Effects of Exenatide on Overweight Adolescents With Prader-Willi Syndrome

Study Overview
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Brief Summary
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Prader-Willi Syndrome (PWS) is one of the most common genetic causes of obesity. Obesity is a major source of morbidity and mortality in this population. It can lead to sleep apnea, cor pulmonale, diabetes mellitus, and atherosclerosis. PWS has distinct characteristics that set it apart from other forms of obesity including insatiable appetite and food-seeking behavior which can be disruptive to home and school activities, and can cause severe social and psychological turmoil within families. PWS is also associated with unique hormonal abnormalities, most notably hyperghrelinemia. Ghrelin is a gut hormone produced in the stomach that stimulates food intake during a fast. It is hypothesized that the extremely high ghrelin levels in patients with PWS may cause or contribute to their insatiable appetite. Exenatide, a medication used in the treatment of type 2 diabetes mellitus in adults, appears to suppress ghrelin levels and cause weight loss. It was designed to mimic glucagon-like peptide 1 (GLP-1), an incretin hormone that stimulates insulin secretion and delays gastric emptying, among other effects. In the present study, the investigators will investigate the effects of a 6 month trial of exenatide in overweight adolescents with PWS. The investigators will quantify the changes in weight and body composition, as well as subjective measures of appetite, and concentrations of appetite-associated hormones. The investigators hypothesize that exenatide will improve weight, body composition, appetite, and plasma ghrelin levels during the treatment period.

Detailed Description
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BACKGROUND: Prader-Willi syndrome (PWS) is associated with hyperphagia and hyperghrelinemia with major morbidity because of obesity without effective medical treatment targeting hyperphagia. Exenatide (Byetta [synthetic Exendin-4]; AstraZeneca, Wilmington DE) is a GLP-1 receptor agonist which reduces appetite and weight and may be an effective treatment in PWS. OBJECTIVE: The objective of this study is to determine the effect of a 6-month trial of exenatide on appetite, weight and gut hormones in youth with PWS.

Official Title
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Effects of Exenatide on Obesity and Appetite in Overweight Patients With Prader-Willi Syndrome

Conditions
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Prader-Willi Syndrome

Intervention / Treatment
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* Drug: Exenatide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of Prader Willi Syndrome confirmed by genetic testing (DNA methylation or FISH) Ages 13-20 years body mass index (BMI) > 85th percentile for age and gender Exclusion Criteria: Is currently using or has previously used a glucagon-like peptide-1 (GLP-1) agonist History of pancreatitis, or renal failure History of familial pancreatitis Amylase, or lipase levels > 2.5 times the upper limit of normal any time in the previous 2 years Creatinine clearance < 30 mL/min Other syndromic diagnoses gastrointestinal (GI) or renal illness in the 1 month prior to entering study Inability to take study drug Pregnancy Initiation of growth hormone (GH), estrogen, or testosterone or change > 25% of dose/kg/day during the 6 months prior to starting study Non-English speaking

Ages Eligible for Study
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Minimum Age: 13 Years
Maximum Age: 20 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exenatide<br>All subjects enrolled in this study will be given Exenatide for 6 months. Exenatide: The investigators will give patients naive to GLP-1 agonists exenatide per manufacturer dosing recommendations for 6 months. The investigators will begin by giving 5 mcg subcutaneously twice a day for 1 month and then increase the dose to 10 mcg subcutaneously twice a day for the remainder of the study (5 months). | Drug: Exenatide<br>* The investigators will give patients naive to GLP-1 agonists exenatide per manufacturer dosing recommendations for 6 months. The investigators will begin by giving 5 mcg subcutaneously twice a day for 1 month and then increase the dose to 10 mcg subcutaneously twice a day for the remainder of the study (5 months).<br>* Other names: Byetta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Weight | Change in weight (kg) after 6 months of treatment with study drug. Described as mean +/- SD | 6 months | 
| % Change in Body Mass Index (BMI) | Prior to analysis, distributions were evaluated for normality and natural log transformation was performed to analyse data not normally distributed. Data are presented as mean ±SD unless not normally distributed, in which case they are presented as median with intra-quartile ranges (25th and 75th percentiles). Within-subject changes between visits were analysed by mixed model repeated measures. When the overall F-test for difference among visits was significant, Dunnett-adjusted pairwise comparisons were made between baseline and each subsequent visit. | 6 months | 
| Change in BMI Z-Score |  | 6 months | 
| Change in HbA1c (%) |  | 6 months | 
| Change in Insulin Levels |  | 6 months | 
| Change in Leptin |  | 6 months | 
| Change in Acy Ghr |  | 6 months | 
| Change in Pancreatic Peptide (PP) |  | 6 months | 
| Appetite Scores | Appetite scores using a syndrome-validated hyperphagia questionnaire 11 item questionnaire divided into subcategories of behavior (5 questions), drive (4 questions), severity (2 questions). Tallied and analyzed as total and subcategory scores. Each question scored 1-5 with higher scores correlating with worse hyperphagia. Possible ranges: Total 11-55, behavior 5-25, drive 4-20, severity 2-10 | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Prader-Willi Syndrome, Obesity, Weight, Exenatide, Byetta, Pediatrics, Adolescents