Prader-Willi Syndrome
Conditions
Keywords
Prader-Willi Syndrome, Obesity, Weight, Exenatide, Byetta, Pediatrics, Adolescents
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.
Interventions
DRUGExenatide
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).
Sponsors
Children's Hospital Los Angeles
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
13 Years to 20 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Weight | 6 months | Change in weight (kg) after 6 months of treatment with study drug. Described as mean +/- SD |
| % 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 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 | 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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). | 10 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Exenatide |
|---|---|
| Acy Ghr | 362.3 pg ml ^-1 |
| Adiposity | 44.7 percentage of fat |
| Age, Categorical <=18 years | 6 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants |
| Age, Continuous | 16 years |
| Appetite Appetite Behavior | 14.5 units on a scale STANDARD_DEVIATION 4.9 |
| Appetite Appetite Drive | 12.6 units on a scale STANDARD_DEVIATION 3.1 |
| Appetite Appetite Severity | 5.1 units on a scale STANDARD_DEVIATION 1.5 |
| Appetite Total Appetite Score | 32.2 units on a scale STANDARD_DEVIATION 8.7 |
| BMI | 41.7 kg m^-2 |
| BMI Z-Score | 3.5 units on a scale STANDARD_DEVIATION 1.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Glycosylated hemoglobin (HbA1c) | 5.9 percentage of total hemoglobin |
| Insulin | 10.5 uIU ml^-1 |
| Leptin | 36.4 ng ml ^-1 STANDARD_DEVIATION 18.3 |
| PP | 89 pg ml ^-1 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 6 Participants |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 6 Participants |
| Sex: Female, Male Male | 4 Participants |
| Weight | 102.5 kg STANDARD_DEVIATION 18.6 |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 2 / 10 |
| serious Total, serious adverse events | 0 / 10 |
Outcome results
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
Time frame: 6 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exenatide | Appetite Scores | Total Appetite Score Baseline | 32.2 units on a scale | Standard Deviation 8.7 |
| Exenatide | Appetite Scores | Total Appetite Score 6 month | 25.4 units on a scale | Standard Deviation 7.2 |
| Exenatide | Appetite Scores | Behavior Score Baseline | 14.5 units on a scale | Standard Deviation 4.9 |
| Exenatide | Appetite Scores | Behavior Score 6 months | 10.6 units on a scale | Standard Deviation 3.8 |
| Exenatide | Appetite Scores | Drive Score Baseline | 12.6 units on a scale | Standard Deviation 3.1 |
| Exenatide | Appetite Scores | Drive Score 6 months | 10.4 units on a scale | Standard Deviation 2.7 |
| Exenatide | Appetite Scores | Severity Score Baseline | 5.1 units on a scale | Standard Deviation 1.5 |
| Exenatide | Appetite Scores | Severity Score 6 months | 4.4 units on a scale | Standard Deviation 2.2 |
p-value: 0.004Mixed Models Analysis
Primary
Change in Acy Ghr
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Change in Acy Ghr | 263 pg ml^-1 | Standard Deviation 99.5 |
p-value: 0.2Mixed Models Analysis
Primary
Change in BMI Z-Score
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Change in BMI Z-Score | .1 units on a scale | Standard Deviation 0.4 |
p-value: 0.8Mixed Models Analysis
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.
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | % Change in Body Mass Index (BMI) | 1.3 % change in BMI | Standard Deviation 2 |
p-value: 0.08Mixed Models Analysis
Primary
Change in HbA1c (%)
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Change in HbA1c (%) | -.3 percentage | Standard Deviation 0.2 |
p-value: 0.04Mixed Models Analysis
Primary
Change in Insulin Levels
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Change in Insulin Levels | 3 u/U ml^-1 | Standard Deviation 0.5 |
p-value: 0.8Mixed Models Analysis
Primary
Change in Leptin
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Change in Leptin | -7.4 ng ml^-1 | Standard Deviation 3.8 |
p-value: 0.2Mixed Models Analysis
Primary
Change in Pancreatic Peptide (PP)
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Change in Pancreatic Peptide (PP) | 15 pg ml^-1 | Standard Deviation 6 |
p-value: 0.04Mixed Models Analysis
Primary
Change in Weight
Change in weight (kg) after 6 months of treatment with study drug. Described as mean +/- SD
Time frame: 6 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Exenatide | Change in Weight | -.5 kg | Standard Deviation 0.9 |
p-value: 0.07Mixed Models Analysis