Effects of Exenatide on Overweight Adolescents With Prader-Willi Syndrome

Not Applicable

Completed

Conditions: Prader-Willi Syndrome

Interventions: Drug: Exenatide

Registration Number: NCT01444898

Lead Sponsor: Children's Hospital Los Angeles

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 10

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Exenatide	Exenatide	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).

Primary Outcome Measures

Name	Time	Method
Change in Weight	6 months	Change in weight (kg) after 6 months of treatment with study drug. Described as mean +/- SD
Change in BMI Z-Score	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	6 months	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
% Change in Body Mass Index (BMI)	6 months	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.
Change in HbA1c (%)	6 months