Effects of Exenatide on Overweight Adolescents With Prader-Willi Syndrome

• Sponsor: Children's Hospital Los Angeles (Other)
• Overall Status: Completed
• CT.gov ID: NCT01444898
• Collaborator: (none)
• Enrollment: 10
• Location: 1
• Arm: 1
• Duration (Months): 21
• Patients Per Site Per Month: 0.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Prader-Willi Syndrome	Drug: Exenatide	N/A

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Effects of Exenatide on Obesity and Appetite in Overweight Patients With Prader-Willi Syndrome
• Study Start Date: Mar 1, 2012
• Actual Primary Completion Date: May 1, 2013
• Actual Study Completion Date: Dec 1, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: 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).

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).; Other Names: Byetta

Outcome Measures

Primary Outcome Measures

1. Change in Weight [6 months]

   Change in weight (kg) after 6 months of treatment with study drug. Described as mean +/- SD

2. % 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.

3. Change in BMI Z-Score [6 months]

4. Change in HbA1c (%) [6 months]

5. Change in Insulin Levels [6 months]

6. Change in Leptin [6 months]

7. Change in Acy Ghr [6 months]

8. Change in Pancreatic Peptide (PP) [6 months]

9. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 13 Years to 20 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Children's Hospital of Los Angeles	Los Angeles	California	United States	90027

Sponsors and Collaborators

• Children's Hospital Los Angeles

Investigators

• Principal Investigator: Debra Jeandron, MD, Children's Hospital Los Angeles

Study Documents (Full-Text)

None provided.

More Information

Publications

• 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.
• Goldstone AP. Prader-Willi syndrome: advances in genetics, pathophysiology and treatment. Trends Endocrinol Metab. 2004 Jan-Feb;15(1):12-20. Review.
• Goldstone AP. The hypothalamus, hormones, and hunger: alterations in human obesity and illness. Prog Brain Res. 2006;153:57-73. Review.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.

• Responsible Party: Mitchell E. Geffner, Principal Investigator, Children's Hospital Los Angeles
• ClinicalTrials.gov Identifier: NCT01444898
• Other Study ID Numbers: CCI 11-00227
• First Posted: Oct 3, 2011
• Last Update Posted: Sep 29, 2016
• Last Verified: Sep 1, 2016

• Individual Participant Data (IPD) Sharing Statement: Undecided
• Plan to Share IPD: Undecided
• Keywords provided by Mitchell E. Geffner, Principal Investigator, Children's Hospital Los Angeles: Prader-Willi Syndrome; Obesity; Weight; Exenatide; Byetta; Pediatrics; Adolescents
• Additional relevant MeSH terms: Prader-Willi Syndrome; Syndrome; Overweight; Exenatide

Study Results

Participant Flow

Arm/Group Title	Exenatide
Arm/Group Description	All subjects enrolled in this study will be given Exenatide for 6 months. 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).
Period Title: Overall Study
STARTED	10
COMPLETED	9
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Exenatide
Arm/Group Description	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).
Overall Participants	10
Age (Count of Participants)
<=18 years	6 60%
Between 18 and 65 years	4 40%
>=65 years	0 0%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	16
Sex: Female, Male (Count of Participants)
Female	6 60%
Male	4 40%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 10%
Not Hispanic or Latino	6 60%
Unknown or Not Reported	3 30%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 10%
White	6 60%
More than one race	2 20%
Unknown or Not Reported	1 10%
Region of Enrollment (participants) [Number]
United States	10 100%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	102.5 (18.6)
BMI (kg m^-2) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [kg m^-2]	41.7
BMI Z-Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	3.5 (1.1)
Glycosylated hemoglobin (HbA1c) (percentage of total hemoglobin) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [percentage of total hemoglobin]	5.9
Insulin (uIU ml^-1) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [uIU ml^-1]	10.5
Leptin (ng ml ^-1) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [ng ml ^-1]	36.4 (18.3)
Acy Ghr (pg ml ^-1) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [pg ml ^-1]	362.3
PP (pg ml ^-1) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [pg ml ^-1]	89
Appetite (units on a scale) [Mean (Standard Deviation) ]
Total Appetite Score	32.2 (8.7)
Appetite Behavior	14.5 (4.9)
Appetite Drive	12.6 (3.1)
Appetite Severity	5.1 (1.5)
Adiposity (percentage of fat) [Number]
Number [percentage of fat]	44.7
Adiposity (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	20 (4.6)

Outcome Measures

1. Primary Outcome

Title	Change in Weight
Description	Change in weight (kg) after 6 months of treatment with study drug. Described as mean +/- SD
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exenatide
Arm/Group Description	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).
Measure Participants	10
Mean (Standard Deviation) [kg]	-.5 (.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.07
	Comments
	Method	Mixed Models Analysis
	Comments

2. Primary Outcome

Title	% Change in Body Mass Index (BMI)
Description	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.
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exenatide
Arm/Group Description	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).
Measure Participants	10
Mean (Standard Deviation) [% change in BMI]	1.3 (2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.08
	Comments
	Method	Mixed Models Analysis
	Comments

3. Primary Outcome

Title	Change in BMI Z-Score
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exenatide
Arm/Group Description	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).
Measure Participants	10
Mean (Standard Deviation) [units on a scale]	.1 (.4)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.8
	Comments
	Method	Mixed Models Analysis
	Comments

4. Primary Outcome

Title	Change in HbA1c (%)
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exenatide
Arm/Group Description	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).
Measure Participants	10
Mean (Standard Deviation) [percentage]	-.3 (.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.04
	Comments
	Method	Mixed Models Analysis
	Comments

5. Primary Outcome

Title	Change in Insulin Levels
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exenatide
Arm/Group Description	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).
Measure Participants	10
Mean (Standard Deviation) [u/U ml^-1]	3 (.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.8
	Comments
	Method	Mixed Models Analysis
	Comments

6. Primary Outcome

Title	Change in Leptin
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exenatide
Arm/Group Description	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).
Measure Participants	10
Mean (Standard Deviation) [ng ml^-1]	-7.4 (3.8)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.2
	Comments
	Method	Mixed Models Analysis
	Comments

7. Primary Outcome

Title	Change in Acy Ghr
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exenatide
Arm/Group Description	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).
Measure Participants	10
Mean (Standard Deviation) [pg ml^-1]	263 (99.5)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.2
	Comments
	Method	Mixed Models Analysis
	Comments

8. Primary Outcome

Title	Change in Pancreatic Peptide (PP)
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exenatide
Arm/Group Description	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).
Measure Participants	10
Mean (Standard Deviation) [pg ml^-1]	15 (6)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.04
	Comments
	Method	Mixed Models Analysis
	Comments

9. Primary Outcome

Title	Appetite Scores
Description	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
Time Frame	6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exenatide
Arm/Group Description	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).
Measure Participants	10
Total Appetite Score Baseline	32.2 (8.7)
Total Appetite Score 6 month	25.4 (7.2)
Behavior Score Baseline	14.5 (4.9)
Behavior Score 6 months	10.6 (3.8)
Drive Score Baseline	12.6 (3.1)
Drive Score 6 months	10.4 (2.7)
Severity Score Baseline	5.1 (1.5)
Severity Score 6 months	4.4 (2.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.004
	Comments
	Method	Mixed Models Analysis
	Comments

Adverse Events

Arm/Group Title	Exenatide
Arm/Group Description	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).
All Cause Mortality
	Exenatide
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Exenatide
	Affected / at Risk (%)	# Events
Total	0/10 (0%)
Other (Not Including Serious) Adverse Events
	Exenatide
	Affected / at Risk (%)	# Events
Total	2/10 (20%)
Gastrointestinal disorders
abdominal discomfort with diarrhea	2/10 (20%)	2

Limitations/Caveats

small sample size referral bias due to small recruitment area confounding factors during the study, including variations in eating schedule, psychotropic medications, caretaker supervision and activity

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.