Prader-Willi Syndrome
Conditions
Keywords
Childhood obesity, Prader-Willi Syndrome, Octreotide, Ghrelin, Weight loss, Body composition, Energy expenditure
Brief summary
The purpose of this study is to investigate over a 6 month period the effect of octreotide therapy on food intake, sense of hunger, body weight, body composition, efficiency of burning calories, biomarkers of weight regulation and growth hormone markers in children and young Adults with Prader-Willi Syndrome(PWS).
Detailed description
Obesity continues to be a prevalent health concern affecting every race of the American population. According to data from the World Health Organization, 54% of U.S. adults are overweight (body mass index (BMI) \>25 kg/m2 ) and 22% are obese (BMI \>30 kg/m2) (1). In addition, 25% of U.S. children are overweight or obese (1). Studies show that obese children are likely to become obese adults (2-5). Also, recent studies report significant years of life lost due to the impact of being an obese adult (6, 7). Thus, insights into the pathogenesis of childhood obesity and preventative measures are needed to combat the inevitable increase in worldwide incidence of obesity and its associated co-morbidities. Recent studies have identified a new gastroenteric hormone, ghrelin, as a long-term regulator of energy balance in humans (12). Ghrelin is a 28 amino acid acylated peptide which is an endogenous ligand of the growth hormone secretagogue receptor (GHS-R), a hypothalamic G-protein-coupled receptor (13). Enteroendocrine cells (X/A-like cells) of the stomach are the major site of ghrelin synthesis, although a minor proportion of ghrelin synthesis occurs in other sites such as the hypothalamus, pituitary, duodenum, jejunum and lung (14) (15, 16). The hypothesis that hyperghrelinemia causes some of the features of PWS predicts that this disorder will be ameliorated (partially or completely) by lowering ghrelin levels. We have recently shown that the somatostatin agonist, octreotide, suppresses ghrelin levels in humans. If octreotide remains effective in longer term studies, the drug may become an adjuvant therapy, in addition to growth hormone, to control the insatiable appetite and morbid obesity seen in this condition.
Interventions
DRUGOctreotide
Octreotide to be administered by subcutaneous injection three times daily
DRUGPlacebo
Placebo to be administered by subcutaneous injection three times daily while on study
Sponsors
National Institutes of Health (NIH)
National Center for Research Resources (NCRR)
Novartis
Duke University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
5 Years to 21 Years
Healthy volunteers
No
Inclusion criteria
* Diagnosis of PWS confirmed by chromosome analysis * Ages 5 years to 21 years * BMI for age ≥ (greater-than or equal to)85th percentile * Written informed consent and assent obtained and willingness to comply with the study schedule and procedures * Free T4, Thyroid stimulating hormone (TSH) values in the normal range (either endogenous or with thyroxine replacement)
Exclusion criteria
* Patients with any other clinically significant disease that would have an impact on body composition, including diabetes mellitus, chronic inflammatory bowel disease, chronic severe liver or kidney disease or neurologic disorders * Concomitant use of an investigational drug or Octreotide in the past year * Use of steroids for longer than 7 days within the past 30 days
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Improved Peptide YY (PYY) Regulation From Baseline to 6 Months | 6 months | Number of participants with improved Peptide YY (PYY) regulation from baseline to 6 months of Octreotide or Placebo therapy |
| Number of Participants With Improved Adiponectin Regulation From Baseline to 6 Months | 6 months | Number of participants with improved Adiponectin regulation from baseline to 6 months of Octreotide or Placebo therapy |
| Number of Participants With Improved Leptin Regulation From Baseline to 6 Months | 6 months | Number of participants with improved Leptin regulation from baseline to 6 months of Octreotide or Placebo therapy |
| Number of Participants With Decrease in Fasting Total Ghrelin | 6 months | Number of participants showing a decrease in Fasting total ghrelin from baseline to 6 months of treatment with Octreotide or placebo |
| Number of Participants With Decrease in Weight From Baseline to 6 Months | 6 months | Number of participants who had a decrease in weight from baseline to 6 months of Octreotide or placebo therapy |
| Number of Participants With Decreased BMI Z-score From Baseline to 6 Months | 6 months | Number of participants with decreased BMI z-score from baseline to 6 months of Octreotide or Placebo therapy |
| Number of Participants With Decreased Skin-fold Measurements From Baseline to 6 Months | 6 months | Number of participants with decreased skin-fold measurements from baseline to 6 months of Octreotide or Placebo therapy |
| Number of Participants With Decrease in Hunger and Food Intake | 6 months | Measured by hunger and hyperphagia by questionnaires and parent-reported 72-hour food recall from baseline to 6 months. Multiple questionnaires consisting of a battery of free text answer questions and food diaries are combined in order to make a behavioral assessment of the participants food state of hunger and food intake. There is no defined scale for this assessment. Each participants responses and parent responses are combined. |
| Number of Participants With Improved Insulin Regulation From Baseline to 6 Months | 6 months | Number of participants with improved Insulin regulation from baseline to 6 months of Octreotide or Placebo therapy. Insulin regulation was measured by immunochemiluminescent assay. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Decreased Body-composition From Baseline to 6 Months by DEXA | 6 months | Number of participants with decreased body-composition as Measured by Dual Energy X-ray Absorptiometry (DEXA) scan from baseline to 6 months of Octreotide or Placebo therapy |
| Number of Participants With Decreased Body Composition From Baseline to 6 Months by BOD POD® | 6 months | Number of participants with decreased body-composition as Measured by BOD POD® body composition tracking system from baseline to 6 months of Octreotide or Placebo therapy |
Countries
United States
Participant flow
Recruitment details
Participants for the study were recruited over a period of 2.5 years. Participants were identified from the medical clinics or from IRB approved advertisements.
Pre-assignment details
Participants were eligible to enroll into the study with a diagnosis of PWS proven by chromosome analysis and thyroid function tests within normal ranges. Participants could not have used the study drug within the past year and could not have been on steroids within the past 30 days. These items would exclude participation.
Participants by arm
| Arm | Count |
|---|---|
| Octreotide Octreotide :
Octreotide : Octreotide or placebo to be administered by subcutaneous injection three times daily | 2 |
| Placebo Comparator Placebo to be administered by subcutaneous injection three times daily while on study | 3 |
| Total | 5 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo Comparator | Octreotide | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 3 Participants | 2 Participants | 5 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 13 years STANDARD_DEVIATION 4.6 | 11 years STANDARD_DEVIATION 4.2 | 11.8 years STANDARD_DEVIATION 4 |
| Region of Enrollment United States | 3 participants | 2 participants | 5 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 2 Participants | 0 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 2 | 1 / 3 |
| serious Total, serious adverse events | 0 / 2 | 0 / 3 |
Outcome results
Primary
Number of Participants With Decreased BMI Z-score From Baseline to 6 Months
Number of participants with decreased BMI z-score from baseline to 6 months of Octreotide or Placebo therapy
Time frame: 6 months
Population: A participant withdrew but was included in analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Octreotide | Number of Participants With Decreased BMI Z-score From Baseline to 6 Months | 0 participants |
| Placebo Comparator | Number of Participants With Decreased BMI Z-score From Baseline to 6 Months | 2 participants |
Primary
Number of Participants With Decreased Skin-fold Measurements From Baseline to 6 Months
Number of participants with decreased skin-fold measurements from baseline to 6 months of Octreotide or Placebo therapy
Time frame: 6 months
Population: The skin fold measurements were performed; however, the data was not completed in a manner that could be analyzed; therefore we could not analyze the data. Completed data is not available to complete this outcome.
Primary
Number of Participants With Decrease in Fasting Total Ghrelin
Number of participants showing a decrease in Fasting total ghrelin from baseline to 6 months of treatment with Octreotide or placebo
Time frame: 6 months
Population: Descriptive statistics or percent of change from the baseline for the 5 patients was used.~A patient withdrew but included in analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Octreotide | Number of Participants With Decrease in Fasting Total Ghrelin | 1 Participants |
| Placebo Comparator | Number of Participants With Decrease in Fasting Total Ghrelin | 1 Participants |
Primary
Number of Participants With Decrease in Hunger and Food Intake
Measured by hunger and hyperphagia by questionnaires and parent-reported 72-hour food recall from baseline to 6 months. Multiple questionnaires consisting of a battery of free text answer questions and food diaries are combined in order to make a behavioral assessment of the participants food state of hunger and food intake. There is no defined scale for this assessment. Each participants responses and parent responses are combined.
Time frame: 6 months
Population: For this outcome measure, data from questionnaires and forms was not completed. Data for all questionnaires is not available to report.
Primary
Number of Participants With Decrease in Weight From Baseline to 6 Months
Number of participants who had a decrease in weight from baseline to 6 months of Octreotide or placebo therapy
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Octreotide | Number of Participants With Decrease in Weight From Baseline to 6 Months | 0 participants |
| Placebo Comparator | Number of Participants With Decrease in Weight From Baseline to 6 Months | 2 participants |
Primary
Number of Participants With Improved Adiponectin Regulation From Baseline to 6 Months
Number of participants with improved Adiponectin regulation from baseline to 6 months of Octreotide or Placebo therapy
Time frame: 6 months
Population: A participant withdrew but data was used for analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Octreotide | Number of Participants With Improved Adiponectin Regulation From Baseline to 6 Months | 2 participants |
| Placebo Comparator | Number of Participants With Improved Adiponectin Regulation From Baseline to 6 Months | 2 participants |
Primary
Number of Participants With Improved Insulin Regulation From Baseline to 6 Months
Number of participants with improved Insulin regulation from baseline to 6 months of Octreotide or Placebo therapy. Insulin regulation was measured by immunochemiluminescent assay.
Time frame: 6 months
Population: Participant withdrew but was used in the data analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Octreotide | Number of Participants With Improved Insulin Regulation From Baseline to 6 Months | 2 participants |
| Placebo Comparator | Number of Participants With Improved Insulin Regulation From Baseline to 6 Months | 0 participants |
Primary
Number of Participants With Improved Leptin Regulation From Baseline to 6 Months
Number of participants with improved Leptin regulation from baseline to 6 months of Octreotide or Placebo therapy
Time frame: 6 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Octreotide | Number of Participants With Improved Leptin Regulation From Baseline to 6 Months | 1 participants |
| Placebo Comparator | Number of Participants With Improved Leptin Regulation From Baseline to 6 Months | 2 participants |
Primary
Number of Participants With Improved Peptide YY (PYY) Regulation From Baseline to 6 Months
Number of participants with improved Peptide YY (PYY) regulation from baseline to 6 months of Octreotide or Placebo therapy
Time frame: 6 months
Population: Participant withdrew but data was used for analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Octreotide | Number of Participants With Improved Peptide YY (PYY) Regulation From Baseline to 6 Months | 1 participants |
| Placebo Comparator | Number of Participants With Improved Peptide YY (PYY) Regulation From Baseline to 6 Months | 1 participants |
Secondary
Number of Participants With Decreased Body Composition From Baseline to 6 Months by BOD POD®
Number of participants with decreased body-composition as Measured by BOD POD® body composition tracking system from baseline to 6 months of Octreotide or Placebo therapy
Time frame: 6 months
Population: Participant withdrew but data was used for analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Octreotide | Number of Participants With Decreased Body Composition From Baseline to 6 Months by BOD POD® | 2 participants |
| Placebo Comparator | Number of Participants With Decreased Body Composition From Baseline to 6 Months by BOD POD® | 3 participants |
Secondary
Number of Participants With Decreased Body-composition From Baseline to 6 Months by DEXA
Number of participants with decreased body-composition as Measured by Dual Energy X-ray Absorptiometry (DEXA) scan from baseline to 6 months of Octreotide or Placebo therapy
Time frame: 6 months
Population: Data for this outcome was not analyzed
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Octreotide | Number of Participants With Decreased Body-composition From Baseline to 6 Months by DEXA | 0 participants |
| Placebo Comparator | Number of Participants With Decreased Body-composition From Baseline to 6 Months by DEXA | 0 participants |