Conditions: Prader-Willi Syndrome Hyperphagia
Keywords: Prader-Willi Syndrome Hyperphagia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 32
Healthy volunteers: no

Brief summary:
This study is a phase 2 randomized double blind 8-week treatment trial of intranasal OXT vs. placebo in 50 subjects aged 5 to 17 years with PWS in order to assess IN-OXT's affect on measurements of (1) eating behaviors (2) repetitive behaviors (3) weight and body composition (4) quality of life (5) salivary OXT and hormone levels (including ghrelin, pancreatic polypeptide, peptide YY, Glucagon-Like Peptide-1 (GLP-1), insulin, glucagon, testosterone, and estrogen). If superior to placebo, this data will add to the current knowledge that OXT is an effective treatment for hyperphagia as well as other symptoms of PWS.

Funding Source- FDA OOPD

Detailed description:
Prader-Willi Syndrome (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 primary goal of this study is to examine the safety and efficacy of IN-OXT on hyperphagia, as measured by the Hyperphagia Questionnaire-Clinical Trails, from baseline to week 8. Currently, there are no effective treatments available to manage hyperphagia in patients with PWS.

STUDY DESIGN: This is an 8-week double-blind, randomized study in 50 children with PWS aged 5-17. Participation involves 2 in-person visits to our program and 5 remote visits. Travel expenses will be reimbursed to participating families.

Arms:
arm 1: Syntocinon (synthetic oxytocin) will be used in this protocol. Each subject will receive a dose of 16 IU QD ("quaque die" or once a day) and will be instructed to inhale 2 puffs per nostril (4 IU each). arm 2: Each subject will receive a dose of 16 IU QD, and will be instructed to inhale 2 puffs per nostril (4 IU each).

Interventions: intervention 1: Intranasal Oxytocin (IN-OXT) intervention 2: Matched Placebo
Intervention descriptions: intervention 1: Each subject will receive a dose of 16 IU QD, and will be instructed to inhale 2 puffs per nostril every day (4 IU each). If needed, treatment will be titrated due to side effects or non-response. intervention 2: Each subject will receive a dose of 16 IU QD, and will be instructed to inhale 2 puffs per nostril every day (4 IU each). If needed, treatment will be titrated due to side effects or non-response.

Protocol document:
Prot_SAP_000.pdf: 
STUDY TITLE: "PHASE 2 STUDY: INTRANASAL 
OXYTOCIN VS. PLACEBO FOR THE TREATMENT 
OF HYPERPHAGIA IN PRADER-WILLI SYNDROME" 
IRB NUMBER: 2017-8076
NCT03197662
v.1.17
03/25/2021
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SPECIFIC AIMS
OBJECTIVE
The primary objective of this Phase 2 trial is to compare the change from baseline to week 8 of 
the peptide intranasal oxytocin (IN-OXT) on changes in hyperphagia using the Hyperphagia 
Questionnaire-Clinical Trials (HQ-CT) in children and adolescents with PWS. We have obtained 
an IND for the use of IN-OXT for PWS (IND 121109) and have acquired both the IN-OXT and 
matching placebo (Manufactured by Novartis as Syntocinon - see letter and COA of Batch in 
appendix). We will also compare the effects of IN-OXT from baseline to week-8 on repetitive 
behaviors (RBS-R), weight, BMI and body composition, quality of life (WHOQOL, Caregiver 
Strain Questionnaire), salivary oxytocin concentration, and safety measures. Safety will be 
assessed with routine laboratory monitoring, physical exam, urine pregnancy test for 
menstruating females, and collection of vital signs. The Aberrant Behavior Checklist (ABC) will 
also be used as a safety measure for both suicidality (per FDA guidelines) and for adverse 
events (aggression/temper tantrums). 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 rare diseases or 
conditions.  Our proposed treatment will target hyperphagia in subjects with PWS, a symptom 
for which there is currently no effective treatment.
This study will provide essential data that is needed for drug development and eventually drug 
approval.
We propose a three-year randomized, double-blind, placebo-controlled 8-week treatment trial of 
IN-OXT 16 IU/day in 50 subjects aged 5 to 17 years with PWS. To allow for dose optimization, 
we allow one downward titration to 12 IU if adverse events occur, and one upward titration to 24 
IU at week 2 for lack of response on hyperphagia.
Primary: To compare IN-OXT vs. placebo on changes on the Hyperphagia Questionnaire-
Clinical Trials (HQ-CT) 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).
-
We hypothesize that IN-OXT will significantly reduce repetitive behaviors from baseline 
to endpoint as measured by a reduction of the score on the RBS-R when compared to 
placebo.
-
We hypothesize that IN-OXT will significantly reduce rigid behaviors from baseline to 
endpoint as measured by a reduction of the score on the MERS-PWS when compared 
to placebo.
2.
Weight, BMI (z-score) and Body composition via bioelectrical impedance analysis
-
We hypothesize that IN-OXT will significantly reduce weight and BMI compared to 
placebo.
3.
We hypothesize that IN-OXT will significantly reduce body fat compared to placebo, as 
measured by body composition via bioelectrical impedance analysis
4.
Quality of Life Measures
–
World Health Organization Quality of Life Questionnaire (WHOQOL)
•
We hypothesize that IN-OXT will improve quality of life measured by an increase in 
overall score on the WHOQOL from baseline to endpoint when compared to 
placebo.
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-
Caregiver Strain Questionnaire (CSQ)
•
We hypothesize that IN-OXT will improve quality of life measured by a reduction in 
overall score on the CSQ from baseline to endpoint when compared to placebo.
5.
Salivary Oxytocin Concentration
-
We hypothesize that higher concentrations of salivary oxytocin will be correlated with 
positive changes on each outcome measure, indicating improvement in symptoms.
6.
Safety Analyses
-
We hypothesize that IN-OXT will not increase side-effect burden from baseline to 
endpoint compared to placebo.
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.
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Phase 2 Study: Intranasal Oxytocin vs. Placebo for the Treatment of Hyperphagia in 
Children and Adolescents with Prader-Willi Syndrome
[IND 121109 acknowledged 8/27/14]
BACKGROUND AND SIGNIFICANCE
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. Maternal duplications and triplications of the 15q11-q13 
region also account for the most frequently observed autosomal abnormalities in idiopathic ASD 
[11 – 19]. 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.
This study supports the Orphan Product Divisions goal of identifying and promoting the 
development of treatments indicated for a rare disease or condition. The proposed product is 
intranasal oxytocin (IN-OXT) (Syntocinon, manufactured by Novartis). The batch certificate of 
analysis for the product lot manufactured on 9/13/2014 and having an expiration date of 2017 
has been submitted to the IND; see letter in appendix). This proposal aims to target symptoms 
of PWS for which treatment options do not currently exist, and will provide essential data that is 
needed for product development and eventually product approval. In this Phase 2 trial of IN-
OXT we will evaluate the effectiveness of the product for individuals with PWS and determine 
the common short-term side effects and risks associated with the treatment. We have submitted 
this protocol to FDA and have received IND 121109. All required documents are on file with the 
FDA and are included in the appendix of this proposal, including the Certificates of Analysis for 
both drug and placebo, the product insert and the Container Label Statement.
We propose a three-year randomized, double-blind, placebo-controlled 8-week treatment trial of 
IN-OXT 16 IU/day in 50 subjects aged 5 to 17 years with PWS. A recent 1 week crossover trial 
by Jennifer Miller (a consultant on this proposal) using this dose of IN-OXT in PWS 
demonstrated improvement in hyperphagia, and we discuss her results, as well as our pilot data 
with this dose below. To allow for optimization, we allow one downward titration to 12 IU if 
adverse events occur, and one upward titration to 24 IU at week 2 for lack of response on 
hyperphagia.
We will determine if IN-OXT is effective in improving hyperphagia in PWS as measured by 
changes on the Hyperphagia Questionnaire-Clinical Trials (HQ-CT). We will also examine 
secondary outcomes of changes in repetitive behaviors (i.e. skin picking and nail-biting that co-
occur with hyperphagia) using the reliable and valid Repetitive Behavior Scale-Revised (RBS-
R).  We will also measure weight, BMI (z-score) and body composition (via bioelectrical 
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impedance analysis), quality of life, salivary oxytocin concentration, and safety measures in 
patients with PWS. PWS has well-known genetic targets and documented structural and 
functional lesions of the OXT neurons of the PVN. PWS is a unique and relatively genetically 
homogenous syndrome. Furthermore, IN-OXT has a favorable side effect profile and will target 
core symptoms for which there are no effective available treatments. Previous studies of IN-
OXT treatment for PWS had several limitations in study design which our group has improved 
upon, as noted above. Based on Jennifer Miller’s positive short-term trial of IN-OXT for the 
treatment of hyperphagia in PWS, we have opted to use a dose of 16 IU/day. Her study yielded 
weight based dosing of 0.2 IU/lb – 0.4 IU/lb. One patient who was underweight (32 lb) had a 0.5 
IU/lb weight based dose and experienced temper tantrums. Thus we will not enroll subjects who 
weigh less than 40lb in order to maintain weight based dosing below 0.4 lb/IU. It is 
hypothesized that lower doses of IN-OXT may reduce binding to vasopressin receptors, and 
decrease the risk of the temper tantrum side effect observed in other trials. This is consistent 
with a recent single-dose crossover trial of IN-OXT in healthy controls with a modified nasal 
delivery device demonstrated that plasma OXT levels were similar in low-dose and high-dose 
IN OXT groups and both were greater than in the placebo group, but that the low dose IN-OXT 
was superior to the high dose IN OXT and to placebo in reducing anger ratings in response to 
emotionally ambiguous faces [101]. As the two existing trials of IN-OXT in PWS have enrolled 
both males and females, and the hyperphagia symptoms of PWS are not sexually dimorphic, 
we intend to enroll both sexes in equal numbers. IN-OXT has been used safely in multiple 
human studies involving men and women and is well tolerated in both adult and pediatric PWS 
populations and we expect a similar safety profile in our proposed study.
In selecting an orphan population, PWS, with a known specific genetic locus, and in selecting a 
treatment, IN- OXT, that specifically matches the underlying deficit in the structure and function 
of OXT neurons in PWS, we expect that this study will have substantially greater power to detect 
significant drug vs placebo differences.
Hyperphagia and Obesity in Prader-Willi Syndrome: Behavioral and fMRI studies have 
demonstrated that compulsive eating in PWS is due to decreased satiety rather than increased 
hunger. The characteristic behavioral pattern of PWS begins around age four in tandem with 
the onset of hyperphagia and is characterized by obsession with food, temper tantrums, 
stubbornness, controlling and manipulating behavior, compulsive behaviors and difficulty with 
changes in routine [4, 22].These behavioral problems are the most challenging problems in 
PWS and greatly impact the quality of life of individuals with PWS and their families [23 – 25].
Several studies have determined that the eating behaviors observed in PWS are due to 
decreased satiety rather than increased hunger [33, 34]. Functional magnetic resonance 
imaging data has revealed that after eating a meal, PWS subjects display hyperfunctionality in 
the limbic and paralimbic reward regions (amygdala, NAc) that drive eating behavior, and in 
regions that suppress food intake such as the medial prefrontal cortex. They also had lower 
activity in the hypothalamus and hippocampus in response to food [38, 39]. These results 
further implicate the failure of satiety that is observed in PWS and suggest an abnormal food 
motivation phenotype that involves hyperactivation of the subcortical reward circuitry and 
hypoactivation in cortical inhibitory regions resulting in compulsive eating. Obesity secondary to 
the disordered eating behaviors that characterize the PWS phenotype also contributes to the 
increased morbidity and mortality of the syndrome.
Obesity-related cardiovascular complications and sleep apnea are among the most common 
causes of death in adults with PWS. Additionally, diabetes mellitus secondary to disordered 
eating and obesity is common [27]. The mortality rate in PWS is up to six times higher than in 
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IQ matched controls, with obesity being the main factor [28].
There is conflicting evidence relating to the levels of hormones responsible for feelings of 
satiety and hunger in PWS. Comparisons of PWS patients to BMI and adiposity-matched obese 
patients demonstrated similar responses of gut hormones fasting and post-prandial, aside from 
overall increased levels of ghrelin [36]. It is believed that the increased levels of ghrelin could be 
responsible for increased hunger, despite high levels of postprandial satiety in PWS patients. 
Other studies have demonstrated increased leptin levels, and decreased fasting pancreatic 
polypeptide levels in PWS patients compared to BMI matched patients [37]. More recently, 
ghrelin concentrations were measured across nutritional phases in a 12-year longitudinal study 
of individuals with PWS (5 weeks old to 21 years old), individuals with early onset obesity of 
unknown origin and non-obese sibling controls.  They concluded that ghrelin concentrations are 
significantly higher in early nutritional phases of PWS long before the onset of hyperphagia and 
especially during phases of poor appetite and feeding. Thus it is possible that high ghrelin 
concentrations do not contribute to the hyperphagic nutritional switch seen in PWS [102].
Clearly there are multiple neuropeptide and neurotransmitter mechanisms that can contribute to 
obesity and the onset of hyperphagia in PWS. In order to collect more information about these 
mechanisms we will measure ghrelin concentrations, as well as pancreatic polypeptide, peptide 
YY, GLP-1, insulin, glucagon, testosterone and estrogen, and HbA1C at baseline and endpoint 
to observe potential effects of IN-OXT treatment as it relates to both hyperphagia and the 
concentration of ghrelin and these other measures.
Proposed Mechanism of Oxytocin In Prader-Willi Syndrome, Hyperphagia And Obesity
Pathophysiology: Dysfunction of the oxytocin (OXT) system is implicated in the pathophysiology 
of PWS. Oxytocin (OXT) is a nonapeptide synthesized in the paraventricular (PVN) and 
supraoptic nuclei (SON) of the hypothalamus. It is proposed to play a role in social recognition, 
pair bonding, anxiety, maternal behaviors, metabolism, food motivation and hyperphagia. OXT 
receptors are expressed in numerous brain regions including the amygdala, ventromedial 
hypothalamus, and the brainstem. The number and size of OXT neurons in the PVN is 
significantly reduced in PWS [29;45].
Animal Models: Faulty OXT signaling is also associated with obesity, which is a large issue in 
the PWS population. OXT’s role in obesity has been studied in mouse models. For example, 
OXT supplementation is demonstrated to reduce food intake and body weight in a mouse 
model of diet-induced obesity [26;46]. Mice with haploinsufficiency of SIM1, a gene essential for 
the formation of the PVN, are characterized by hyperphagic obesity, similar to patients with 
PWS, and reduced OXT and melanocortin-4 receptors [46]. When OXT was administered to 
these mice, their food intake decreased and they lost weight in excess of what could be 
explained by decreased food intake alone [46]. Thus, peripheral administration of OXT has 
been shown to treat obesity by reducing food intake and visceral fat mass in a mouse model 
[26]. In addition, neuronal c-Fos expression, a marker for cell proliferation, differentiation and 
survival, increases in the NTS and AP in response to peripheral OXT. The nucleus of the 
solitary tract (NTS) and area postrema (AP) are hindbrain areas heavily involved in the 
processing of satiety signals.
In early studies of hypothalamic function, lesions of oxytocin containing hypothalamic nuclei 
were shown to result in an increase in food intake and body weight [81-84]. In the 1990s, 
several studies reported on the anorexigenic effects of central oxytocin. Low doses of oxytocin 
given intracerebroventricular (ICV) dose- dependently inhibited food intake in rats, increased 
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the latency to begin feeding and reduced meal duration in both hungry and satiated animals. 
These actions could also be blocked by oxytocin receptor antagonists [85;86]. Longer term 
central infusions of oxytocin were also reported to reduce body weight gain in rats given a high-
fat diet. However, in contrast to oxytocin’s acute effects, chronic oxytocin infusions did not alter 
total food intake or meal patterning, but instead appeared to stimulate lipid metabolism in 
adipose tissue [88]. This suggests that similar to the effect of LH/FSH in inducing puberty, a 
pulsatile release of oxytocin may be preferable than a chronic infusion administration. 
Additionally, both male and female oxytocin-knockout mice show an elevation in body weight 
and fat stores in adulthood, but as with oxytocin receptor-deficient mice, this is not due to an 
increase in food intake and is solely related to the lack of oxytocin receptors [87]. While there 
have been no published reports of humans that completely lack either oxytocin or its receptor, 
most likely due to the fact that the absence of oxytocin or its receptor is incompatible with 
successful reproduction, a partial deficiency in central oxytocin production has been associated 
with the development of obesity in humans in two documented conditions.
Data from Studies in Humans: As shown above, oxytocin and its role in obesity and food 
motivation have been repeatedly investigated at the animal model level, but in humans it has 
only been studied limitedly, despite many models that demonstrate its role in these processes. 
Fortunately, studies are currently underway to study the effect of oxytocin on food motivation in 
humans [78:NCT02276677]. Additionally, a recent study of healthy volunteers [79] showed that 
IN-OXT reduced snack intake by 25%; attenuated basal and postprandial levels of 
adrenocorticotropic hormone and cortisol; and curbed post-meal glucose elevation. Although 
data on oxytocin as a treatment for hyperphagia in humans is limited, one study in human 
subjects with PWS demonstrated that 45% of those on IN-OXT vs. 10% of those on placebo 
had reduced hunger and decreased food intake (OR = 7.85) after a single dose of 24 IU IN-
OXT [47]
Data from a Similar Disorder: Autism Spectrum Disorder (ASD): In addition to PWS, OXT 
has also been implicated in the pathophysiology of ASD, and multiple clinical trials of IN-OXT in 
this population have been completed as a result. While trials have differed in age range, 
outcome measures, dose of OXT and some studies have yielded mixed results, in general over 
different age ranges and with different outcome measures, most findings suggest some 
improvement of repetitive behavior (especially lower order repetitive behaviors) and social 
cognition with IN-OXT in ASD. Abnormalities in the neural pathways for OXT contribute to the 
behavioral manifestations of ASD [41]. Treatment with intranasal oxytocin (IN-OXT) vs. placebo 
in ASD populations has resulted in improvement in repetitive behaviors and social information 
processing deficits that are characteristic of PWS, in particular improvement was observed in 
the lower order self-stimulatory behaviors [42-44].
A recent double-blind, placebo-controlled, parallel design pilot study of 24 IU BID IN-OXT vs. 
placebo in 19 adults with ASD showed significant improvement on measures of repetitive 
behaviors, social cognition and quality of life with IN-OXT when compared to placebo [44]. 
Safety data showed no serious adverse effects, with mild to moderate irritability, nasal 
congestion/allergy symptoms, headache and increased energy reported when the patient was 
taking IN-OXT. The study included women (3/19) and after evaluating distributions to assess 
the need for data transformations, no statistical evidence of distributional concerns were found, 
therefore, no transformations were made [44]. Previous studies have shown a reduction in 
repetitive behaviors and an increased ability to assign emotion to speech intonation with titrated 
intravenous oxytocin in adults with ASD [42, 43], in addition to improved empathic accuracy in 
healthy volunteers with high scores on the Autism Quotient scale with 24 IU of IN-OXT [41].
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The safety and efficacy of IN-OXT has also been demonstrated in children and adolescents 
with ASD. Adolescents with ASD treated with open label IN-OXT with 2 month stepwise dosage 
increases (8, 16, 24 IU) showed improvement on communication and social interaction domains 
of the Autism Diagnostic Observation Schedule (ADOS) and trends in improvement on the 
social withdrawal scale of the Aberrant Behavior Checklist (ABC) and the delinquent behavior 
scale of the Child Behavior Checklist (CBCL). As in previous studies there were no serious 
adverse effects or impairments in short-term memory. This is one of the few studies 
demonstrating the safety of long term administration (6 months) of IN-OXT [54]. In a similar 
study, males aged 12 to 19 years with ASD or Asperger’s Disorder received a single challenge 
of IN-OXT (18 IU or 24 IU) one week apart.  IN-OXT was noted to improve performance on the 
Reading the Mind in the Eyes Test (RMET), with a highly significant effect on the easy items of 
the assessment [55]. As seen in prior studies there was no difference across sessions with 
regard to drug identification or in the number of reported side effects. Side effects from IN-OXT 
included feeling tired and relaxed, and sweating, while those with placebo also reported feeling 
tired and relaxed, in addition to headaches and coughing. A recent negative trial of IN-OXT in 
male children aged 7 to 16 years looked at the effect of a 24 IU or 12 IU dose over the course 
of 5 days combined with Parent-Child Interaction Therapy (PCIT).  Although there was no 
separation between placebo and IN- OXT, minimal side effects were observed, further 
demonstrating the safety of IN-OXT younger populations [56].
Previous Studies Of Intranasal Oxytocin In Prader-Willi Syndrome And Their Limitations: 
The first study showed that a single low dose of 24 IU IN-OXT vs. placebo in 24 adult patients 
with PWS (16 female and 8 male) had significant effects on reducing disruptive behaviors using 
a clinician-rated behavior grid (d = 0.72), and on increasing trust. IN-OXT was determined to be 
safe and effective. Additionally, although not statistically significant, 45% of those on IN-OXT 
vs. 10% of those on placebo had reduced hunger and decreased food intake (OR = 7.85). 
However, this study only involved a single administration of IN-OXT and did not employ any 
standardized measure to monitor food intake or behavioral measures [47].
The second study [72] enrolled 30 subjects aged 12 – 30 years (20 males and 10 females) in 
an 18-week, randomized, double-blind, placebo-controlled crossover trial. 11 subjects received 
24 IU IN-OXT BID (16 years and older) or 18 IU BID (13 – 15 years). 18 subjects received 40 IU 
BID (16 years and older) or 32 IU BID (1315 years). The study found little impact on any of its 
outcome measures (Developmental Behavior Checklist Monitor, Parent, Teacher, and Adult; 
Yale-Brown Obsessive Compulsive Scale; The Dykens Hyperphagia questionnaire; Reading 
the Mind in the Eyes Test; Epworth Sleepiness Scale and the Movie Stills). However, there was 
an increase in the number of temper tantrums (p = 0.023) on the higher doses of IN-OXT (40 
and 32 IU), which could have been due to increased binding of oxytocin to V1a receptors and 
have resulted in increased aggression.  This could also be bias against finding improvement on 
other behavioral measures.
Jennifer Miller recently completed a double-blind, placebo-controlled crossover study of IN-OXT 
vs. Pbo in 24 children with PWS. Children were randomized to receive 5 days of either IN-OXT 
followed by placebo, or vice versa, with a minimum 4-week washout between the treatment 
periods. All children were in the Phase 2b or Phase 3 nutritional phase. Results revealed that all 
scales factor improvement from Day 3 to Day 6 favored oxytocin over placebo. In addition, after 
5 days of treatment with IN-OXT, there was a 2.5 point decrease (i.e., improvement) on the 
Hyperphagia Questionnaire compared to a 1.6 point decrease on placebo. In addition, 
improvements were demonstrated on IN-OXT versus placebo on the ABC Factors of 
lethargy/social withdrawal, inappropriate speech, irritability, stereotypical behaviors and 
hyperactivity (107). Another recent multicenter trial using the oxytocin analogue carbetocin 
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conducted by Ferring Pharmaceuticals also demonstrated improvement in hyperphagia in PWS 
using the Revised Hyperphagia Scale [Personal Communication, July 2015].
Aside from Dr. Miller’s study, these previous studies of IN-OXT treatment for PWS had several 
limitations which our group intends to improve upon. Firstly, the studies had small sample sizes. 
One was a pilot study and not powered to find statistically significant changes between 
treatment vs. placebo groups. Secondly, only a single dose of IN-OXT was administered and no 
standardized measures of hyperphagia or other outcomes were used. The second study found 
no separation between treatment with placebo vs. IN-OXT at high doses on the Dykens 
Hyperphagia Questionnaire or other outcome measures. However, this study was small (n = 30) 
and the dose of IN-OXT may have been too high and have worked against detecting a signal 
for the reasons noted above. Dr. Miller’s study was also a small sample size and only dosed 
patients for 1-week with IN-OXT. Both she, and we, agree that further studies are necessary to 
look at long term effects of IN-OXT in PWS and to replicate findings at this dose of OXT.
In our currently blinded and ongoing pilot study of 16IU/day intranasal oxytocin vs. placebo, 
sponsored by the Foundation for Prader-Willi Research, we have enrolled 12 and randomized 9 
patients with PWS over the last 3 months. Our recruitment goal is 24 patients. Thus far we have 
observed minimal adverse events, with only one, polyuria, possibly related to study drug. There 
have been no serious adverse events. We have also noted positive reports of hyperphagia, 
compulsivity and other behaviors (below).
Oxytocin and Vasopressin Effects and Evidence Supporting Efficacy of Low Dose 
Oxytocin: Vasopressin and oxytocin are molecularly similar and there is some overlap in 
receptor occupancy. As vasopressin (V1a) acts to increase behavioral activation and can lead 
to aggression and irritability, occupation and thus activation of vasopressin receptors by 
oxytocin, could theoretically lead to increased aggression and irritability. Increased aggression 
and irritability could be exacerbated in individuals with PWS who are known to have genetic 
lesions of the oxytocin system. This also raises issues over ligand selectivity [90]. Oxytocin and 
vasopressin are structurally related analogs that differ by only two amino acids and share an 
evolutionary history. They also lack absolute receptor subtype selectivity and their receptor 
subtype selectivity is always relative and concentration dependent. Selectivity may be defined 
on the basis of the binding affinity of the ligand. To be ‘‘selective’’ on one receptor subtype, a 
ligand’s affinity constant on the other receptor subtypes should be at least two orders of 
magnitude higher. Thus, we posit that the increase in the number of temper outbursts observed 
in the Einfeld study [72] could have been caused by ligand promiscuity. Higher concentrations 
of oxytocin may have overwhelmed the OXT-R subtype and spilled over to bind with 
vasopressin receptors, an event that could have led to the observed increased aggression and 
irritability. This is particularly likely in the PWS population, a population known to have abnormal 
oxytocin production.  Using the lower dose of 16 IU qd in our study replicates the dose that 
yielded positive findings in children with PWS by Jennifer Miller and addresses this issue.  
Converging biological and behavioral evidence suggests that lower OXT doses may be more 
efficacious than higher doses.  For instance, compared with higher doses, lower doses 
increased peripheral levels of OXT in saliva [65] attenuated cortisol stress responses [66] and 
increased eye gaze in patients with Fragile X syndrome [67]. In animals, a low dose of OT 
administered shortly after birth increased partner preference later in life, whereas higher doses 
did not [68]. Similarly, lower doses have been associated with stronger increases in social 
recognition compared with higher doses [69,70]. The dose–response data reported for 
reduction of anger in response to ambiguous faces in healthy controls in low dose vs high dose 
IN OXT also supports the selected dose of the study.
Gender Effects of Oxytocin: Justification for Inclusion of Both Genders: While IN-OXT 
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has been shown to have a sexually dimorphic effect on social cognition measures, we do not 
believe this will be the case for the primary outcome of changes in hyperphagia on the Dykens 
Hyperphagia Questionnaire. PWS is not a sexually dimorphic disorder and all patients are 
equally affected by hyperphagia symptoms and weight gain regardless of sex. Including both 
genders in this study is a strength of our proposal. Additionally, data on the use of IN- OXT in 
females is needed. Families are already trying this treatment off-label and the evaluation of the 
use of IN-OXT in females, in any disorder, is lacking. Although it is not our primary outcome 
measure, it is also important to assess for gender effects on social cognition, which is deficient 
in individuals with PWS. Animal models have shown that low doses of OXT seem to enhance 
social recognition, [91] in both female and male rats. Although, previous studies have shown 
sexually dimorphic effects on social cognition tasks with IN-OXT administration [77], and further 
data is needed regarding this gender split in syndromes such as PWS. Nevertheless, it is 
unlikely that the same gender effects will be observed in our primary outcome measuring 
hyperphagia.
Summary: Given the limited number of trials, the lack of sufficient information about IN-OXT’s 
effects on hyperphagia, and the conflicting results with higher doses, more information is 
needed to determine whether IN-OXT is a safe and effective treatment for hyperphagia in PWS. 
Administering IN-OXT in childhood could slow or prevent the onset of obesity and reduce its 
long-term sequela.  In this study, we will determine if IN- OXT reduces hyperphagia in children 
with PWS as assessed by changes on the PWS specific Revised Dykens Hyperphagia 
Questionnaire. Secondary outcomes of changes in repetitive behaviors, weight and body 
composition via bioelectrical impedance analysis, quality of life measures, salivary oxytocin 
concentration, and safety measures will also be assessed. IN-OXT is a promising treatment for 
hyperphagia and other symptom domains of PWS, such as repetitive behaviors.
INNOVATION
This proposal shifts current drug development paradigms by selecting an orphan population, 
PWS, characterized by a known genetic and neuropathological mechanism (disruption of 
chromosome 15q11-q13 and a decreased of number and size of OXT-producing neurons in the 
PVN nuclei of the hypothalamus), and matching an available well tolerated treatment, IN-OXT, 
with a mechanism that targets the specific pathophysiology of the condition (faulty OXT 
signaling) to a specific homogeneous disorder. This novel drug development approach provides 
a substantially greater chance of detecting a drug vs. placebo signal in a more targeted and 
homogeneous population. This approach also targets the core deficits of PWS, disordered 
eating behaviors, which currently lack effective therapeutic interventions and contribute to 
disease burden and caregiver strain.
Our study will improve upon the design from the Einfeld study of IN-OXT [72] in six key 
parameters.
1.
We have lowered the dose in response to the temper tantrums side effect observed, which 
we believe is a result of excess oxytocin binding to vasopressin receptors. Additionally, a 
lower dose may have a better impact on hyperphagia issues, as discussed above.
2.
The Einfeld study [72] was a crossover design which raises issues regarding carryover and 
phase order effects, whereas our proposed study is a parallel design study.
3.
The Einfeld study [72] sample size was much smaller (n=30). Our sample size is 50 
subjects (25 vs 25).
4.
Their population was older (ranging from 12 – 30 years), whereas in our proposed 
population (5 - 17), we have the ability to intervene at an earlier stage of the illness.
5.
We only include subjects in PWS nutritional phase 2b or 3, in order to maximize severity of 
hyperphagia at baseline in our subjects. This will enhance our ability to detect a significant 
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reduction in hyperphagia for our active treatment vs placebo.
6.
We will replicate the dose from the successful trial of Jennifer Miller in childhood PWS, and 
from our current pilot trial of IN-OXT in patients with PWS.
PRELIMINARY DATA
Our group has extensive experience with IN-OXT for the treatment of ASD in clinical trials. The 
following study synopses present our findings that IN-OXT is safe, well-tolerated and effective 
in managing repetitive behaviors and social cognition deficits and improving quality of life for 
patients and caregivers.
Preliminary Study 1: Feasibility Treatment Study of Intranasal Oxytocin in Adults with 
ASD:
In a 6-week pilot study, we investigated the effects of IN-OXT on core ASD symptoms [44]. 
Nineteen high functioning patients meeting criteria for an ASD based on DSM-IV diagnoses and 
Autism Diagnostic Interview were randomized into IN-OXT 24 IU IN BID (i.e. 3 puffs/nostril 
twice daily, morning and noon) or placebo. Side effects were minimal. One patient randomized 
to IN-OXT reported side effects of fatigue and sneezing, which were mild in nature. No 
additional side effects were 
recorded for either IN-OXT or 
placebo subjects. On primary 
outcome measures, there 
were significant differences 
in performance on the 
repetitive behavior measure 
Repetitive Behavior Scale-
Revised (RBS-R) lower-
order behaviors (t = -2.17, 
df = 16.78, p = 0.045, 
Cohen’s d effect size = 0.64) 
but not on the Diagnostic 
Analysis of Nonverbal Accuracy (DANVA) or Clinical Global Impressions Severity and 
Improvement Scales (CGI-S/CGI-I). Although baseline differences were not statistically 
significant, they were somewhat large and as such the analysis was repeated with baseline 
added as a covariate. The difference in the RBS-R lower-order behaviors then showed a trend 
towards significance (t = -1.971, df = 17.18, p = 0.065). For the rest of the measures, co-varying 
for baseline did not change the conclusions of the analyses. Thirty percent (3/10) of participants 
in the IN-OXT group were rated as improved on the CGI-I, whereas 11% (1/9) of participants in 
the placebo group were rated as improved. On secondary measures, significant improvements 
were noted on the Reading the Mind in the Eyes Test-Revised (RMET-Revised), a social 
cognition measure, (t = 3.91, df = 9.01, p = 0.004, Cohen’s d effect size = 1.2) and the World 
Health Organization Quality of Life (WHOQOL) emotional subscale (t = 2.42, df = 10.89, 
p=0.034, Cohen’s d effect size = 0.84 (Table 1). The results remained significant for the RMET 
(t = 4.045, df = 10, p = 0.002) and the WHOQOL-emotional (t = 2.43, df = 12.37, p = 0.031) with 
baseline covariate. Differences did not reach significance on the Social Responsiveness Scale 
(SRS), Yale-Brown Obsessive Compulsive Scale (YBOCS), and RBS-R higher-order behaviors; 
however this pilot study in idiopathic ASD was powered to detect only very large effect sizes.
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Preliminary Study 2: Intravenous Oxytocin and Repetitive Behaviors in Adults with ASD:
We obtained preliminary support for the therapeutic effects of OXT on repetitive behaviors in 
ASD in a randomized, double-blind, placebo- controlled 
crossover challenge in which 15 adults with ASD 
completed both OXT and placebo challenges on 
separate days. Participants reported to the General 
Clinical Research Center where they spent the night 
before the challenge session; all participants fasted 
overnight. At 8:00 am participants were awoken and an 
indwelling intravenous catheter was inserted; vital signs 
were taken at 8:30 am. At 9:00 am, 6 cc3 of blood was 
drawn and participants were randomized in a double-
blind fashion to receive synthetic OXT (Pitocin) or 
placebo via intravenous infusion. The initial vial of 
Pitocin (10 u/ml), combined aseptically with a 1.0 l bag 
of normal saline, was first given at a rate of 10 ml/h to 
minimize potential side effects, and was gradually titrated up to 700 ml/h during the fourth hour. 
Participants reported the frequency of characteristic repetitive behaviors such as need to know, 
repetitive language , ordering, need to tell/ask, self-injury, and touching at baseline (0), 60, 120, 
180, and 240 minutes. Results from repeated measures analyses of variance comparing 
the two infusions (OXT vs. placebo) over the five time points revealed a significant 
Treatment x Time interaction, F = 3.487, df  = 4, 52, p = .027. Frequency of repetitive 
behaviors was reduced over time following OXT compared to placebo infusion (Figure 
1). Moreover, OXT decreased the total number of different repetitive behaviors. Side effects 
from OXT were mild and included drowsiness, anxiety, depression, headache, tingling, 
backache, trembling, restlessness, stomach cramps, and enuresis.
Preliminary Study 3: Intravenous Oxytocin and Social Cognition in Adults with ASD:
We also have preliminary data on the effects of intravenous OXT on aspects of social cognition 
in adults with ASD [43]. Patients with autism or Asperger’s Disorder received an intravenous 
infusion of OXT or placebo over a 4-hour period and ability to assign affective significance to 
speech was assessed using the ASR (see above for challenge methods) at baseline, just prior 
to the infusion, and at 30, 60, 120, 180, and 240 
minutes over the course of the infusion. In this 
task, participants were presented with four pre-
recorded sentences of neutral content (e.g., “The 
boy went to the store”); each sentence was 
presented with one of four emotional intonations 
(happy, indifferent, angry, and sad), with the 
pairing of emotional expression and sentences in 
1 of 6 counterbalanced orders. Participants were 
instructed to identify the emotional mood of the 
speaker. This task turned out to be relatively easy 
for the adult participants in this study and the 
findings were negatively skewed. To reduce the 
negative skew and better balance the difficulty of 
the task, the outcome measure was scored dichotomously as 1 (all items correct) and 0 (not all 
items correct). Results from the mixed regression analysis revealed a significant three-way 
interaction of Time x Treatment x Order for the dichotomized comprehension of affective 
speech score (z = -2.134, p = 0.033, estimate = -0.170). As depicted in Figure 2, Subjects 
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showed pretest to posttest improvement for 3 of the 4 Treatment x Order conditions (i.e. OXT 
1st, Placebo 1st, OXT 2nd), whereas for the Placebo 2nd condition, there was a slight drop in 
comprehension of affective speech from pretest to posttest (0.958 to 0.898). Thus, subjects 
who received OXT 1st showed increased levels of retention on the task, and did not show a 
tendency to revert to baseline when retested after a delay, whereas subjects who received 
placebo 1st tended to revert to baseline after the delay. The difference between predicted 
pretest scores for subjects who received placebo 2nd (0.958) and placebo 1st (0.712) is 0.246, 
which corresponds to a medium-large effect size d = 0.66.
Preliminary Study 4: Ongoing Pilot Study of IN-OXT/Placebo in Childhood PWS:
Our current pilot study of an 8-week randomized placebo-controlled double-blind trial of 16 
IU/day of IN-OXT in children and adolescents with PWS is ongoing and blinded. To date, over a 
3 month time period, we have enrolled 12 pediatric PWS subjects, and randomized 9 subjects. 
We aim to randomize 24 subjects. Although the data remain blinded at this time, we briefly 
describe reports of efficacy and side effects observed in the study thus far. The only AE noted 
in 1 blinded subject was polyuria/nocturia, of mild severity, and possibly related to study drug. 
Subjects on the blinded 16 IU/day of IN-OXT/placebo dose were noted to have the following 
responses by parent report to study clinician: 1. improvements in hyperphagia- “for the first time 
left food on the plate”, “best Thanksgiving ever”, “less asking for food”, “less freak-outs around 
food”; 2. improvements in compulsivity- “better able to transition and switch to another topic 
other than food”, “less compulsive questioning”, “less skin picking”, “less need for control”, “less 
restricted interests in stuffed animals”; and 3. improvements in other behaviors- “less anxiety”, 
“less tantrums”, “more verbal utterances”,” longer string of words”, and “more back and forth 
banter”. Of note, the study has not been complicated by unmasking of medical co-morbidities. 
There have been no tolerability or safety issues to date. Subjects have not required downward 
titration or had worsening of laboratory parameters to date.
APPROACH
Objective: The overall objective of this Phase 2 trial is to compare the change from baseline to 
week 8 of IN- OXT on hyperphagia in children with PWS. We have obtained an IND for the use 
of IN-OXT for PWS (IND 121109) and will utilize IN-OXT and matching placebo (Manufactured 
by Novartis as Syntocinon - see letter in appendix regarding batch number and certificate of 
analysis).
We will also compare the effects of IN-OXT from baseline to week-8 on repetitive behaviors 
(Repetitive Behavior Scale-Revised - RBS-R), weight, BMI (z-score), and body composition via 
bioelectrical impedance analysis, quality of life (World Health Organization Quality of Life scale 
– WHOQOL and Caregiver Strain Questionnaire -CSQ), salivary oxytocin concentration, and 
safety measures. Safety will be assessed with monitoring of routine laboratory tests and levels 
of testosterone and estrogen, physical exam, urine pregnancy test for menstruating females, 
and collection of vital signs. The Aberrant Behavior Checklist (ABC) will also be used as a 
safety measure for both suicidality (per FDA guidelines) and for adverse events 
(aggression/temper tantrums). In addition, we will monitor measures of hypogonadism and 
sleep apnea throughout the study. 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 rare diseases or conditions. Our proposed treatment 
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will target hyperphagia in subjects with PWS, a symptom for which there is currently no 
effective treatment. This study will provide essential data that is needed for drug development 
and eventually drug approval.
SPECIFIC AIMS
Primary: To compare IN-OXT vs. placebo on changes on the Hyperphagia Questionnaire-
Clinical Trials (HQ-CT) 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).
•
We hypothesize that IN-OXT will significantly reduce repetitive behaviors from 
baseline to endpoint as measured by a reduction of the score on the RBS-R when 
compared to placebo.
•
We hypothesize that IN-OXT will significantly reduce rigid behaviors from baseline to 
endpoint as measured by a reduction of the score on the MERS-PWS when compared 
to placebo.
2.
Weight, BMI (z-score) and Body composition via bioelectrical impedance analysis
•
We hypothesize that IN-OXT will significantly reduce weight and BMI compared to 
placebo.
•
We hypothesize that IN-OXT will significantly reduce body fat compared to placebo, as 
measured by body composition via bioelectrical impedance analysis.
3.
Quality of Life Measures
•
We hypothesize that IN-OXT will improve quality of life measured by an increase in 
overall score on the WHOQOL from baseline to endpoint when compared to placebo.
•
We hypothesize that IN-OXT will improve quality of life measured by a reduction in 
overall score on the CSQ from baseline to endpoint when compared to placebo.
4.
Salivary Oxytocin Concentration
•
We hypothesize that higher concentrations of salivary oxytocin will be correlated with 
positive changes on each outcome measure, indicating improvement in symptoms.
5.
Safety Analyses
•
We hypothesize that IN-OXT will not increase side-effect burden from baseline to 
endpoint compared to placebo.
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.
Research Strategy And Feasibility: We propose a three year, phase 2, randomized double-
blinded 8-week treatment trial of IN-OXT vs. placebo in 50 child and adolescent subjects (25 
male and 25 female) aged 5 to 17 years with a diagnosis of PWS. PWS diagnosis will be 
confirmed by study team via patient interview and confirmation by patient’s past medical 
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records and genetic testing results. At the screening visit, patient will have the opportunity to 
learn about the study and seek clarification on any outstanding questions. If patient voluntarily 
agree to participate, study team will work with the patients to complete the informed consent 
and if applicable, assent. In addition, a psychiatric interview and medical history review will be 
conducted to screen the patient for eligibility. The study team will also review patient’s 
concomitant medications, assess for patient condition with CGI-S and hyperphagia using the 
Hyperphagia Questionnaire-Clinical Trials (HQ-CT). If patient meets selection criteria, the study 
team will arrange on behalf of the patient for an out-patient Quest visit, at which time patient will 
be asked for a screening blood draw to provide information on CBC, BMP, LFT, IGF-1, thyroid 
panel, lipid panel, testosterone, estrogen, hemoglobin A1C, and for applicable patient, a urine 
pregnancy test. Once the screening blood work results are available and all results are within 
acceptable range, and patient is otherwise eligible, patient will be invited for an in person visit to 
clinic where additional assessments including a complete physical and neurological exam, 
intelligence test, interval health or medication change, and if applicable, repeat urine pregnancy 
test will be conducted. If patient continues to meet all study inclusion and exclusion criteria and 
agrees to continue with study participation, the study team will formally submit the patient for 
randomization.  The randomization is done in a 1:1 placebo to oxytocin ratio and stratified for 
gender. The result is blinded to the study team and the process is performed by the study 
pharmacist at the Clinical Research Pharmacy using a computer generated randomization 
table. Patients will receive a supply of oxytocin spray bottle with each spray dispensing 4 IU, or 
a matching placebo. The participant will start with an initial dose of 2 sprays per nostril (4 
sprays per day), or 16 IU/day IN-OXT or placebo. To allow for optimization for adverse events 
or lack of response, we allow for one downward titration to 12 IU (3 sprays per day), and one 
upward titration to 24 IU (6 sprays per day) at week 2. This will also allow us to examine the 
relationship between weight based dosing and treatment response. Syntocinon (synthetic 
intranasal oxytocin) and matched placebo made by Novartis will be used in this protocol. We 
have an IND for the use of IN-OXT in PWS (IND 121109).
Study Intervention: OXT and placebo will be administered intranasally. There have been 
multiple trials of IN- OXT in children, adolescents and adults with ASD, and related genetic 
disorders with ASD features, such as PWS. To date, no trials of IN-OXT in these populations 
have recorded any serious adverse effects and the treatment has been well tolerated.  We are 
choosing an initial dose of 16 IU/day, as used in Dr. Jennifer Miller’s recent successful trial and 
our current ongoing pilot trial of IN-OXT vs. placebo in children with PWS.
Inclusion Criteria:
1.
Male or female pediatric outpatients aged 5 to 17 years.
2.
Must be in PWS nutritional phase 2b or 3 as determined by PI.
3.
Must be on growth hormone treatment and have been receiving stable dose of growth 
hormone treatment for at least three months prior to screening date. Treatment cannot 
have been interrupted for more than one week within 3 months of screening.
4.
Diagnosis of PWS confirmed by exam, genetic testing and patient medical records.
5.
A score of at least moderate severity on the Hyperphagia Questionnaire-CT at both 
screening and baseline visits 
6.
Stable dosages of hormone treatments (including testosterone and estrogen 
supplements) for 4 weeks prior to randomization and for the duration of the study.
7.
Stable dosages of metabolic treatments that could affect appetite (including metformin) 
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for 4 weeks prior to randomization and for the duration of the study.
8.
Stable pharmacologic, educational, behavioral and/or dietary interventions for 4 weeks 
prior to randomization and for the duration of the study.
9.
Physical exam and laboratory results that are within the normal range for individuals 
with PWS.
10. Presence of a parent/caregiver/guardian that is able to consent for their participation 
and complete assessments regarding the child’s development and behavioral change 
throughout the study.
Exclusion Criteria:
1.
Exposure to any investigational agent in the 30 days prior to randomization
2.
Child not receiving growth hormone treatment.
3.
Children weighing less than 40 lbs.
4.
Children with unstable Type 2 Diabetes confirmed by Hemoglobin A1C level  >=6.5% 
at screening.
5.
Children with unstable medical co-morbidities at baseline.
6.
Children with active upper respiratory infections at screening.
7.
A primary psychiatric diagnosis other than ASD, including bipolar disorder, psychosis, 
schizophrenia, PTSD or MDD. These patients will be excluded due to potential 
confounding results.
8.
Pregnant or lactating patients or patients who will not agree to use a double barrier 
method of contraception. IN-OXT has not been studied in pregnant or lactating women.
9.
Females using an estrogen-based contraceptive. As an alternative to an estrogen 
based contraceptive, subjects will be counseled to use progesterone-based 
contraceptives; cervical caps; cervical sponges; or spermicidal foam in combination 
with a condom. Subjects will need to use a double barrier method to be in the study.
10. A medical condition that might interfere with the conduct of the study, confound 
interpretation of study results or endanger the subject’s well-being.
11. A known diagnosis of Rett’s Syndrome or Childhood Disintegrative Disorder or marked 
sensory impairment such as deafness or blindness.
12. Subjects who have had changes in allied health therapies, behavioral or educational 
interventions within four weeks prior to randomization other than those associated with 
school holidays.
13. Subjects who have had changes in medications or medication doses of risperidone, 
aripiprazole, other antipsychotic medications, clonidine, guanfacine, stimulants or anti-
convulsants within four weeks of randomization.
Titration Plan and Schedule: If side effects occur, the medical monitor, PI and co-I’s will 
determine if and when to titrate based on severity of the adverse event and relation to the study 
drug. If there is a significant exacerbation of known PWS co-morbidities, including Type 2 
diabetes, sleep apnea or hypogonadism, or any other adverse event rated by the study 
physician as severe, a clinical determination will be made by the medical monitor, PI and co-I’s, 
as to the patient’s eligibility to continue in the study, or to follow the titration schedule, as 
described below. Both co-investigators, Dr. Rubina Heptulla and Dr. Judith Wylie-Rosett, have 
extensive expertise in co-morbidities associated with PWS, as does consultant Dr. Moris 
Angulo.
Titration Schedule:
Adverse events: Study physician will review with study participants regarding the nature, 
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duration and severity of noted adverse events. The study physician will make clinical 
judgements on the relationship between reported adverse events with study medication. If there 
is a high likelihood of adverse events being related drug effects, the subject will titrate down 
from 16 IU/day (4 sprays per day) to 12 IU/day (3 sprays per day) and will be reassessed in one 
week). At the next assessment the side effects and tolerability will again be reviewed by the PI 
and medical monitor. If the side effects have resolved, the subject will be titrated back up to 16 
IU/day. If the side effects persist, the subject may continue on the 12 IU/day for another week; 
or will be discontinued from the study at the judgement of the PI. Subjects who do not receive 
the full dose by week four will be discontinued. Any subject who is discontinued from the study 
will be referred for continued medical follow up.
Lack of response: One upward titration will be allowed at week 2 to 24 IU/day (4 sprays per 
day) if study clinician, with consultation of the PI, determines that study subject experiences no 
response on hyperphagia via a categorical yes/no determination, and has no adverse events. In 
our current ongoing pilot study, and in Jennifer Miller’s study, the initial hyperphagia response 
was observed at the week 1 and week 2 ratings.
Instructions for Dosing: Once the cap has been removed from the spray, the device should 
be held upright to the nostril and the actuator depressed. The patient should be in the sitting 
position and should be instructed to inhale gently through the nose while the actuator is being 
depressed. The head should be tilted back once the actuator is depressed to ensure that no 
fluid runs out of the nose. Parents may assist the child with dosing.
Outcome Measures: Project outcomes will be determined by changes in scores of parent and 
clinician rated measures from baseline to week 8 and comparisons of week 8 measures 
between active treatment and placebo groups. Assessments will be administered according to 
the schedule of events in Table 2. 
Safety monitoring will be completed at each visit in both remote and in-clinic settings. 
Participant will complete concomitant medication review, adverse event (AE) monitoring, ABC 
rating, and be monitored for hypogonadism, sleep apnea and lethargy, In addition, a complete 
physical and neurological exam and full panels of clinical labs (CBC, BMP, LFT, IGF-1, thyroid 
panel, lipid panel, HbA1C, testosterone, estrogen, growth hormone, ghrelin, pancreatic 
polypeptide, peptide YY, leptin, GLP-1, insulin and glucagon) will be completed at baseline and 
week 8 in person visits. 
For participants who are able to provide salivary samples and co-operate with the collection 
process, the study team will attempt to obtain pre- and 1 hour post- study IP administration 
saliva at baseline, week4, and week 8 using the Oragene-Discover collection kit (ORG-500). 
The salivary samples will be used to measure patient oxytocin levels. 
. 
As required by the Division of Psychiatry Products and suggested by FDA review, we have also 
included the ABC-I subscale at every visit as a prospective assessment for suicidal 
ideation.The ABC will also be used to assess for adverse events, including increased 
aggression or temper tantrums. Urine pregnancy tests will be completed at every visit to ensure 
subject safety. If a subject becomes pregnant during the study, she will immediately be 
discontinued from the medication. All subjects must use abstinence or a valid method of non-
estrogen based double barrier contraception to participate in the study.
While some of these secondary measures have not been studied in PWS, we believe that they 
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are appropriate for this population as a valid measure of treatment efficacy and focus on 
important target issues of PWS – including repetitive behaviors (Repetitive Behavior Scale- 
Revised). The WHOQOL is a validated measure used to assess quality of life and has been 
used in a vast array of clinical trials in varied disorders (muscular dystrophy, hypertension, 
tuberculosis, etc.). The Caregiver Strain questionnaire (CSQ) is a commonly used and well-
validated self-report questionnaire developed to assess caregiver strain for families with a child 
living with an emotional or behavioral disorder. The ABC has been used to assess disruptive 
behaviors in other disorders such as Down Syndrome and other intellectual disabilities 
Study Time Commitment and Reduction of Burden: Every effort to reduce the time burden 
on patients and caregivers has been made. In the era of COVID-19 pandemic and travel 
restriction, we are implementing telemedicine for remote visits in some of the study visits to 
reduce patient’s potential exposure and travel, while ensure adequate study monitoring are in 
place. 
The HQ-CT, ABC, WHOQOL, CSQ, MERS-PWS and RBS-R assessments are completed with 
the parent and not the patient, as specified in the schedule of events. As is the case in most 
clinical trials, the most significant burden to the parent and child is the screening visit, which is 
done remotely and avoided participant’s need to travel. Each parent questionnaire takes 
between 5 and 25 minutes to complete and child assessments are kept to a minimum, with 
optional breaks to maximize patient comfort. Screening lab work will be done locally at 
participants nearest Quest lab. This is particularly beneficial for out of state participants. Clinical 
lab works are collected only at in person visits at baseline and week 8 during in person clinic 
visits. We have eliminated the eye- tracking measures as they are not central to our 
hyperphagia and repetitive behavior aims and to reduce burden. This ensures minimal burden 
to the family and decreases the time commitment while reducing testing bias on measures. As 
parent rated measures are questionnaires, no repeat testing bias is expected.
The time commitment and study burden is similar to other current studies in this population and 
the ASD population. If needed, visits can be split into two visits. Parents may prefer to attend a 
visit by themselves without the child to complete their measures. Visits at screening, weeks 2, 
4, 6, and 10 (follow-up) are remote visits done via tele-medicine.  The study clinicians will 
complete the video conference call with the parent. This will further reduce the family’s burden 
and decrease the amount of times they need to travel to the study site. As much flexibility in 
scheduling as necessary will be given to the patients and families. Reimbursement for time and 
travel is provided at each visit ($150 – in-person; $30 – phone visit). Additional reimbursement 
for travel will be provided as needed for families traveling long distances. The average time 
needed for parents, child and clinician to complete the assessments is detailed below. Details 
about which measures are included in each visit can be seen in Table 2: Schedule of Events. 
Some assessments require the participation of both the parent and child and times reflect how 
long each individual is needed independent of combined measures. Families may differ in how 
long it takes them to complete certain measures and the times do not include any breaks for 
meals or walking between sites at the clinic.
Screening Visit (remote):  3-4 hours 
Baseline Visit (in-person): 4-5 hours 
Week 2 and Week 6 (remote): 30 minutes 
Week 4 (remote): 2-3 hours 
Week 8 (in-person): 4-5 hours 
Week 10 Follow Up (remote): 2-3 hours
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PRIMARY OUTCOME:
Hyperphagia Questionnaire-Clinical Trials (HQ-CT): The Hyperphagia Questionnaire-Clinical 
Trials (HQ-CT) is the standard for assessing how potential therapies may impact hyperphagia in 
PWS clinical trials. It is a caregiver-rated assessment comprised of 9-items that measure and 
track the food seeking behaviors and drive for food that is associated with PWS. The HQ-CT is 
a modified version of the Dykens-Hyperphagia Questionnaire (a well-established 
questionnaire), with changes based on industry and regulatory standards (e.g., Food and Drug 
Administration, 2009). These modifications included a reduced recall period, optimization of 
response scales, and limiting item content to observable behaviors that have the potential to 
change during the course of a clinical trial. Psychometric evaluation demonstrated the HQ-CT’s 
reliability and validity, and the HQ-CT total score has demonstrated improvements in 
hyperphagia-related behavior between treatment groups in children with PWS. The HQ-CT will 
be administered at screening, baseline, and at all subsequent visits. In order to be eligible to 
participate in the trial, scores on the HQ-CT will need to be at least of moderate severity at both 
screening and baseline visits. It will take about 15 minutes to complete. 
SECONDARY OUTCOME MEASURES:
Repetitive Behavior Scale-Revised (RBS-R): The RBS-R is a 44-item self-report 
questionnaire that is used to measure the breadth or repetitive behavior in children, adolescents 
and adults with PWS. The RBS-R provides a quantitative, continuous measure of the full 
spectrum of repetitive behaviors. The RBS-R consists of six subscales including: Stereotyped 
Behavior, Self-injurious Behavior, Compulsive Behavior, Routine Behavior, Sameness 
Behavior, and Restricted Behavior that have no overlap of item content. This permits differential 
identification and scoring of discrete varieties of repetitive behaviors. Participants are asked to 
read a list of behaviors and choose a score that best describes how much of a problem the 
behavior has been of the last month. Behaviors are rated on a 4-point scale: 0 - behavior does 
not occur, 1 - behavior occurs and is a mild problem, 2-behavior occurs and is a moderate 
problem, 3 - behavior occurs and is a severe problem. On the last question, participants are 
asked to “lump together” all of the behaviors described in the questionnaire and provide a rating 
for how much of a problem these repetitive behaviors are overall on a scale from 1 – 100. 1- 
Not a problem at all to 100-as bad as you can imagine. The RBS-R measures repetitive 
behaviors that are specific to PWS symptomatology. It has been used in previous trials of 
oxytocin in adults with success, as seen in our preliminary data. It is completed by the parents 
at baseline and weeks 4 and 8 and takes approximately 25 minutes to complete.
Montefiore-Einstein Rigidity Scale-Revised PWS (MERS-PWS): The Montefiore-Einstein 
Rigidity Scale-Revised (MERS-PWS) is designed to assess three domains of rigid behavior in 
children and adults with PWS: 1. Behavioral Rigidity (e.g., insistence on sameness, things must 
be done in his/her way, etc.) 2. Cognitive Rigidity (e.g., special interests, inflexible adherence to 
rules, etc.) 3. Protest (in response to deviation from rigidity; e.g., verbal objection, tantrum, 
physical aggression) The MERS-PWS is a clinician-rated scale in that will be completed at 
baseline, week 4, week 8 and follow up and takes about 20 minutes to complete.
Weight, BMI (z-score) and Body Composition via Bioelectrical Impedance Analysis: 
Weight and BMI (z-score) will be measured at each visit using a regularly calibrated scale. Body 
composition, in particular fat mass, will also be measured at each visit using bioelectrical 
impedance analysis. The Einstein-Mount Sinai Diabetes Research Center regularly completes 
and advises on the administration of bioelectrical impedance analysis and will provide the 
necessary equipment and services for this proposal. Both subject weight and body composition 
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will serve as markers of treatment efficacy as weight and fat loss are expected outcomes of 
treatment with IN-OXT. Although it is possible oxytocin could modulate energy expenditure, 
weight and fat loss observed during the 8 week period would be a strong indicator of a 
decrease in hyperphagia. This should take 15 minutes.
World Health Organization Quality of Life Questionnaire (WHOQOL): The WHOQOL is a 
quality of life assessment developed by the WHOQOL group with fifteen international field 
centers in an attempt to develop a quality of life assessment that would be applicable cross-
culturally. The full-scale assessment WHOQOL-100 comprises 100 questions while the 
WHOQOL-BREF is a shorter version comprised of 26 items which measure the following broad 
domains: physical health, psychological health, social relationships and environment which is 
more convenient for use in large research studies or clinical trials. As seen in our preliminary 
data, it has proven to have significant change in trials with OXT and will be used to measure 
quality of life and caregiver burden in this study. PWS has a substantial impact on caregiver 
burden and quality of life. Thus, it is important to demonstrate that symptom reduction is also 
clinically meaningful. This scale, completed by parents on a bi- weekly basis, has been 
validated in other studies, including in PWS. However, WHOQOL is not a PWS- specific 
assessment. It has been used in multiple disorders including muscular dystrophy, tuberculosis 
and hypertension. WHOQOL is a parent questionnaire that will be completed at baseline, week 
4, week 8 and follow up and takes about 20 minutes to complete. This scale is completed by 
the parent and is meant to show the burden to the caregiver and the family by the disorder 
being studied, in this case, PWS.
Caregiver Strain Questionnaire (CSQ): 
The Caregiver Strain Questionnaire is a well-validated, reliable 21-item measure of self-
reported strain experienced by caregivers and families of youth with emotional problems, with 
responses on a 5-point Likert scale (0 = Not at all, 4 = very much).
Clinical Global Impression Scale – Improvement (CGI-I): The CGI-I will be used as a 
measure of improvement and contains a 7 point scale as follows: 1 = very much improved, 2 = 
much improved, 3 = minimally improved, 4 = no change, 5 = minimally worse, 6 = much worse, 
7 = very much worse. The CGI-I has been used as a measure in previous clinical 
psychopharmacology trials and will be completed by the study physician and clinician at each 
visit based upon clinical observations. It is a clinician rated global measure of improvement that 
will be completed at baseline, weeks 2 through 8 and at follow-up. It takes about 5 minutes.
Salivary Oxytocin Levels: Saliva will be collected by means of an Oragene-Discover collection 
kit (ORG-500). If able, subjects will spit saliva directly into the collection tube. If the child is 
unable to spit into the tube, we will use Oragene’s OG-AC1 assisted collection swabs to collect 
saliva from the inside subject’s cheeks. Samples will be collected pre-dose and one-hour post-
dose at baseline, week 4 and week 8. A salivary sample will also be taken at the follow up visit. 
It takes approximately 10 minutes to complete.
Justification for Measurement of Salivary Levels: We have selected salivary measures of OXT, 
since Gordon et al [73] demonstrated that salivary OXT levels are directly correlated with brain 
activity and enhancements in brain function. After administration of IN-OXT, levels of salivary 
OXT increase markedly and have been shown to remain elevated for up to 7 hours after 
administration vs. placebo. In fact, low doses (16 IU OXT) did not show weaker effects and 
tended to elevate the initial salivary OXT compared to higher doses (24 IU). Salivary OXT levels 
on placebo were highly correlated over time, indicating individual stability of OXT levels. 
Another study [100], utilized a double-blind placebo-control within-subject design. Ten subjects 
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were administered IN- OXT or placebo and salivary OXT was measured ten times over four 
consecutive hours. IN-OXT increased salivary OXT across the entire period. OXT rose 
dramatically 15 min after administration (from 6.9 pg/ml at baseline to 1265.4 pg/ml), reached 
plateau at 45—120 min (range = 131.6 and 105.3 pg/ml), and did not return to baseline by 4 h. 
The findings from these studies support target engagement in the CNS and refute the idea that 
salivary elevation results solely from movement of mucus from the nasal cavities back into the 
mouth.
We believe that plasma OXT levels are of less importance, as central and clinical effects do not 
reflect plasma PK levels, but that salivary OXT levels may be more closely correlated with CNS 
effects. We do not expect our one hour post-dose measurements to be affected by IN-OXT 
residue in the nasal cavity. As stated above, Gordon et al. [73] demonstrated salivary levels of 
OXT 30 minutes post-dose were strongly correlated with changes in brain activity and van 
IJzendoorn et al [99] demonstrated that salivary OXT levels peak 1 hour post- dose and a dose 
of 16 IU was correlated with higher salivary OXT levels than a 24 IU dose. Salivary 
concentrations are being measured at weeks 4 and 8 to determine if salivary OXT 
concentrations accumulate over time with chronic treatment of IN-OXT and to determine if the 
levels correlate with changes in clinical symptoms. We will measure both group and individual 
differences in salivary OXT concentration in addition to correlating individual salivary OXT 
concentrations at day 1 and weeks 4 and 8 with changes on the Dykens Hyperphagia 
Questionnaire. We also believe that salivary OXT concentration measurements will induce less 
discomfort than plasma measurement for the children enrolled in the study. In sum, while levels 
of salivary oxytocin remain elevated for up to 7 hours, the standard and maximum levels 
observed in prior studies was observed at the 1 hour post-treatment measurement.
IQ Test: Stanford-Binet Intelligence Scales, Fifth Edition: The Stanford-Binet will be 
administered to obtain data on adaptive behavior and intellectual functioning for correlation 
during analyses. It is a gold standard measure of intelligence used in clinical and research 
settings in those aged 2 to 85 years. The fifth edition has a 50/50 balance between verbal and 
nonverbal subtests, and the Stanford-Binet is considered the best assessment of intelligence in 
those with intellectual disability and mental retardation 12. Administration time is approximately 
5 minutes per subtest.
Dietary Assessment: Dietary intake will be assessed using the National Cancer Institute (NCI) 
24-hour automated recall method, which will be completed by the primary caregiver in 15 to 20 
minutes. Three dietary recalls (randomly assigned days to include two weekdays and one 
weekend day) will be obtained to assess pre-treatment dietary habits at baseline and repeated 
at endpoint.  The NCI nutritional program output will allow for secondary analyses of impact of 
treatment on both dietary macronutrient ratio (percent carbohydrates, proteins and fats) and 
caloric intake.
Safety Measures:
Aberrant Behavior Checklist – Irritability (ABC-I): The ABC is an informant rating instrument that 
was empirically derived by principal component analysis to measure behavior in those with 
developmental disability and ASD. It contains 58 items that resolve into 5 subscales. The 
subscales and the respective number of items are as follows: (a) irritability – 15 items, (b) 
lethargy/social withdrawal – 16 items, (c) stereotypic behavior – 7 items, (d) 
hyperactivity/noncompliance – 16 items, and (e) inappropriate speech items. The ABC was 
designed to be completed by any adult who knows the patient well, such as a parent/caregiver 
or teacher. This instrument measures behavior on a four point severity scale where 0 = no 
problem at all, 1 = behavior is a problem but in a slight degree, 2 = problem is moderately 
serious, and 3 = problem is severe in degree. As suggested by the FDA, we have included the 
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ABC-I subscale as a prospective assessment for suicidal ideation and behavior at every visit. 
Given the concern over the possibility of increased temper tantrums raised by a previous study 
of high dose IN-OXT in the PWS population, the ABC-I can also inform investigators if there are 
any trends towards increased irritability and disruptive behavior. The Division of Psychiatry 
Products (DPP) has developed a policy that all clinical protocols for products developed in DPP, 
whatever the indication, include a prospective assessment for suicidal ideation and behavior. 
Per the DPP, these assessments need to be included in every clinical protocol at every planned 
visit and in every phase of development. Collecting this data ensures that patients in clinical 
trials who are experiencing suicidal ideation or behavior are detected and adequately managed. 
This is important whether or not a particular drug is associated with treatment-emergent suicidal 
behavior. As per the recommendation of the FDA, in studies of subjects with ASD, investigators 
frequently use the ABC-I subscale to fulfill this requirement. The ABC may help identify any 
increased risk to self through observation rather than self-report. In particular, the ABC-I can be 
useful for obtaining information about treatment-emergent irritability, self-injurious behavior or 
worsening of aggressive behavior. The ABC will be completed at every visit and requires 
approximately 25 minutes.
Monitoring for Co-morbidities- The study doctor will monitor hypogonadism, sleep apnea and 
lethargy throughout the course of the study.
Hormone Levels: Ghrelin, Pancreatic Polypeptide, Peptide Y, Leptin, insulin, glucagon, GLP-1, 
Growth Hormone, Testosterone and Estrogen will be measured using blood plasma at baseline 
and endpoint.
COVID-19 Related Assessments:
COVID Stressors questionnaire: This questionnaire will be used to assess any changes in 
eating patterns or weight changes caused due to COVID-19 stressors.
Adverse Event Reporting and Measures of Compliance:
Drug accountability will be completed by the Pharmacist at the Clinical Research Pharmacy and 
will serve as a measure of study compliance. IN-OXT and Placebo nasal spray bottles will be 
weighed pre-and post- dispensing to ensure the correct amount of drug/placebo was 
administered to the patient. The pharmacist will notify the study team if a subject is non-
compliant with the study drug/placebo, and the study team will address this with the subject and 
his/her parent.
Adverse events will be reported on logs kept in the subject binder and completed by the study 
physician at each visit. Reporting requirements for the FDA (within 7 days) and the IRB (within 
5 days) will be followed for any suspected unexpected related adverse event. For any SAE the 
IRB will be notified within 24 hours, and the FDA within 48 hours.
Special Circumstances 
During special circumstances (e.g. COVID-19 pandemic), the specific guidance from local public 
health and other competent authorities regarding the protection of individuals’ welfare must be 
applied. In cases where participants are not able to perform all protocol-defined assessments 
due to special circumstances, the investigator must discuss with the medical monitor potential 
mitigation approaches.
 
For the duration of such special circumstances, the following measures may be implemented for 
enrolled subjects:
 
A. Safety follow-up may be done by a telephone call, other means of virtual contact or 
home visit, if appropriate.
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B. Patient and/or clinician-rated outcomes assessments may be done by video-conference, 
telephone call, other means of virtual contact, if possible.
C. An alternative approach for IMP dispensing, secure delivery and collection may be 
sought
D. Visits may take place in a different location than defined in the protocol. If this is not 
feasible, then the visit may take place virtually with documentation of the means of 
communication (e.g., phone call or videoconference). 
E. Biological samples may be collected and analysed at a different location than defined in 
the protocol. Biological samples should not be collected if they cannot be processed in a 
timely manner or appropriately stored until shipping/processing. 
F. If despite best efforts it is not possible to collect the biological samples or safety 
assessments (e.g. ECG, vital signs), the investigator must review the benefit-risk for 
patient continuation in the study and record this in the medical records
 
The rationale (e.g., the specific limitation imposed by the special circumstances that led to the 
inability to perform the protocol-specified assessment) and outcome of the discussion with the 
medical monitor will be documented in the medical record.  Information on how each visit was 
performed will be recorded in the eCRF.
 
Procedure
Time
Completed By
Scre
ening
(rem
ote)
Baseline
(in-person)
Week 2
(remote)
Week 4
(remote)
Week 
6
(remot
e)
Week 8
(in-
person)
Week 
10 
Follo
w Up
(remo
te)
Informed Consent
60 min
Parent/Child/Cli
nician
X
I/E Criteria
10 min
Clinician/ 
Parent
X
X
Medical Hx/Demographics
30 min
Parent/Child/Cli
nician
X
Hypogonadism/sleep apnea Hx
10 min
Parent/Child/Cli
nician
X
Physical/Neuro Exam
20 min
Clinician/ Child
X
X
Psychiatric Interview
30 min
Parent/Child/Cli
nician
X
Intelligence Test 
60 min
Clinician/ Child
X
Randomization
0 min
X
Concomitant Medications
5 min
Parent/Child/Cli
nician
X
X
X
X
X
X
X
Adverse Events/Monitoring for 
hypogonadism, sleep apnea, 
lethargy
10 min
Parent/Child/Cli
nician
X
X
X
X
X
X
X
Standard Laboratory Tests*
10 min
Clinician/ Child
X***
X
X
Hormone and Metabolic 
Laboratory Tests**
10 min
Clinician/ Child
X
X
Treatment Given
10 min
Parent/Child/Cli
nician
X
X
X
Urine Pregnancy Test (if 
appropriate)
5 min
Child/Clinician
X
X
X
Vital signs
15 min
Clinician/ Child
X
X
Eating Behavior Measures
Hyperphagia Questionnaire- 
Clinical Trials (HQ-CT)
15 min
Parent/Child/Cli
nician
X
X
X
X
X
X
X
Weight, Body Composition and 
BMI
5 min
Parent/Child/Cli
nician
X
X
Dietary Diary 
ASA24 Automated Self-
15 min
Parent
X
X
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Administered 24 Hour Recall 
Repetitive Behavior Measures
Montefiore-Einstein Rigidity Scale 
–Revised (MERS-PWS)
15 min
Clinician
X
X
X
X
RBS-R 
15 min
Parent
X 
[pre-dose]
X
X
X
Oxytocin Measures
Salivary Oxytocin Levels
10 min
Clinician/Child
X 
[pre- and 1 
hour post 
dose]
X 
[pre- and
1 hour 
post dose]
X 
[pre- and 1 
hour post 
dose]
X
Global Clinical Improvement 
and Quality of Life Measures
ABC-I  (Full ABC will be completed 
to measure this subscale)
25 min
Parent
X
[pre-dose]
X
X
X
X
X
CGI-I 
5 min
Clinician
X
X
X
X
X
CGI-S
5 min
Clinician 
X
X
WHOQOL
20 min
Parent/Child/ 
Clinician
X
X
X
X
Caregiver Strain Questionnaire
10 min
Parent
X
X
X
X
* Standard Laboratory Tests: CBC, CMP including sodium, IGF-1, thyroid panel, lipid panel, hemoglobin A1C, and urine pregnancy test
** Hormone and Metabolic Laboratory Tests: testosterone, estrogen, growth hormone, ghrelin, pancreatic polypeptide, peptide YY, 
leptin, GLP-1, insulin, glucagon 
*** To be done at local Quest 
Table 2: Intranasal Oxytocin vs. Placebo for the Treatment of Hyperphagia in Prader-Willi Syndrome
SCHEDULE OF EVENTS 
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RECRUITMENT
We have received letters of support from Theresa Strong from the Foundation for Prader-Willi 
Research, Jennifer Miller, MD, Elisabeth Dykens, PhD and Moris Angulo, MD. We are in 
communication with the local chapter of the Prader-Willi Syndrome Association USA. We have 
also collected over 40 patients who are interested in the study and meet with 
inclusion/exclusion criteria.  These patients contacted us after Dr. Eric Hollander presented at 
the Foundation for Prader-Willi Research Meeting (November 2014), Prader-Willi Syndrome 
Mental Health Strategy Workshop (March 2015) and the “Overcoming Bottlenecks in Clinical 
Trials of Investigational Medicinal Products for Hyperphagia in Prader-Willi Syndrome” FPWR 
Meeting (July 2015), all which were geared toward the development of clinical trials for this 
population.  Additionally, Dr. Hollander’s team presented at the recent Foundation for Prader-
Willi Research Meeting held in Austin, Texas. These families are very enthusiastic about 
participating in research trials.
Theresa Strong PhD, the Chair of the Scientific Advisory Board for the Foundation of Prader-
Willi Research (FPWR), is a co-investigator on this proposal, brings a wealth of research and 
clinical PWS expertise to the proposal, and is committed to aid us in recruitment. The mission of 
the Foundation for Prader-Willi Research (FPWR) is to eliminate the challenges of Prader-Willi 
syndrome through the advancement of research. FPWR has over 1,000 members, including 
families in the USA, Canada and around the world with a social media reach of >7,500 
individuals, and continues to grow rapidly. Their largest concentration of members is in the 
northeast, within quite reasonable travel distance to our institution. Their community is highly 
engaged and enthusiastic in its support of research; in fact, a recent online family survey 
indicated that more than 95% ~ 750 respondents would consider enrolling in a clinical trial. To 
ensure the successful completion of our clinical study, FPWR is committed to assisting us in the 
recruitment of participants by posting information on the FPWR website and social networks. 
They will also feature our study in their “Clinical Trials Alert” e-newsletter, which reaches 
approximately 700 families, and in their “Clinical Trials” webinar series, which is also well 
attended.
Jennifer Miller, MD is an Associate Professor in the division of pediatric endocrinology at the 
University of Florida. She graduated with her M.D. from the University of Florida in 1998, and 
her M.S. in Clinical Investigation from the University of Florida in 2005. Her research focus 
includes: investigating the effects of growth hormone treatment on brain development, sleep, 
and appetite in individuals with PWS; investigating the effects of early-onset weight gain on 
brain development; studying the sleep abnormalities in individuals with PWS; and finding 
treatments for the hyperphagia and obesity in individuals with PWS. Dr. Miller has followed 
hundreds of patients with PWS and provides ongoing advice to patients on the most effective 
and newest management strategies and treatments for handling PWS. To date, Dr. Miller has 
been at the helm of several research projects with a focus on evaluating the effects of early-
onset obesity (i.e. obesity occurring before age
5)
on the developing brain. She currently sits on the Scientific Advisory Board for the 
Foundation for Prader- Willi Research, and recently completed a clinical trial at the University of 
Florida on the effects of Intranasal Oxytocin on individuals with PWS. She follows over 450 
patients per year with PWS at the University of Florida, the largest PWS program in the country. 
Dr. Miller will serve as a consultant on this proposal and will be an integral part of the protocol 
design and study recruitment.
Elizabeth Dykens, PhD is a Professor of Psychology and Director of the Vanderbilt Kennedy 
Center for Research on Human Development, and Co-Director for the University Center for 
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Excellence in Developmental Disabilities. Her research examines psychopathology and areas 
of strength in persons with intellectual and developmental disabilities, especially those with 
genetic syndromes. Her studies focus on the development and correlates of psychopathology 
and behavioral problems in Prader-Willi syndrome, including marked obsessive- compulsive 
behaviors in Prader-Willi syndrome. Dykens also examines profiles of neurocognitive and 
adaptive strengths and weaknesses in PWS, and how these unusual profiles refine treatment 
and shed light on normal development.  Some of her current studies include looking at the 
physiological and neurological mechanisms of compulsive behavior in persons with Prader-Willi 
syndrome and the visual-spatial strengths in persons with Prader-Willi syndrome. Dr. Dykens is 
also the creator of the Dykens Hyperphagia Scale, a validated measure that has been used to 
measure hyperphagia severity in children and adults with PWS in multiple clinical trials. Dr. 
Dykens will serve as a consultant on this proposal.
Moris Angulo, MD is a pediatric endocrinologist and genetic specialist who established one of 
the largest PWS centers in the country at Winthrop University Hospital in Mineola, New York. 
Winthrop’s Division of Pediatric Endocrinology and Genetics has more than 300 patients with 
Prader-Willi Syndrome in its care and has helped to establish three local PWS group homes 
with trained personnel for the care of adult individuals. Winthrop also has parental and familial 
support groups that are run by a genetic counselor and play a key role in the management of 
the syndrome and the emotional issues in those caring for PWS children and adults. Dr. Angulo 
will serve as a consultant on this proposal.
The Prader-Willi Syndrome Association USA (PWSA): PWSA is an organization of families 
and professionals working together to raise awareness, offer support, provide education and 
advocacy, and promote and fund research to enhance the quality of life of those affected by 
Prader-Willi Syndrome.
Global PWS Registry: The Global Prader-Willi Syndrome Registry is sponsored by the 
Foundation for Prader-Willi Research (FPWR) and hosted by the National Organization of Rare 
Diseases (NORD). The primary objective of the Registry is to develop a comprehensive 
database of individuals with PWS to better understand the full spectrum of the PWS phenotype. 
Secondary objectives include accelerating enrollment in clinical trials by locating potential 
research participants quickly and efficiently. The Registry question set was developed in 
collaboration with leading clinicians in the field of PWS, including Drs. Jennifer Miller (University 
of Florida, Endocrinology); Merlin Butler (Kansas University Medical Center, Genetics); Harold 
van Bosse (Shriner’s Hospital, Orthopedic Surgery), and Tony Holland (Cambridge University, 
Psychiatry). The registry will collect data from parents/caregivers (or the person with PWS, if 
s/he is able) with respect to Demographics (including weight, height and age), Diagnosis, 
Development, Medical History (eg, endocrine, neurological, orthopedic), Medications, Behavior 
and Appetite, Mental Health and Quality of Life.
The design and implementation of the Registry was guided by current best practices in 
advocacy group- sponsored rare disease registries. To this end, Dr. Strong participated in the 
Genetic Alliance “Registry and Biobank Boot Camp” in Washington DC (2012), while Dr. 
Bohonowych attended registry-focused sessions at the annual meeting of the National 
Organization of Rare Disorders (2013) and at the annual DIA conference (2014), where she 
was a DIA Patient Advocate Fellow. Drs. Strong and Bohonowych have also consulted with 
other advocacy groups who have launched successful registries and Dr. Yaffa Rubenstein, 
Director of Patient Resources for Clinical and Translational Research, Office of Rare Disease 
Research, NCATS, NIH. The Registry protocol and informed consent have been reviewed and 
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Table 3: Adverse Event Relationship to Study Drug
approved by an Institutional Review Board (Chesapeake). A governing body consisting of the 
Registry Investigators (Drs. Strong, Bohonowych, Miller and Butler), parent advocates (2), has 
been established.
Predicted Enrollment: We expect that the Foundation of Prader-Willi Research (FPWR) and 
their Global PWS Registry to be the greatest source of recruitment for our study. There are over 
700 patients interested in participating in research that we will have access to with their Clinical 
Trials Alert newsletter. Additionally, the Global PWS Registry will collect data that will allow us 
to pre-screen patients based on our inclusion/exclusion criteria. Through Dr. Miller’s center we 
will have access to over 450 patients.  Dr. Angulo’s practice has over 300 patients with PWS. 
We have budgeted significant funding to provide travel reimbursement to patients that will need 
to travel long distances to our center and do not expect that to play an issue in the recruitment 
and enrollment for our study due to the enthusiasm of this population for clinical research. In 
total we will thus have access to, at minimum, 1450 patients and families affected by Prader-
Willi Syndrome. Even if we use an elevated pre-screening/screen failure rate of 80%, to 
account for patients that are not interested, do not meet I/E criteria, or who do not wish to travel 
to our site, we would still have access to approximately 300 patients that would be study 
eligible.
As mentioned above, we are already in contact with 40 families/patients that are interested in 
research and meet the criteria for this study. Study subjects will be drawn from the resources 
above and referrals, as well as from the diverse and large clinical practice of the PI, Dr. Eric 
Hollander. Additional recruitment methods include advertisements in local media, referrals from 
patients’ personal physicians and the clinical affiliations of the PI and collaborators. Pre-
screening/screening procedures are detailed below. Study visits have been kept to the safest 
minimum to reduce caregiver burden and travel time. Reimbursement of $150 for each in-
person visit (2 visits) and $30 for each remote visit (5 visits) will be provided, for a total of $450 
over the course of the study. This reimbursement covers compensation for time and 
reimbursement for travel expenses to the site. Additional funds have been allocated to provide 
for long-distance travel for patients outside of the tri-state area.
Timeline: We anticipate completing this study in 3 years, with 10 subjects enrolled in year 1, 20 
subjects enrolled in year 2, and 20 subjects enrolled in year 3. A 6 month start-up period will 
allow for IRB approval and an update to the IND; followed by 24 months of 
recruitment/enrollment and a 6 month period to complete data analysis and prepare for 
publication. Data will be entered into the database prospectively.
Assessment of Safety:
The safety and tolerability of the intranasal oxytocin will be determined by clinical laboratory 
results, physical examination and adverse events monitoring. Adverse Event (AE) collection will 
begin when subjects are enrolled and randomized at the baseline visit, and will occur 
throughout the study, or last study visit if the patient withdraws or is discontinued from the 
study. AEs will 
be recorded as 
volunteered by 
the patient or 
solicited 
through indirect 
questioning. An 
AE will be 
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considered “related” or “not related” to the use of the product based on the criteria listed in 
Table 3. Assessment of the causal relationship between any Serious Adverse Event (SAE) and 
study drug administration will be performed by both the Investigator and the Sponsor. If at least 
one of the parties assesses the event as related, it will be reported expeditiously as related to 
the appropriate parties (i.e. FDA and IRB). The severity of each AE should be characterized 
and then classified into one of three clearly defined categories as follows:
Mild: The AE does not interfere in a significant manner with the subject’s normal functioning 
level. It may be an annoyance.
Moderate: The AE produces some impairment of functioning, but is not hazardous to health. It 
is uncomfortable or an embarrassment.
Severe: The AE produces significant impairment of functioning or incapacitation and is a 
definite hazard to the subject’s health.
These 3 categories are based on the Site Investigator’s clinical judgment, which in turn 
depends on consideration of various factors such as the subject’s reports, the physician’s 
observations and the physician’s prior experience. The severity of the AE should be recorded in 
the source documentation. The evaluation of severity is distinguished from the evaluation of 
“seriousness.” A severe event might not meet the criteria for seriousness and a serious event 
might be evaluated as mild.
Safety Analyses: Safety will be evaluated from concomitant medications, study drug exposure, 
treatment emergent adverse events, serious adverse events, death, suicidal ideation, physical 
examinations, clinical laboratory test results and vital signs. All summaries of adverse events 
and suicidal evaluation will be presented. Serious adverse events, deaths (if any), abnormal 
laboratory results and abnormal vital signs will be listed in patient listings. All AEs will be coded 
by the system organ class (SOC) and preferred term (PT) using the Medical Dictionary for 
Regulatory Activities (MedDRA).
Non-treatment emergent AEs are defined as
●
AEs that started and resolved prior to the first study drug dosing
●
AEs that started prior to the first study drug dosing, resolved after first study drug dosing 
and the grade remained the same or reduced.
Treatment emergent adverse events (TEAEs) are defined as all AEs that begin or worsen after 
the patient receives the first dose of the study drug until follow –up. All reported AEs (including 
non-treatment-emergent adverse events) will be listed. Overall summary of TEAEs, such as 
total number of reported TEAEs, total number of patients reporting at least one TEAE, severity 
of TEAEs, relation to study drug, serious AEs, any deaths, TEAEs leading to study drug 
discontinuation, will be summarized by treatment group. In addition, TEAEs will be tabulated by 
SOC and PT. A table will contain the number of TEAEs (frequency of occurrence, number and 
percentage of patients) by treatment group will be created.
For summaries of TEAEs by maximum severity, body system, and preferred term, the rule will 
be as follows: if a patient experiences more than one episode of a particular coded adverse 
event, the patient will be counted only once by the maximum severity of these episodes 
(preferred term). Similarly, if a patient has more than one adverse event within a body system, 
the patient will be counted only once by the maximum severity among adverse events in that 
body system. For the purpose of summary of adverse events, missing severity events will be 
included in the Grade 3 (Severe) event category. Summary of TEAEs by SOC and PT will also 
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be presented fort the following categories, when data are available.
1.
Grade 3 TEAEs
2.
Related and Grade 3 TEAEs
3.
TEAES leading to study drug discontinuation
4.
Serious events
5.
Serious and related events
6.
Events resulting in death
Additional Safety Monitoring and Adverse Event Reporting Adverse events that are serious and 
unexpected will be immediately reported to the IRB, and FDA. Non-serious unanticipated 
problems will be described in annual reports to the IRB and FDA. Additionally, a pediatrician not 
affiliated with this study will serve as a medical safety monitor for this study. The safety monitor 
will review subjects’ laboratory values and adverse events on at least a monthly basis. This 
physician will be available to immediately address the clinical circumstances for any acute 
problem and will promptly notify appropriate regulatory bodies.
Independent Data Safety Monitoring Committee 
An Independent Data Safety Monitoring Committee (DSMC) will review safety and clinical 
outcome data including data on adverse events (AEs) and serious adverse events (SAEs) at 
regular intervals. They will meet biannually to review study reports.  The DSMC will be 
independent of the investigator and will be empowered to recommend stopping the study due to 
safety concerns, but not for efficacy or futility. The DSMC may review blinded, unblinded, or 
partially unblinded data, but the investigator will remain blinded until the official unblinding of the 
database.
Statistical Analyses: Analyses will be based on the intent-to-treat approach in which subjects 
are analyzed in the group to which they were originally assigned regardless of treatment 
compliance. All variables will be initially screened for inconsistent or abnormal values, and 
continuous measures will be assessed for skew and outliers. Transformations to improve 
normality will be applied when necessary. The demographic characteristics of all randomized 
patients will first be summarized using standard descriptive statistics (means, medians, 
standard deviations, and ranges for continuous variables and frequencies for categorical 
variables). Although subjects will be randomized 1:1 to the two treatment groups, imbalances in 
patient characteristics may still occur by chance given the limited sample size of the Phase 2 
trial. Between group differences in the baseline demographic and other prognostic variables will 
be assessed using the chi- square test for discrete variables and the T-test or Wilcoxon rank 
sum test for continuous variables. Baseline characteristics which are found to be significantly 
different will be considered for inclusions as potential confounders in secondary analyses of 
treatment effects.
Summary of Analytic Approach: The primary outcome measure is change on the continuous 
measure of the Hyperphagia Questionnaire-Clinical Trials, a valid and reliable measure of the 
food seeking pathology in PWS. Secondary outcome measures include a measure of repetitive 
behavior (RBS-R and MERS-PWS), weight, measures of Quality of Life and Global Functioning 
(WHOQOL, CGI), and measures of salivary Oxytocin concentration. Given that these outcomes 
are all continuous variables, they will be analyzed using the same general statistical strategy as 
outlined below.
Measurements obtained at a specific time point (e.g. 8 weeks) will be compared between the 
IN-OXT and placebo groups with the two sample t-test or Wilcoxon rank sum test. In addition, 
the change in outcome measures between baseline and 8 weeks will be compared between 
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treatment groups. Exploratory analyses will first be performed to evaluate whether the 
magnitude of changes in these variables between the two time points depends on the baseline 
value. If there is no evidence that change is dependent on baseline, then two sample tests will 
be used to compare the mean change in each variable between treatment groups; otherwise, 
analysis of covariance models will be fit to the data where the outcome is the level measured at 
8 weeks, and the main effects are treatment group and baseline value [15;37]. Adjustment for 
any patient characteristics which appear to be imbalanced across treatment groups will be 
accomplished by including the relevant terms as additional covariates into the model. To 
compare longitudinal trends in outcomes between treatment groups, linear mixed effects 
models will be fit to all repeated measures obtained during follow-up, with main effects for time 
and treatment group and a time x treatment interaction term; this is a widely used statistical 
approach in longitudinal studies of psychiatric outcomes. Appropriate data transformations, 
such as the log transform, will be applied if the data deviate from the normal distribution. 
Although a number of different outcomes will be analyzed, we will not adjust for multiple testing 
given the exploratory nature of this study.
Additional subgroup analyses will also be performed to evaluate and compare treatment effects 
in males and females. Given the limited sample size of this Phase 2 trial, however, any 
subgroup analyses will be viewed as exploratory.
Detailed Description of Analyses
Primary Analyses: Analyses for Specific Aim (1): To compare IN-OXT vs. placebo with respect 
to improvement in the hyperphagia severity in children with PWS via improvement in scores on 
the Hyperphagia Questionnaire-Clinical Trials.
The primary analysis will evaluate the hypothesis that IN-OXT will decrease hyperphagia vs. 
placebo.
1.
Response to treatment will be assessed in two ways:
a.
The effects of IN-OXT on hyperphagia will be analyzed using an intent-to-
treat approach with the two-sample T-test or Wilcoxon rank sum tests to 
compare treatment groups at specific visits as well as linear mixed effects 
models to analyze the repeated measures and changes over time.
b.
The proportion of responders in each treatment group will also be compared. 
Response will be defined as a 30% or greater decrease in food-seeking and 
eating behaviors from baseline on the Hyperphagia Questionnaire-Clinical 
Trials. Dropouts for clinical reasons will be coded as non- responders. 
Differences in the proportion of responders in each treatment group will be 
evaluated using the chi-square test and time to response will be assessed 
using survival analytic techniques.
c.
All tests will be two-tailed with an alpha level of 0.05.
Secondary Analyses: Analyses for Specific Aims (2) through (8): To compare IN-OXT vs. 
placebo in children with PWS on change in:(2 ) Repetitive behaviors via scores on the 
Repetitive Behavior Scale –Revised (RBS-R) and Montefiore-Einstein Rigidity Scale-Revised 
(MERS-PWS)(3) Weight and body composition via impedance analysis. (4) Quality of Life 
Measures on the World Health Organization Quality of Life Scale (WHOQOL)(5) Clinical Global 
Impression Scale (CGI-I) (6) Salivary Oxytocin Concentration  (7) Safety Analyses
IN-OXT and placebo groups will be compared to the above secondary measures will be 
analyzed using methods similar to those outlined above. Associations between outcome 
measures at a specific time point will be analyzed with the Spearman rank or Pearson 
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correlation coefficient.
1.
Secondary Aim (1) Repetitive Behaviors
a.
The effects of treatment on frequency and severity of repetitive behaviors will 
be assessed by fitting linear mixed effects models to the data on the RBS-R 
scores. We hypothesize that IN- OXT will significantly reduce repetitive 
behaviors from baseline to endpoint compared to Placebo.
b.
The effects of treatment on frequency and severity of repetitive behaviors will 
be assessed by fitting linear mixed effects models to the data on the MERS-
PWS scores. We hypothesize that IN- OXT will significantly reduce repetitive 
behaviors from baseline to endpoint compared to Placebo.
2.
Secondary Aim (2) Weight, BMI (z-score) and body composition via bioelectrical 
impedance analysis
a.
Weight and BMI (z-score) will be measured at each visit. It will be utilized to 
evaluate whether IN-OXT significantly modulates energy metabolism and 
reduces weight compared to placebo. Body composition via impedance 
analysis will be measured at baseline and endpoint.
3.
Secondary Aim (3) Quality of Life Measures
a.
The relationship between quality of life and treatment will be assessed using 
scores on the WHOQOL. We hypothesize that IN-OXT will improve quality of 
life from baseline to endpoint as measured by an increase in overall score on 
the WHOQOL from when compared to placebo.
b.
The relationship between caregiver strain and treatment will be assessed 
using scores on the CSQ. We hypothesize that IN-OXT will caregiver strain 
from baseline to endpoint as measured by an reduction in overall score on the 
WHOQOL from when compared to placebo.
4.
Secondary Aim (4) Salivary Oxytocin Levels
a.
Both group and individual differences in salivary OXT concentration will be 
measured. Correlations between individual salivary OXT concentrations at 
day 1 and weeks 4 and 8 as well as correlations between OXT and changes 
in our primary outcome measure, hyperphagia assessed by the Dykens 
Hyperphagia Questionnaire, will be evaluated using the Spearman rank or 
Pearson correlation.  Additional correlation analysis will be performed on 
salivary oxytocin levels and secondary outcome measures: RBS-R, 
WHOQOL and CGI-I. We hypothesize that higher concentrations of salivary 
oxytocin will be correlated with positive changes on each outcome measure, 
indicating improvement in symptoms.
5.
Secondary Aim (5) Safety Analyses
a.
Rates of specific side effects and other adverse events will be tabulated and 
compared between treatment groups using the chi-square test.  Please see 
the section labeled “Safety Analyses” for further details on how adverse 
events will be monitored and rated.
b.
The relationship between frequency of suicidal behaviors will be assessed on 
the ABC-I to evaluate whether IN-OXT vs. placebo is associated with a 
change in the irritability subscale of the ABC-I which serves as a surrogate for 
suicidal ideation in this population.
Additional Analyses
1.
Sample size permitting, we will explore the potential for ethnicity-by-treatment 
interactions. If effects of minority status are found that might be clinically meaningful, 
even if not statistically significant, we will report these to guide future research. 
Please see the Planned Enrollment Table for the breakdown of anticipated 
percentages of children of each ethnicity that will be enrolled.
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2.
We will test for gender by treatment interactions.
3.
We will explore IQ by treatment interactions.
4.
We will explore for co-morbidity (e.g. Type 2 Diabetes, Hypogonadism etc.) by 
treatment interactions.
5.
We will explore for weight based dosing by treatment interactions.
Missing data: In any clinical trial, some subjects will be lost to follow up or will miss study 
visits but the expected rate is low given that this is only an 8 week trial. Primary analysis will be 
based on available data at each time point. The advantage of the linear mixed effects 
approach is that it can handle data which are missing at random and measurement times 
which are not evenly spaced. However, when the missingness mechanism depends on 
unobserved information, i.e., non-ignorable, parameter estimates and resulting tests on 
hypotheses will be biased without further adjustment. Different approaches for handling 
missing data will be performed in this study. Multiple imputation will be applied if missing data 
rates are observed to differ across observed covariates. Regardless of the technique, 
characteristics of patients who are lost to follow-up will be compared to those that remain in the 
study to assess the degree of any selection bias, and sensitivity analyses will be performed to 
evaluate robustness of conclusions to the different missing data approaches.
Power Analysis: Sample size justification: The target sample size for this Phase 2 trial is 25 
patients per treatment group. The power for the study has been calculated to generate a 
detectable signal with the sample size of 50 subjects.  With this sample size,  the study will 
have 80% power to detect a minimum effect size of d= 0.8 standard deviations in the outcome 
measures between groups using a two-sample T-test and a two sided Type I error rate of 5%. 
The study is powered based on a conservative estimate from a heterogeneous population. We 
expect that in this homogeneous PWS population selected to match study drug to underlying 
mechanism, the true power will exceed the conservative estimate. This minimum detectable 
difference is smaller than the treatment effects observed in our previous studies of IN-OXT in 
adults with ASD, which demonstrated an effect size of d=1.2 on a social cognition measure 
(RMET) [3], and an effect size of d = 0.84 on a quality of life measure (WHOQOL) [3]. In 
addition, our previous study of a V1a antagonist in adults with ASD demonstrated an effect 
size of d=0.8 on a social cognition measure (ASR Lust) [80], and an effect size of d = 0.8 on an 
Eye Tracking measure (Biological Motion Preference) [90]. The above effect sizes observed in 
our pilot data were based on a heterogeneous sample of ASD patients characterized by over 
100 known different genetic contributing factors. In the proposed trial, both males and females 
will be included, and any heterogeneity in outcomes due to gender may attenuate overall 
treatment differences. However, by selecting an orphan population (PWS) with a single unique 
genetic contribution, and selecting a treatment that matches the known molecular mechanism 
(IN-OXT), we expect that the treatment effects in this study will nevertheless be greater than 
the effects observed in earlier studies.
Data Management: The Biomedical Research Informatics Core (RIC) of the Institute for 
Clinical and Translational Research (ICTR) at Einstein and Montefiore will be used to create 
and manage the database for the trial. The RIC supports the clinical data pipeline for both 
Einstein and Montefiore including supporting EDC tools, customized databases and a solution 
to securely link patient specimens to clinical and pathological data. Database programming will 
begin at the study start date, and will be ready by the 6 month milestone mark, when study 
enrollment begins, so that data can be entered prospectively as subjects move through the 
study. Data will be encoded using unique patient identifiers, and not patient names. IDs will be 
assigned sequentially, in a manner unrelated to name or other easily identifiable information. 
Data will be entered for both screened and randomized subjects to allow analyses to assess 
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the degree to which randomized subjects may differ from other potential subjects. Periodic 
reports on recruitment, treatment, retention and follow up will be generated and reviewed by 
the study team. All subject files will be kept in a locked room at the study site. Another ICTR 
core, the Biostatistics and Study Design Core, directed by Mimi Kim, ScD, will be responsible 
for the statistical support of the study, including the final data analysis. The PI will meet 
regularly with the study team, including staff from the two ICTR cores, to review the status of 
the study and devise any strategies needed to meet the study goals.
Ethical Considerations: Parents/caregivers of potential participants that are referred or 
indicate interest in the study will be phone screened by trained staff to determine eligibility.  If 
there are no clear exclusionary criteria, a consent form will be sent and an appointment will be 
set up to discuss the benefits and risks of study participation, duration of study, alternative 
treatment options and to answer any questions about the study.
When all questions are answered and the parent/caregiver and their child, when appropriate, 
indicate that they understand the study, written informed consent and/or assent will be 
obtained. Child assent/consent will be obtained as appropriate to age and capacity determined 
by the study physician/psychologist. Consent procedures will be completed by a trained 
member of the study staff and will be reviewed by the PI.
Risks: Studies have shown risks of IN-OXT to be minimal with no difference in AE burden 
between IN-OXT and placebo [46].  The most common categories of side-effects seen include:
●
increased calmness/euphoria or more energy
●
light headedness
●
drowsiness/fatigue
●
headache
●
nasal irritation
●
dry mouth/throat
As noted above, one study of IN-OXT in PWS noted increased levels of aggression, via temper 
tantrums, at higher doses of IN-OXT.  As very few studies have reported on the extended use 
of IN-OXT there may be other unknown side effects, although our 6-week studies showed no 
difference in AEs. Other risks relate to venipuncture procedures for blood sampling taken at 
key points in the study as a safety measure. Blood draws and anthropometric measures will be 
completed at the CTSA sponsored Clinical Research Center (CRC), which has trained nursing 
and lab staff. In addition, patients may feel uncomfortable answering some of the questions 
presented during the assessments and breaks will be provided if needed. There is a risk of 
loss of confidentiality, although every step is being taken to keep patient files and data secure. 
All data is locked in staff offices or on staff computers and only authorized personnel or 
organizations indicated in the consent (IRB; FDA etc.) will have access.  Pediatric neurologist 
Aleksandra Djukic, MD, PhD is the independent medical monitor and will review side effects 
after each study visit to ensure subject safety and to determine if a subject’s participation 
should be terminated due to an AE.
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