Metformin to Treat Obesity in Children With Insulin Resistance

Study Overview
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Brief Summary
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This study will examine the safety and effectiveness of the medicine metformin to help overweight children control their food intake, weight, insulin, cholesterol, and triglyceride (blood fat) levels. Obesity and high insulin levels can lead to high blood pressure, diabetes, high cholesterol and triglyceride levels and heart disease. Metformin-approved by the Food and Drug Administration to treat adults with type 2 diabetes mellitus-helps lower insulin levels and may control weight gain in adults. Overweight children 6 to 11 years old who are in general good health may be eligible for this study. Children will be studied at the National Institutes of Health in Bethesda, Maryland. Candidates will have a medical history and physical examination and fasting blood test, and will provide a 7-day record of their food intake as part of the screening process. Those enrolled will be randomly assigned to receive either metformin or placebo (a look-alike tablet with no active medicine) twice a day for a six month period. After the 6 month study period, all children will be offered the opportunity to take metformin for another 6 months. Participants will be hospitalized for 2-3 days for the following procedures: history and physical examination; fasting blood test; several urine collections; X-ray studies to determine bone age and amount of body fat and muscle; magnetic resonance imaging (MRI) scan to measure body fat; hyperglycemic clamp study to evaluate insulin resistance; food intake testing; nutrition consultation; resting metabolic rate; and a doubly labeled water test. For the hyperglycemic clamp study, a catheter (thin flexible tube) is inserted into a vein in each arm. A sugar solution is given through one tube and blood samples are drawn every 5 minutes through the other to measure insulin. For the food intake testing, the child is asked about his or her hunger level, then given various foods he or she may choose to eat, then questioned again at various intervals both during and after finishing eating about his or her hunger level. The doubly labeled water study involves drinking heavy water (water which is enriched to have special kinds of hydrogen and oxygen). Urine specimens are collected 2, 3 and 4 hours after drinking the water. The child also drinks a special milk shake called a Scandishake and repeats the calorie intake and hunger study. (Two food intake studies are done on separate days.) One week after the heavy water test, additional urine samples are collected one week later. After completing the tests, the child will begin treatment with metformin or placebo, plus a daily vitamin tablet. Participants will be followed once a month with a brief history and physical examination, including a blood test. After 6 months, all of the tests described above will be repeated. All children who complete the second round of tests-both those who took metformin and those who took placebo-will be offered metformin for an additional 6 months and will be seen once a month for follow-up evaluations. Parents will not be told which children received metformin and which received placebo until all children in the study complete the first 6 months of the trial.

Detailed Description
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The prevalence of overweight and obesity in children and adolescents in the United States has doubled during the past 20 years. Obesity is closely linked with development of insulin resistance and other mediators of unfavorable cardiovascular risk, such as hypertension and dyslipidemia. These obesity-related risk factors often first appear during childhood. Since obese children tend to become obese adults, such children are at increased risk for persistence of these abnormalities into adulthood and for the early occurrence of obesity-related morbidity and mortality. Obesity-related insulin resistance is also largely responsible for the recently documented rise in the incidence of Type 2 diabetes in youth. To date, there is no FDA-approved pharmacotherapy for children with obesity and insulin resistance. Metformin is a medication approved for use in adults with Type 2 diabetes that is unique in that it promotes weight loss and improves features of the insulin resistance syndrome. Preliminary studies suggest that metformin may promote weight loss in obese non-diabetic children. However, the mechanism of metformin-induced weight loss has not been elucidated. We propose to evaluate the safety, tolerability, efficacy and mechanism of metformin-induced weight loss in obese, hyperinsulinemic children aged 6-12.99 years. We will conduct a six-month randomized, double blind placebo-controlled trial of metformin. All study participants will receive nutritional consultation and advice on appropriate diet. We will study the effects of metformin on weight, food intake, energy expenditure, insulin sensitivity, and lipids. At the end of the six-month placebo-controlled trial, all subjects will be offered metformin in an open label phase for an additional six months.

Official Title
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Effects of Metformin on Energy Intake, Energy Expenditure, and Body Weight in Overweight Children With Insulin Resistance

Conditions
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Hyperinsulinemia, Obesity

Intervention / Treatment
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* Drug: Metformin HCL
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Good general health. Age greater than or equal to 6 and less than 13 years. Pre-pubertal or having at most early puberty (breast Tanner I, II or III for girls, testes size less than or equal to 8 mL for boys). Hyperinsulinemia, defined as fasting insulin concentration greater than or equal to 15 mIU/mL. The insulin level must be greater than or equal to 15 at either the NIH Clinical Center lab or the NIDDK lab at PIMC in Phoenix. Obesity, defined as body mass index greater than or equal to 95th percentile determined by NHANES I age and sex specific data. Subjects must have fasting plasma glucose less than 126 mg/dl Subjects must have glycosylated hemoglobin (HgbA1C) of less than or equal to 6.5%. Females who begin menstruating (or who are at risk for pregnancy) during the study must have a negative pregnancy test and must use an effective method of contraception if they are engaging in sexual intercourse. EXCLUSION CRITERIA: Baseline creatinine greater or equal to 1.0 mg/dl. Significant cardiac or pulmonary disease likely to or resulting in hypoxia or decreased perfusion. Hepatic disease with elevated liver function tests (ALT or AST) greater than or equal to 1.5 the upper limits of normal. An alcohol history concerning for development of hepatic toxicity. Pregnancy. Evidence for Type 2 diabetes, including fasting plasma glucose greater than or equal to 126 mg/dl or HgbA1C greater than 6.5%. Weight loss of greater than 2% of bodyweight within the past 6 months. Presence of other endocrinologic disorders leading to obesity (e.g. Cushing's Syndrome). Individuals who have, or whose parent or guardians have current substance abuse or a psychiatric disorder or other condition that, in the opinion of the investigators, would impede competence or compliance or possibly hinder completion of the study. Recent use (within six months) of anorexiant medications. Individuals receiving medical treatment other than diet for hypertension or dyslipidemia. Individuals with evidence of precocious puberty.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

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: 1 - Metformin HCL<br>Subjects receive metformin plus a weight loss program | Drug: Metformin HCL<br>* Medication studied for ability to alter body weight and body composition.<br>|
| Placebo Comparator: 2 - Placebo<br>Subjects receive placebo plus a weight loss program | Drug: Placebo<br>* Control capsules for metformin<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Body Weight as Determined by Body Mass Index-standard Deviation Score (BMI-SDS). | Change in Body Mass Index standard deviation score (BMI-SDS) determined using tables created by the CDC in 2000. BMI-SDS is a unitless transformation of the body mass index (measured in kg divided by the squared height in meters) using the L M S method. Possible values range from -3 to +3. See http://www.cdc.gov/growthcharts/percentile_data_files.htm for details. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Body Weight as Determined by BMI | Change in body weight as determined by body mass index (kg/m2) | 6 months | 
| Change in Body Weight | Change in body weight (kg) | 6 months | 
| Change in Body Fat by DEXA | Change in body fat mass by Dual Energy X-Ray Absorptiometry (kg) | 6 months | 
| Change in Body Fat by Bod Pod | Change in body fat mass measured by air displacement plethysmography (kg) | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Child, Body Fat, Food Intake, Diabetes Mellitus, Dyslipidemia, Vitamin B12, Childhood Obesity