Intranasal Oxytocin to Promote Weight Loss in Children, Adolescents, and Adults With Brain Tumors and Hypothalamic Obesity Syndrome
Phase: PHASE2
Conditions: Craniopharyngioma, Hypothalamic Obesity
Sponsor: Shana McCormack, MD

 
 
 
 
 
 
 
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PROTOCOL SYNOPSIS 
Study Title 
Intranasal oxytocin to promote weight loss in children, adolescents, 
and adults with brain tumors and hypothalamic obesity syndrome 
Funder 
Doris Duke Charitable Foundation 
Clinical Phase 
Exploratory therapeutic trial, Phase II 
Study Rationale 
Brain tumors are the most common solid tumor in childhood (37). 
While rates of survival are improving, severe obesity is a frequent 
complication, in particular for children with tumors that affect the 
hypothalamus (32). Oxytocin (OXT) is a hormone that is produced 
in the hypothalamus (54). Although endocrinologists routinely 
replace other deficient hormones in children who have brain tumors, 
it is not current practice to replace OXT. In diet-induced obese non-
human primates, chronic exogenous OXT increases total energy 
expenditure and inhibits food intake (11), two important physiologic 
targets for the treatment of brain-tumor related obesity (8, 50). In 
humans, OXT may promote weight loss (88) and has a favorable 
safety profile in both adults and children (81). Thus, the proposed 
study has the potential to identify a rational, effective, and safe 
treatment strategy for a highly morbid condition for which no 
alternatives currently exist. For extremely obese individuals, obesity 
may be entrenched and more challenging to address.  Thus, anti-
obesity interventions may be more effective in individuals who have 
not yet developed persistent obesity, as is expected given the natural 
history of this condition. Increased cardio metabolic risk is present 
even at BMI > 85%ile or BMI > 25 kg/m2.  For this reason, we will 
include overweight and obese individuals. Moreover, the insights 
gained with respect to the pathophysiology of this highly 
recalcitrant form of obesity are expected to inform the development 
of innovative strategies to address other rare human obesity 
syndromes, as well as the more widespread epidemic of diet-
induced obesity in children (61). 
Study Objective(s) 
Primary  
 
To determine whether 8 weeks of treatment with intranasal OXT 
promotes weight loss in individuals with HypOb syndrome 
compared to 8 weeks of placebo.  
Secondary 
 
To assess the safety and tolerability of treatment with 
intranasal OXT over this duration 
 
To profile OXT serum levels (pulsatility profiling) following 
exogenous OXT vs placebo during pharmacokinetic 
measurements 

  
 
 
 
 
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 
To assess the impact of OXT on body composition and ectopic 
muscle fat.  
 
To test the impact of OXT on energy intake and cognition at 
mealtimes, including calories consumed (test meal, 3-day diet 
record) and validated measures of cognition and eating 
behaviors. 
 
To test the impact of OXT on energy output, including resting 
energy expenditure (REE), respiratory quotient (RQ), muscle 
mitochondrial oxidative phosphorylation (OXPHOS) capacity, 
body composition and muscle fat, and voluntary physical 
activity. 
 
To test the impact of OXT on mental/emotional health and 
family function, via validated assessments. 
 
To facilitate future mechanistic studies by banking biological 
specimens. 
Test Article(s) 
 
Intranasal oxytocin (Syntocinon, Novartis/Mylan Pharma) is a 
synthetic form of the hypothalamic hormone. This drug was 
previously approved in the U.S. for induction of milk let-down and 
was voluntarily withdrawn for lack of profitability. There were no 
safety concerns. The drug is currently approved and used for this 
indication in Europe from where it will be imported for the present 
study. 
Study Design 
 
Randomized, double-blinded, placebo-controlled, cross-over trial. 
Subject Population 
Key Criteria for 
Inclusion and 
Exclusion: 
Inclusion Criteria 
1) Proficient in English. 
2) Males or females age 10 to 35 years, inclusive.   
3) Weight  51 kg 
4) Girls must have a negative urine/serum pregnancy test and post-
menarchal girls must use an acceptable method of contraception, 
including abstinence, a barrier method (diaphragm or condom), 
Depo-Provera, or an oral contraceptive, for the duration of the 
study. 
5) Hypothalamic obesity, defined for the purposes of this protocol 
as: 
- 
previously diagnosed with a brain tumor* 
- 
currently overweight or obese (BMI >85%ile for age/sex for 
< 18 years, BMI > 25 kg/m2 for 18 – 35 years) 
- 
has at least one other endocrinopathy, indicating 
hypothalamic damage

  
 
 
 
 
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- 
rate of annualized weight gain during any 6 month period 
(given variability in clinical course) preceding or after 
diagnosis and treatment greater than 2 standard deviations 
above population reference ranges for age and sex (45). 
 
6) At least 6 months since completion of therapy with stable 
disease/lack of recurrence. 
7) Stable (dose adjustments of < 20% allowed) for at least 2 
months on any pituitary replacement (e.g., glucocorticoid, 
thyroid hormone, estrogen/progestin or testosterone, growth 
hormone). 
*Desmopressin is not required to be stable for at least 2 months. 
Even when taken as directed, duration of effect can vary.  
Participants with DI, taking desmopressin, are required to have 
intact thirst and be well-controlled on their current dosing 
regimen. 
8) Stable (no dose adjustments) for at least 2 months on any 
appetite-modulating medications (e.g., stimulants). 
9) Be able to ambulate independently. 
10) Parental/guardian permission (informed consent) and child 
assent. 
*In hypothalamic obesity related to brain tumors, it is the damage to 
the hypothalamus caused by the tumor itself, or its treatment 
(surgery or radiation) that leads to excess weight gain. The majority 
of such tumors will be craniopharyngioma; a minority will be 
hypothalamic astrocytomas, germinomas, or other lesions. Given 
the overall rarity of these tumors, it is not practical to stratify by 
tumor type or recruit children with only one tumor type. Instead, we 
will minimize clinical heterogeneity by applying the criteria 
proposed above with respect to endocrinopathies (indicating 
hypothalamic damage) and rapid weight gain.  
Exclusion Criteria 
Exclusion criteria and AEs will be defined based on Common 
Terminology Criteria for AEs (CTCAE), version 4.0 (33).  
1) Diabetes insipidus without intact thirst mechanism (i.e., history 
that participant is not thirsty when hypernatremic and/or 
continues to be thirsty when hyponatremic, by participant/family 
and/or practitioner report and medical records) and/or “brittle” 
diabetes insipidus, defined as requiring >1 admission in the past 
year and/or any admission within the previous 3 months.  

  
 
 
 
 
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Laboratory values: <130 or >150 mEq/L 
2) Diabetes mellitus requiring insulin or insulin secretagogue. 
Laboratory values: HgbA1c ≥8% 
3) Cardiovascular condition, as defined as any of the following: i) 
abnormal blood pressure, defined as <3%ile or >97%ile for age, 
sex and height (39) for adult participants abnormal blood 
pressure is defined as Stage 2 hypertension (systolic BP > 160 
mm Hg or diastolic BP > 100 mm Hg); ii) history of cardiac 
arrhythmia or arrhythmia detected on screening ECG; iii) 
history of heart failure and/or cardiomyopathy; iv) prolonged 
QTc interval (QTc > 460 msec), and/or long QT syndrome 
phenotype and/or positive genotype for long QT syndrome 
pathogenic mutations. 
4) Concurrent chronic use of medications known to prolong QTc 
interval and pose high risk for Torsades de Pointes (TdP) 
according to the current information available 
(www.crediblemeds.org). Concomitant medications will be 
assessed by IDS pharmacist, in collaboration with study 
cardiologist, if additional clarification is needed. In addition, we 
require that potential participants be on a stable dose for at least 
2 months of any medication with the potential to alter cardiac 
rhythm to ensure the screening ECG reflects steady-state 
physiology. 
5) History of liver disease, with screening laboratory studies: 
Laboratory values: ALT/SGPT > 3.0X ULN or AST/SGOT > 
3.0X ULN 
6) History of chronic kidney disease, with screening laboratory 
studies: 
Laboratory values: eGFR < 60 mL/min/1.73m2, as defined by 
the Schwartz formula (71) 
7) Clinically significant anemia, with screening laboratory studies: 
 
Laboratory values: Hemoglobin < 10 g/dL 
8) Seizure in the past 12 months. 
9) History of gastrectomy, gastric bypass, small or large bowel 
resection. 
10) History of active substance abuse. 

 
 
 
 
 
 
 
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11) Current psychotic disorder and/or suicidality. 
12) Supra-physiologic (>15 mg/m2/day) prescribed doses of 
hydrocortisone equivalent. 
13)  Anticipated clinical plan to initiate or modify pituitary hormone 
replacement and/or appetite-modulating drugs during the course 
of the study, at the time of enrollment.  After enrollment, 
changes to pituitary hormone replacement will be as outline in 
Section 4.8. 
14)  Any investigational drug use within 30 days prior to enrollment. 
15)  Pregnant or lactating females.  
16)  Individuals with a known sensitivity to either oxytocin or the 
components of its formulation. 
17)  Inability to take an intranasal medication (e.g., recent injury). 
18) Parents/guardians or subjects who, in the opinion of the 
Investigator, may be non-compliant with study schedules or 
procedures. 
If vital signs and/or laboratory tests initially indicate ineligibility, 
select metrics may be repeated, and if eligibility is then 
demonstrated on repeat, subject will be enrolled. Subjects that do 
not meet all of the enrollment criteria may not be enrolled. Any 
violations of these criteria must be reported in accordance with IRB 
Policies and Procedures. 
Number Of Subjects  
 
N = 150 enrolled participants (Children’s Hospital of Philadelphia); 
because parents are engaged in research, we anticipate 150 
participant-parent/legal guardian dyads, N = 20 participants with 
complete data. Adult participants, living independently, may enroll 
individually. 
Study Duration 
Each subject’s participation will last approximately 7 months. 
The entire study is expected to last 3 years. 
Study Phases 
Screening 
Study Treatment 
Participants will undergo a telephone screening and then, within 4 
weeks, complete an in-person screening visit to determine 
eligibility. Then, within 4 weeks they will be randomized and begin 
8 weeks of treatment with either OXT or placebo. After a 4-week 
“washout,” participants will cross-over to 8 weeks of treatment with 
the other condition (i.e., placebo or OXT). 

 
 
 
 
 
 
 
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Efficacy Evaluations 
Efficacy will be evaluated for each subject by the difference in body 
weight over the 8 weeks while on OXT versus the 8 weeks while 
taking placebo. 
Pharmacokinetic 
Evaluations 
During one of the CHPS-monitored doses of each of OXT and 
placebo, serial peripheral blood measurements of OXT will be 
made. 
Safety Evaluations 
i) Heart rate and blood pressure during CHPS-monitored doses of 
OXT/placebo; ii) EKG; iii) serum sodium; iv) any need to adjust 
synthetic vasopressin therapy for diabetes insipidus; v) safety 
monitoring uniform report form (SMURF) assessments (including 
potential symptoms such as fluid retention, nausea/vomiting, nasal 
irritation) 
Statistical And 
Analytic Plan 
The within-subject effect of OXT (versus placebo) on weight 
change over 8 weeks will be assessed using linear mixed-effects 
model with the outcome being the difference of the post-treatment 
weight between two periods (treatment vs. placebo), adjusted for the 
difference of the baseline weight between the two periods as 
covariate. 
DATA AND SAFETY 
MONITORING PLAN 
The PI will be responsible for data quality management and ongoing 
safety assessment. A DSMB will be convened and will meet as per 
DSMB charter.