Effects of Exenatide on Overweight Adolescents With Prader-Willi Syndrome

Prader-Willi Syndrome Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01444898
• Other study ID #: CCI 11-00227
• Status: Completed
• Phase: N/A
• First received: September 27, 2011
• Last updated: September 27, 2016
• Start date: March 2012
• Est. completion date: December 2013

Study information

• Verified date: September 2016
• Source: Children's Hospital Los Angeles
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: December 2013
• Est. primary completion date: May 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 13 Years to 20 Years

Eligibility

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

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Overweight
• Prader-Willi Syndrome
• Syndrome

Intervention

Drug:
• 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).

Locations

Country	Name	City	State
United States	Children's Hospital of Los Angeles	Los Angeles	California

Sponsors (1)

Lead Sponsor	Collaborator
Children's Hospital Los Angeles

Country where clinical trial is conducted

United States, 

References & Publications (10)

Cummings DE, Clement K, Purnell JQ, Vaisse C, Foster KE, Frayo RS, Schwartz MW, Basdevant A, Weigle DS. Elevated plasma ghrelin levels in Prader Willi syndrome. Nat Med. 2002 Jul;8(7):643-4. — View Citation

Goldstone AP. Prader-Willi syndrome: advances in genetics, pathophysiology and treatment. Trends Endocrinol Metab. 2004 Jan-Feb;15(1):12-20. Review. — View Citation

Goldstone AP. The hypothalamus, hormones, and hunger: alterations in human obesity and illness. Prog Brain Res. 2006;153:57-73. Review. — View Citation

Paik KH, Jin DK, Song SY, Lee JE, Ko SH, Song SM, Kim JS, Oh YJ, Kim SW, Lee SH, Kim SH, Kwon EK, Choe YH. Correlation between fasting plasma ghrelin levels and age, body mass index (BMI), BMI percentiles, and 24-hour plasma ghrelin profiles in Prader-Willi syndrome. J Clin Endocrinol Metab. 2004 Aug;89(8):3885-9. — View Citation

Pérez-Tilve D, González-Matías L, Alvarez-Crespo M, Leiras R, Tovar S, Diéguez C, Mallo F. Exendin-4 potently decreases ghrelin levels in fasting rats. Diabetes. 2007 Jan;56(1):143-51. — View Citation

Rosenstock J, Klaff LJ, Schwartz S, Northrup J, Holcombe JH, Wilhelm K, Trautmann M. Effects of exenatide and lifestyle modification on body weight and glucose tolerance in obese subjects with and without pre-diabetes. Diabetes Care. 2010 Jun;33(6):1173-5. doi: 10.2337/dc09-1203. Epub 2010 Mar 23. — View Citation

Salehi P, Hsu I, Azen CG, Mittelman SD, Geffner ME, Jeandron D. Effects of exenatide on weight and appetite in overweight adolescents and young adults with Prader-Willi syndrome. Pediatr Obes. 2016 Apr 13. doi: 10.1111/ijpo.12131. [Epub ahead of print] — View Citation

Seetho IW, Jones G, Thomson GA, Fernando DJ. Treating diabetes mellitus in Prader-Willi syndrome with Exenatide. Diabetes Res Clin Pract. 2011 Apr;92(1):e1-2. doi: 10.1016/j.diabres.2010.12.009. Epub 2011 Jan 11. — View Citation

Suzuki K, Simpson KA, Minnion JS, Shillito JC, Bloom SR. The role of gut hormones and the hypothalamus in appetite regulation. Endocr J. 2010;57(5):359-72. Epub 2010 Apr 14. Review. — View Citation

Wren AM, Seal LJ, Cohen MA, Brynes AE, Frost GS, Murphy KG, Dhillo WS, Ghatei MA, Bloom SR. Ghrelin enhances appetite and increases food intake in humans. J Clin Endocrinol Metab. 2001 Dec;86(12):5992. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Weight	Change in weight (kg) after 6 months of treatment with study drug. Described as mean +/- SD	6 months	No
Primary	% 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	No
Primary	Change in BMI Z-Score		6 months	No
Primary	Change in HbA1c (%)		6 months	No
Primary	Change in Insulin Levels		6 months	No
Primary	Change in Leptin		6 months	No
Primary	Change in Acy Ghr		6 months	No
Primary	Change in Pancreatic Peptide (PP)		6 months	No
Primary	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	No