Metformin to Treat Obesity in Children With Insulin Resistance
Condition: Hyperinsulinemia; Obesity
MeSH terms: Obesity; Insulin Resistance; Hyperinsulinism
Study type: Interventional
Phase: Phase 2

Summary: 
      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: 
      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.
    

Intervention name(s): Metformin HCL; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Medication studied for ability to alter body weight and body composition.; Control capsules for metformin
Intervention MeSH terms: Metformin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Child; Body Fat; Food Intake; Diabetes Mellitus; Dyslipidemia; Vitamin B12; Childhood Obesity