GLP-1 Therapy for Weight Loss and Improved Glucose Tolerance in Obese Children
Condition: Obesity, Morbid
MeSH terms: Obesity, Morbid; Weight Loss
Study type: Interventional
Phase: Phase 2

Summary: 
      The prevalence of severely obese children is on the rise. Behavioral therapies for weight
      loss are successful in some, but others need more aggressive approaches such as drug therapy.
      In addition, up to 25% of severely obese children have impaired glucose tolerance (IGT),
      which places them at significantly elevated risk of developing type 2 diabetes mellitus and
      cardiovascular disease. Although various drug therapies for weight loss and IGT have been
      explored in adults, few have been evaluated in children.

      Recently, a new drug class has emerged that targets deficiencies of GLP-1. One of the main
      glycemic mechanisms of action of the GLP-1 agonists such as exenatide is to enhance glucose
      disposal in the postprandial setting and improve glucose tolerance. In addition, exenatide
      can induce weight loss by decreasing appetite and slowing gastric motility.
    

Detailed description: 
      This will be a randomized, open-label, controlled, crossover clinical trial in 12 patients.
      All patients will receive exenatide and undergo the control phase. Following baseline
      testing, participants will be randomly assigned to treatment order: therapy (exenatide) or
      control (lifestyle modification). Half (n = 6) will receive exenatide first (3-months) then
      cross over to control (no drug therapy for 3-months). Half (n = 6) will be assigned to
      control first (3-months) then cross over to exenatide (3-months). All efforts will be made to
      stratify randomization based on gender of the participants. Treatment and control conditions
      will be three months each. Because of the route of administration of exenatide (subcutaneous
      injection), placebo will not be utilized for the control phase of the study.

      Participants in this study will engage in background intensive lifestyle modification offered
      by the University of Minnesota Pediatric Weight Management Clinic for the entire study, even
      during the active drug treatment phase. Intensive lifestyle modification will be purely
      clinical in nature in which children and their families receive continuing counseling from a
      team of trained professionals including physicians, dieticians, and psychologists to reduce
      weight by making healthier eating choices and increasing physical activity.

      The screening visit will take place in the Pediatric Weight Management Clinic and will
      include a complete medical history and physical examination. Screening will include review of
      medical records for previous clinical and laboratory data (including clinically-ordered
      glucose tolerance test results). All research testing will take place in the University of
      Minnesota General Clinical Research Center (GCRC). Subjects will undergo testing at the
      following intervals: baseline, immediately after the first 3-month phase (whether exenatide
      or control), and immediately after the second 3- month phase (whether exenatide or control).
      The following measures will be collected after the subject has been fasting for at least
      twelve hours:

        -  Height, weight, body mass index, waist and hip circumference

        -  Fat and lean mass (dual energy x-ray absorptiometry: DXA)

        -  Tanner stage determination (performed during screening physical exam or may be obtained
           from medical chart)

        -  Fasting lipid profile (total-, LDL-, and HDL-cholesterol, triglycerides)

        -  Systolic and diastolic blood pressure

        -  Oral glucose tolerance test (glucose and insulin measured every 30 minutes for 2 hours)

        -  Endothelial function (digital reactive hyperemia: EndoPAT 2000, Itamar Medical) - in
           addition to the baseline measure, endothelial function testing will occur at hours one
           and two of the oral glucose tolerance test

        -  Frozen plasma for storage - in addition to the baseline blood draw, blood for
           endothelial biomarkers will be obtained at hours one and two of the oral glucose
           tolerance test

        -  Arterial stiffness (pulse wave velocity; augmentation index: Sphygmocor, AtCor Medical)

        -  Frozen plasma for pharmacokinetic determination of exenatide in children
    

Intervention name(s): Exenatide
Intervention type(s): Drug
Intervention description(s): Exenatide, subcutaneous injection, 10 mcg, twice per day
Other intervention name(s): Byetta
Intervention MeSH terms: Exenatide
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Obesity; Impaired Glucose Tolerance; Children