Project Summary/Abstract
Prader-Willi Syndrome (PWS) has been designated as a rare disease by the National Institutes of Health and
is categorized as such with the NIH Office of Rare Diseases Research. [1]. Inclusion on this list requires a
prevalence of less than 200,000 people in the United States. According to the Prader-Willi Syndrome
Association USA and a review of the literature, current estimates of the prevalence of PWS range from 1:
8,000 – 1: 30,000 with the most likely prevalence falling around 1 : 15,000 individuals [2-8]. Based on current
U.S. Census data there are 317,434,622 people living in the U.S. Using the above prevalence estimates, the
prevalence of PWS ranges from 10,581 to 39,679, and the most likely prevalence is approximately 21,000
Americans [9]. Using the most current available data from the U.S. Census (2010), there are 74,181,467
people in the pediatric population in the US (age < 18 years) [10]. Assuming that the prevalence of PWS falls
between 1: 8,000 and 1: 30,000, there are currently between 2,473 and 9,273 people under age 18 with PWS.
PWS is a rare neurodevelopmental disorder caused by lack of expression of paternally derived imprinted
material on chromosome 15q11-q13. PWS is characterized by mild to moderate intellectual disabilities,
repetitive/ compulsive behaviors and rigidity, social cognition deficits and severe hypotonia at birth, followed by
the onset of hyperphagia later in life. Obesity is responsible for the majority of the morbidity and mortality
associated with PWS, and compulsive eating behaviors are most responsible for diminishing the quality of life
for caregivers and family members. Oxytocin has been implicated in the pathophysiology of PWS and there
have been small studies of intranasal oxytocin (IN-OXT) in this population. To date, however, studies have not
been adequately powered to detect significance in target symptoms of hyperphagia and associated symptoms
of individuals with PWS. The overall goal of this proposal is to study the safety and efficacy of IN-OXT on
hyperphagia as measured by the Revised Dykens Hyperphagia Questionnaire from baseline to week 8.
Currently, there are no effective treatments available to manage hyperphagia in patients with PWS.
Objective: The overall objective of this Phase 2 trial is to compare the change from baseline to week 8 of the
peptide IN-OXT on changes on the Revised Dykens Hyperphagia Questionnaire in children with PWS. We
have obtained an IND for the use of IN-OXT for PWS (IND 121109). We have acquired the IN-OXT and
matching placebo (Manufactured by Novartis as Syntocinon - see letter and COA in appendix). This Phase 2
study is designed to generate preliminary data for future Phase 3 trials, and targets symptoms in this
population that currently have no effective treatments. By treating these symptoms earlier in life in a pediatric
PWS population, we may maximize the treatment impact. This study supports the Orphan Product Divisions
goal of identifying and promoting the development of treatments indicated for a rare disease or condition.
We propose a 3 year parallel, double-blind, randomized 8 week trial of IN-OXT vs. placebo in 50 children
(stratified by gender; 25 male and 25 female) enrolled with PWS. Patients will receive a dose of 16 IU/day IN-
OXT or placebo for 8 weeks. To allow for optimization for adverse events or lack of response, we allow for
one downward titration to 12 IU, and one upward titration to 24 IU at week 2, respectively.
Specific Aims:
Primary: To compare IN-OXT vs. placebo on changes on the Revised-Dykens Hyperphagia Questionnaire
from baseline to week 8 in children with PWS. We hypothesize that IN-OXT will be significantly superior to
placebo in improving hyperphagia.
Secondary: To compare the change from baseline to week-8 of IN-OXT vs. placebo on:
1. Repetitive Behavior Scale-Revised (RBS-R).
2. Weight, BMI (z-score) and Body composition via bioelectrical impedance analysis
3. World Health Organization Quality of Life Questionnaire (WHOQOL)
4. Salivary Oxytocin Concentration
5. Safety Analyses
Exploratory:
1. To compare IN-OXT vs. placebo on changes in dietary intake using the ASA 24: Automated, Self-
Administered, 24 hour Recall diet diary system, as provided by the National Cancer Institute (NCI).
2. To examine the impact of medical co-morbidities on treatment outcome.
3. To examine the relationship between weight-based dosing and treatment response on hyperphagia.
4. To compare IN-OXT vs. placebo on changes in hormone levels at baseline and endpoint. Measured
hormones will include ghrelin, pancreatic polypeptide, peptide YY, GLP-1, insulin, glucagon, testosterone and
estrogen. We will also look at changes in HbA1C.
