Pioglitazone Therapy in Obese Children With Insulin Resistance: A Randomized, Controlled Pilot Study

Obesity Clinical Trial

Official title:

Pioglitazone Therapy in Obese Children With Insulin Resistance: A Randomized, Controlled Pilot Study

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT00775164
• Other study ID #: 0811M53986
• Status: Withdrawn
• Phase: Phase 4
• First received: October 16, 2008
• Last updated: August 30, 2012
• Start date: January 2009
• Est. completion date: February 2011

Study information

• Verified date: August 2012
• Source: University of Minnesota - Clinical and Translational Science Institute
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

The primary objective of this study is to examine the effects of four months of pioglitazone vs. metformin treatment on HDL cholesterol, triglycerides, blood pressure, insulin resistance, endothelial function, arterial stiffness, adipokines, oxidative stress, and blood biomarkers of endothelial activation in obese insulin resistant children. 30 obese children with elevated fasting insulin levels will be randomly assigned to pioglitazone or metformin for 16 weeks. Change in clinical variables over the 16-week study period will be compared between groups.

Description:

Background and Specific Aim/Hypothesis Obese, insulin resistant children are at increased risk of future cardiovascular disease due to elevated systolic blood pressure, fasting insulin, triglycerides, inflammation, oxidative stress, and reduced HDL cholesterol. Behavioral/lifestyle therapy should be the foundational approach to treating obesity and insulin resistance in all individuals, especially children. However, some children may need concomitant medical therapy in order to adequately address their severe risk factor profile and early vascular abnormalities. Although not approved by the FDA, metformin has been used with mixed success to treat obesity-associated cardiometabolic risk factors in children with evidence of insulin resistance. Clearly, other drug therapies should be explored to treat cardiovascular risk factors in obese, insulin resistant children.

Thiazolidinediones have been used to improve glucose control in adult patients with type 2 diabetes mellitus for approximately 10 years. These peroxisome proliferator activated receptor agonists are unique among anti-diabetic agents in that they regulate gene transcription to improve insulin sensitivity in peripheral tissues (predominately skeletal muscle and adipose tissue). In addition to improving glycemic control, these drugs also improve multiple cardiometabolic risk factors such as lipoprotein profile, blood pressure, inflammatory markers, adipokines, and endothelial function. Despite the substantial body of data showing benefit in adults, pioglitazone has never been evaluated as a therapy to improve the cardiometabolic risk factor profile in obese children with evidence of insulin resistance.

Specific Aim: To examine the effects of four months of pioglitazone vs. metformin treatment on HDL cholesterol, triglycerides, blood pressure, insulin resistance, endothelial function, arterial stiffness, adipokines, oxidative stress, and blood biomarkers of endothelial activation in obese, insulin resistant children.

Hypothesis: In the context of background behavioral therapy, four months of pioglitazone vs. metformin treatment will significantly improve HDL cholesterol, triglycerides, blood pressure, insulin resistance, endothelial function, arterial stiffness, adipokines, oxidative stress, and blood biomarkers of endothelial activation in obese insulin resistant children.

Significance There is a substantial lack of data in the literature concerning potential drug therapies for reducing risk factors in children at high risk of developing future cardiovascular disease. Since the prevalence of obesity and insulin resistance in children has increased dramatically in the last several decades, there is an urgent need for data from randomized, controlled trials to guide treatment approaches for high risk children. This pilot study will result in the acquisition of valuable preliminary data which will be used to seek funding for and conduct a larger scale clinical trial evaluating the efficacy of pioglitazone for treating cardiometabolic risk factors in obese, insulin resistant children.

Methods Patient Population: 30 obese, hyperinsulinemic children and adolescents entering a Pediatric Weight Management Program at the University of Minnesota will be enrolled. In this program, children and their families work with a team of trained professionals including physicians, dieticians, and psychologists to reduce weight by making healthier eating choices and increasing physical activity.

Study Design: This will be a randomized, double-blind, active-comparator clinical trial. Variables will be assessed at baseline (prior to randomization) and after four months of therapy.

Data Collection: The screening visit will take place in the Pediatric Weight Management Clinic and will include a complete medical history and physical examination. All research testing will take place in the University of Minnesota General Clinical Research Center (GCRC).

Statistical Analysis and Power Considerations: Randomization will be stratified by gender and Tanner stage. Changes between groups over time will be compared with a 2X2 (group by time) repeated measures ANOVA with Bonferroni post-hoc tests. The main analysis of interest will be the ANOVA interaction term, which compares the change in variables over time (pre vs. post) between groups. The purpose of this study will be to obtain preliminary data to design and seek funding for a larger clinical trial.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: February 2011
• Est. primary completion date: December 2010
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 10 Years to 17 Years

Eligibility

Inclusion Criteria:

• Age 10-17 years old

• Subject able to give assent, and parent/guardian capable of giving consent on behalf of the child

• Body mass index (BMI) = 95th percentile (based on gender and age)

• Fasting insulin = 15 µU/mL AND one or more of the following (cutoffs based on the International Diabetes Federation definition of pediatric metabolic syndrome)1:

• Triglycerides = 150 mg/dL

• HDL cholesterol < 40 mg/dL

• Systolic blood pressure = 130 mmHg

Exclusion Criteria:

• Type 1 or 2 diabetes mellitus

• Has begun a new drug therapy within the past 30 days prior to the screening visit

• BMI = 55

• History of weight loss surgery

• Obesity from a genetic cause (e.g., Prader-Willi)

• Central nervous system injury or severe neurological impairment

• Known systolic or diastolic dysfunction or heart failure

• Females who are currently pregnant or planning to become pregnant

• Liver enzymes > 2.5 times upper limit of normal

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Insulin Resistance
• Obesity

Intervention

Drug:
• pioglitazone
15 mg per day for 4 weeks, then up-titrated to 30 mg per day for 12 weeks
• Metformin
Metformin XR; 1000 mg once daily

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
University of Minnesota - Clinical and Translational Science Institute

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	HDL cholesterol, triglycerides, blood pressure, insulin resistance, endothelial function, arterial stiffness, adipokines, oxidative stress, and blood biomarkers of endothelial activation		16 weeks	No