRS
3 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
1 PURPOSESPECIFIC 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
1 Liver histologic response assessed by liver biopsy Steatosis and inflammatory changes will be quantified using a standardized staging system
2 Liver fat content measured by liver magnetic resonance spectroscopy MRS
3 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None