Metformin to Treat Obesity in Children With Insulin Resistance
Condition: Hyperinsulinemia; Obesity
MeSH terms: Obesity; Insulin Resistance; Hyperinsulinism
Intervention: Metformin HCL; Placebo
Intervention description: Medication studied for ability to alter body weight and body composition.; Control capsules for metformin
Intervention MeSH terms: Metformin
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 100.0
Sex: All
Minimum age: 6 Years
Maximum age: 12 Years
Healthy volunteers: No
Keywords: Child; Body Fat; Food Intake; Diabetes Mellitus; Dyslipidemia; Vitamin B12; Childhood Obesity

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.
    

Eligibility criteria:

        -  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.