Clinical trial NCT02849743
Conditions: Craniopharyngioma Hypothalamic Obesity
Keywords: oxytocin hypothalamic obesity craniopharyngioma metabolism
Sponsor: Shana McCormack, MD
Start date: 2016-10-01; Completion date: 2022-05-01
Enrollment: 18 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This research study will test if oxytocin, delivered by nasal spray, will promote weight loss in children, adolescents, and adults with Hypothalamic Obesity as compared to a placebo. The study is divided into two parts. During the first part, subjects will receive either oxytocin or placebo. In the second part, subjects will "cross-over" to receive the other treatment - either oxytocin or placebo. During study visits participants will do blood tests, physical exams, metabolic testing, a MRI scan, and some surveys and questionnaires.

Detailed description:

Arms: arm 1: Week 0 to Week 7: Intranasal oxytocin, administered 3 times per day (at mealtimes) for 8 weeks (dosage based on weight: 16 IU to 24 IU; dose escalation, if appropriate, occurs at 2 weeks)

Week 8 to Week 11: Washout

Week 12 to Week 20: Intranasal placebo, administered 3 times per day (at mealtimes) for 8 weeks (dosage based on weight: 16 IU to 24 IU; dose escalation, if appropriate, occurs at 2 weeks)

\*Dose Escalation, as appropriate, at 2 Weeks arm 2: Week 0 to Week 7: Intranasal placebo, administered 3 times per day (at mealtimes) for 8 weeks (dosage based on weight: 16 IU to 24 IU; dose escalation, if appropriate, occurs at 2 weeks)

Week 8 to Week 11: Washout

Week 12 to Week 20: Intranasal oxytocin, administered 3 times per day (at mealtimes) for 8 weeks (dosage based on weight: 16 IU to 24 IU; dose escalation, if appropriate, occurs at 2 weeks)
Interventions: intervention 1: Syntocinon intervention 2: Placebo (for Syntocinon)
Intervention descriptions: intervention 1: The active substance of Syntocinon is a synthetic nonapeptide identical to the posterior pituitary hormone oxytocin. intervention 2: The placebo is identical to the Syntocinon formulation with the exception of the active compound, i.e., without oxytocin.

Protocol documents:
ICF_002.pdf: 
CHOP IRB#: IRB 16-012730
Effective Date: 10/21/2020
Expiration Date: 10/20/2021
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Informed Consent Form and HIPAA Authorization
Study Title: 
Intranasal oxytocin to reduce excess weight gain in children, adolescents, 
and adults with brain tumors and hypothalamic obesity syndrome
Version Date:  
July 25, 2018
Consent Name:
Main Study Consent
Principal Investigator:
Dr. Shana McCormack, MD
Office: (215) 590-3174
Emergency: (617) 596-9067
You, or your child, may be eligible to participate in a research study. This form provides 
important information and describes the purpose of this research study, including the 
risks and possible benefits of participating. 
If there is any information in this form that you do not understand, please ask questions. 
Please take your time. You do not have to participate in this study if you do not want to. 
If you participate, you can leave the study at any time. 
In the sections that follow, the word “we” means the study doctor and other research team 
members. If you are a parent or legal guardian who is providing permission for a child, 
please note that the word “you” refers to your child.
Why are you being asked to participate in this study?
You are being asked to participate in this research study because you have had treatment 
for a brain tumor and have also struggled with easy weight gain. This condition is called 
“hypothalamic obesity syndrome”.
What is the purpose of this research study? 
The purpose of this research study is to determine if intranasal oxytocin (the hormone 
oxytocin delivered through a nasal spray solution) will promote weight loss in children, 
adolescents, and adults with brain tumors and hypothalamic obesity syndrome.
The hypothalamus is a part of the brain involved in the production of hormones in the 
body, including oxytocin. In individuals with hypothalamic obesity syndrome, the 
production of oxytocin may be too low. Oxytocin is important for the body’s metabolism, 
or use of energy. Low oxytocin could be a cause of easy weight gain in people with 
hypothalamic obesity syndrome.
In previous studies, oxytocin seems to promote weight loss. It also has been studied in 
other health problems without major side effects in either children or adults when used 
appropriately. Therefore, we are determining if using an intranasal spray of synthetic 
oxytocin will safely promote weight loss compared to placebo (no oxytocin).
We will be administering an investigational drug called “Syntocinon”, a synthetic form of 
oxytocin. Although it is not currently approved by the FDA, Syntocinon was previously 
approved for a different indication in the United States and there were no major safety 


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concerns. Syntocinon is currently approved in Europe for a different indication, from 
where it will be imported for this study. Syntocinon has not been used previously in 
hypothalamic obesity syndrome.
How many people will participate?
About 30 individuals will participate in this treatment study at the Children’s Hospital of 
Philadelphia. We anticipate we will need to screen around 150 individuals to enroll this 
number of eligible participants.  Children and adolescents will be enrolled along with 
their parents.  Adult participants, living independently, may enroll individually.
What is involved in the study?
How long will you be in this study?
If you agree to participate, your participation will last for about 7 months and will involve 
9 study visits. If there are safety concerns, extra visits may be required. 
What are the study procedures? 
The study involves the following tests and procedures. Although some procedures will 
occur at every study visit, some procedures will occur only once or twice during the study 
period. Prior to each study visit, we will carefully review your upcoming procedures.
Screening Visit: We will conduct an in-person screening visit to confirm your eligibility. 
If you are determined ineligible, you will not be able to continue with 
study procedures.
Pre-Test Fasting: You will be asked to fast overnight prior to some study visits with 
fasting tests. While fasting, you can drink water and take prescribed 
medications.
Medical Interviews/Questionnaires: A study team member will review and record your 
medical history, along with a listing of your current medications.
In addition, you will complete study questionnaires and surveys—they 
will be related to your mental and emotional health, quality of life, 
cognitive function, level of appetite, and eating behaviors.
Physical Examination: A routine physical examination will be completed at each study 
visit (i.e., listening to your heart and lungs, feeling your abdomen, testing 
brain and nerve function, etc.). We will also measure weight, height, 
abdominal dimensions, and vital signs (blood pressure, heart rate, 
respiration rate, etc.). Finally, a study doctor will perform Tanner staging, 
which is a physical examination method to measure sexual development.  
Tanner staging is not required, and will not be performed, on adult 
participants.
Blood Test:
During the study, blood samples will be collected from you for laboratory 
testing by safely drawing blood from your arm—we will draw no more 
than 90 mL (approximately 18 teaspoons), or 3 cc/kg, whichever is less, of 
blood over the entire study period.  By agreeing to participate in the study, 
you agree to provide these blood samples to CHOP for research purposes.


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In addition, at certain study visits, blood samples will be obtained for 
pharmacokinetic (PK) analysis. We will safely place an intravenous line to 
draw your blood over a period of time during your visit.
Urine Testing: During the study, we will collect urine samples from you in a clean cup 
for laboratory testing. By agreeing to participate in the study, you agree to 
provide these urine samples to CHOP for research purposes.
Stool Sample Collection (Optional): We will ask you to collect a teaspoon-size amount of 
fresh stool in a clean container.
3-Day Diet Log: We will ask you to write down every item you have to eat or drink for 3 
days prior to four of the study visits.
Pregnancy Test: A pregnancy test will be administered to all female study participants. 
These confidential results will be shared with you but not your 
parents/legal guardians. We strongly recommend that you share the results 
with your parents/legal guardians. If you become pregnant, you will not be 
able to continue participating in this study.
You will need to practice safe methods (such as not having sexual 
intercourse, or using a medically accepted form of contraception) to 
prevent pregnancy while you are using oxytocin. If you have questions 
about how to avoid pregnancy, talk with your study doctor or the research 
team and they will provide you with information regarding contraceptive 
options. You should inform your study doctor at once if you become 
pregnant during this study.
Study Medication: Syntocinon, a brand of synthetic oxytocin, and a placebo will be 
administered via intranasal spray during the study period. The placebo is a 
similar-looking intranasal spray, but has no oxytocin.
This is a randomized crossover study—participants will be randomly 
assigned to first take oxytocin (Group 1, below) or to first take placebo 
(Group 2, below).
Each participant holds an equal 50-50 chance of taking oxytocin first or 
placebo first.
Once you are assigned, you will undergo 8 weeks of intranasal oxytocin 
treatment (Group 1) or 8 weeks of placebo (Group 2).
After the first 8 weeks, you will then enter a 4-week “washout” period, 
when you will stop taking either oxytocin or placebo.
After the 4-week washout period, you will “crossover” into the other 
group for another 8 weeks. In other words, if you started taking oxytocin, 
you will then take placebo (Group 1).  If you started taking placebo, you 
will then take oxytocin (Group 2).
Group 1: Oxytocin 

Washout (No Treatment)

Placebo 
------------------------------------------------------------------------------------------------------------
Group 2: Placebo

Washout (No Treatment)

Oxytocin 


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Over the course of the study, each participant will receive both oxytocin 
and placebo, but at different times.
Hand-Grip Dynamometry: Muscle strength will be measured using a hand-grip strength 
dynamometer. You will squeeze the handle on the device with each hand 
and the strength of the "squeeze" will be measured. This measure will take 
approximately 5 minutes to complete and does not involve any radiation.
Resting Energy Expenditure (REE) and Respiratory Quotient (RQ) Test: REE measures 
the amount of calories burned while at rest, and RQ measures how much 
carbon dioxide and oxygen are being used. After an overnight fast and 
sitting comfortably, participants will complete a 60-minute REE/RQ test. 
This involves sitting still in a large hood and breathing in regular, clean 
room air while watching a movie or listening to music.
DXA Scan: 
A special x-ray of the body called a “DXA scan” will be completed to 
measure body composition (i.e., the amount of muscle, fat, and bone) and 
bone mineral density. During the DXA scan, you will be asked to lie flat 
on your back on a table as the machine scans your body. The scan occurs 
for less than 5 minutes.  If there is any reason that you cannot have a DXA 
scan, you may still participate in the study.
Electrocardiogram (ECG): ECG measurements will be completed to check if there are 
any problems with the electrical activity of your heart before and during 
treatment. Extra ECG measurements may be recommended if any 
concerns develop during the study period.
MRI:
Over the entire study, we will ask you to complete 2 MRI scans during 
two separate study visits to measure how your muscles are using energy. 
There is no contrast substance and no sedation. An MRI scan session may 
last between 2 to 3 hours, but you will spend no more than 90 minutes in 
the MRI machine. During the session, we will ask you to perform a brief 
light leg exercise.  You will be asked to press down on a pedal, similar to a 
car accelerator or piano foot pedal, approximately 90 times, or as many as 
you are able, over a 2 minute period. If there is any reason that you cannot 
or do not wish to have an MRI scan, you may still participate in the study.
Stop-Signal Task: This consists of two short tests (together, about 25 minutes) completed 
on a computer where you are asked to press buttons according to test 
instructions. It tests how your brain responds to different signals.
Eye Tracking and EEG Measures: This is a short test (about 15-20 minutes) where you 
will be asked to wear both eye-tracking glasses (Tobii Pro Glasses or Pupil 
Eye Tracking Headset) to track your eye movements and the EPOC+ 
device, whenever possible, to record your brain waves.  If you are not able 
to wear both devices, then we will ask you to wear only the eye-tracking 
glasses.  Information collected from these devices, for example eye gaze 
information (where and how fast you look) and EEG (brain waves, EEG 
rhythms), will supplement behavioral data collected from questionnaires 
and other study activities.  This is an optional procedure at the 3 visits 


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during the study.  If you do not wish to complete this procedure, you may 
still participate in the study.
Mixed Meal Test: We will ask you to order a free study meal before the study visit. We 
will give you this meal to eat during the visit after a dose of either 
oxytocin or placebo. 
Adverse Events Assessment: Our study team will contact you by telephone and see you at 
in-person visits throughout the study to discuss how you are feeling on 
the medication. This is to help make sure you stay safe during your 
participation.
Some of the procedures in this study will be repeated several times. Tests that are part of 
your usual medical care will continue to be completed. We will do our best to coordinate 
any blood draws for your clinical care with our study blood draws. Additional tests or 
procedures may be recommended if we have any concerns about your safety during the 
study, including to follow-up on abnormal results, for example.
What are the other study procedures (for parents)?
The study also involves the following procedures for parents, when enrolled with 
children or adolescent participants.
Questionnaires: You will complete questionnaires related to your child’s current health 
status and factors that affect quality of life at 7 in-person visits, plus any additional safety 
visits that are needed.
*****
The following visit schedule table describes the schedule of key study procedures for individuals 
with hypothalamic obesity syndrome:
Study Visits*
Day
Study Procedures
Duration
Visit 0: Screening 
-28 
Informed consent, medical history review, physical 
examination, questionnaires, ECG, laboratory 
tests, pregnancy test, eye-tracking/EEG
6 hours
Visit 1: Block Start
0
Randomization, medical history review, physical 
examination, ECG, 3-day diet log, laboratory tests, 
pregnancy test, PK analysis or Stop-Signal, study 
medication dispensed
8 hours
Safety Check
2 (-1/+2)
Review Safety Monitoring Uniform Report Form, 
Facilitate laboratory test
30 minutes
Visit 2: Dose 
Escalation
14 (+ 3)
Medical history review, physical examination, 
questionnaires, ECG, laboratory tests, pregnancy 
test, PK analysis or Stop-Signal, study 
medication dispensed
6 hours
Safety Check
16 (-1/+2)
Review Safety Monitoring Uniform Report Form, 
Facilitate laboratory test
30 minutes
Visit 3: Interim
28 (+ 4)
Medical history review, physical examination, 
questionnaires, ECG, laboratory tests, pregnancy 
test, study medication dispensed
6 hours


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Safety Check
42 (+ 5)
Review Safety Monitoring Uniform Report Form, 
Facilitate laboratory test
30 minutes
Visit 4: Block End
56 (+ 6)
Medical history review, physical examination, 3-
day diet log, questionnaires, ECG, REE/RQ, DXA 
scan, MRI, pregnancy test, eye-tracking/EEG
6 hours
Washout Period, then Group “Crossover”
Visit 5: Block Start
84 (+ 6)
Medical history review, physical examination, 3-
day diet log, questionnaires, ECG, laboratory tests, 
pregnancy test, PK analysis or Stop-Signal, study 
medication dispensed
6 hours
Safety Check
86 (-1/+ 2)
Review Safety Monitoring Uniform Report Form, 
Facilitate laboratory test
30 minutes
Visit 6: Dose 
Escalation
98 (+3)
Medical history review, physical examination, 
questionnaires, ECG, laboratory tests, pregnancy 
test, PK analysis or Stop-Signal, study 
medication dispensed
6 hours
Safety Check
100 (-1/+ 2)
Review Safety Monitoring Uniform Report Form, 
Facilitate laboratory test
30 minutes
Visit 7: Interim
112 (+ 4)
Medical history review, physical examination, 
questionnaires, ECG, laboratory tests, pregnancy 
test, study medication dispensed
6 hours
Safety Check
126 (+ 5)
Review Safety Monitoring Uniform Report Form, 
Facilitate laboratory test
30 minutes
Visit 8: Block End
140 (+ 6)
Medical history review, physical examination, 3-
day diet log, questionnaires, ECG, REE/RQ, DXA 
scan, MRI, laboratory tests, pregnancy test, eye-
tracking/EEG
6 hours
Unscheduled Study 
Visit**
Medical history review, physical examination, ECG, 
laboratory tests, pregnancy test
6 hours
*Telephone calls will occur throughout the study period to complete adverse event assessments
**Unscheduled study visit if needed
Your Current Medications:
During the study, you will be allowed to continue with your current medications. It is 
very important that you tell us at the beginning of the study which medicines you are 
currently taking (both prescription and non-prescription drugs), including dietary 
supplements, herbs, and vitamins. Any changes in medications during the study period 
must be reported to the study team.


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What are the risks of this study?
Participating in a research study involves inconveniences and risks. If you have any 
questions about the possible risks listed below, you should talk to your study doctor or 
your primary care provider/family physician.
Like all medicines, the active medication may cause side effects in some people.
For this specific indication and route of administration, the risks associated with 
oxytocin:

Irritation of the nose (nasal mucosa)

Uterine contractions in females

Nausea, vomiting, headache

Cardiac arrhythmias (abnormal heart rhythms)

Fluid retention, low sodium levels

Skin rashes, allergic reactions

Induction of labor in pregnant women

Changes in blood pressure- high blood pressure
In addition, if you have diabetes insipidus and are taking a form of desmopressin, 
oxytocin may have some of the same effects as desmopressin. This could increase the 
chances of your body holding on to extra water and developing low sodium levels. Low 
sodium levels, if left untreated, can cause very serious health consequences, including 
seizures and hospitalization, even death. For this reason, we will be monitoring 
symptoms and sodium levels closely. You may need to reduce the amount of 
desmopressin you are taking while also taking oxytocin. We will carefully review your 
response to oxytocin by telephone and at in-person visits, including with testing of 
sodium levels, so we can help you and your usual endocrinologist adjust the dose of 
desmopressin, if needed.  Desmopressin may be administered in an intranasal form.  In 
order to avoid any confusion with study medication we will provide guidance regarding 
identifying medication containers and will review administration instructions at each visit 
when study drugs is dispensed.
If oxytocin is administered along with medications known for potential QT interval 
prolongation, there is an increased risk of abnormal heart rhythms associated with drug-
induced long QT syndrome.  Your current medications will be reviewed by the study 
team.  If you have any questions about medications that you are taking, please ask the 
study doctor.
Because this drug is experimental, there may be other side effects that we do not know 
about yet. If you experience any other side effects, inform your physician or our study 
team. All clinically significant side effects will be immediately treated. At any time 
during your participation, if you feel that you are experiencing ANY side effects 
from the study medication contact a member of the study team immediately.


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If you are prescribed any new drugs during the study, you must notify the study doctor. 
Also notify the study doctor of any new over-the-counter drugs, supplements, herbal 
products, and vitamins.
If you require a clinical blood test, inform the doctor or nurse that you are actively on an 
oxytocin regimen, as it may affect clinical test results.
Reproductive Risks
For female participants, if you are pregnant or nursing, you cannot participate in the 
study due to the study drug and exposure to radiation.  All female participants, will be 
given a pregnancy test before starting this study and at each study visit (9 times) during 
your participation.   The results will be shared with you (the child) and not with your 
parent(s).  We encourage you to tell your parent(s) the results.  If you are found to be 
pregnant, then you will not be able to continue participation in the study.
You and your partner will need to practice safe methods (such as abstaining from sexual 
intercourse or using a medically accepted form of contraception) to prevent pregnancy 
through the duration of the study. If you have questions about preventing pregnancy, the 
study doctor, Dr. Shana McCormack, will be able to discuss your choices and methods. 
In addition, if you become pregnant during the study, you must immediately contact Dr. 
McCormack.
Risks associated with other study procedures:
Medical Interviews/Questionnaires: There are no physical risks, but in-person and 
telephone interviews may cause temporary discomfort or embarrassment. You do not 
have to answer any questions that cause you to feel uncomfortable. These will be 
performed in private. In addition, if your mental and emotional health surveys reveal 
serious mental health problems, we may require or recommend mental health services.
Fasting: Fasting may cause discomfort and hunger.  We will schedule the study 
procedures as to reduce the amount of fasting time. If you feel unwell fasting before the 
study, you can stop fasting at any time.
Physical Examination: Potential risks include fatigue, feelings of anxiety and frustration, 
and discomfort. Tanner staging will be completed in a private room to protect your 
privacy.
Blood Test: Arm pain, bruising, bleeding, blood clot formation, and in rare instances, an 
infection might occur at the site where blood is drawn. There is also the possibility of 
dizziness or fainting while your blood is drawn.
Stool Sample Collection (Optional): Providing a stool sample may cause embarrassment 
and discomfort.
Urine Test: You may feel embarrassment or discomfort.
Pregnancy Test: Potential risks include feelings of discomfort and anxiety.
Hand-Grip Dynamometry: The hand-grip dynamometer test may result in mild, temporary 
hand or forearm discomfort.  
REE/RQ Test: There are no known risks associated with the measurement of resting 
energy expenditure.


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DXA Scan:  You will be exposed to minimal radiation during the DXA scan. However, 
this is a very minimal dose of radiation.  This radiation dose is not necessary for your 
medical care and will occur only as a result of your participation in the study.  At doses 
much higher than you will receive, radiation is known to increase the risk of developing 
cancer after many years.  At the doses you will receive, it is very likely that you will see 
no effects at all.
ECG: There is a risk of skin irritation, redness, or swelling developing from the 
placement of ECG electrodes on your chest if you are allergic to adhesives. 
Hypoallergenic electrodes can be used. 
MRI Scan: There are no known physical risks associated with MRI scanning. However, 
MRI machines produce loud noises, which may cause discomfort and irritation. We will 
provide you with earplugs or earphones to quiet the noise. You may also feel 
uncomfortable lying inside the magnet due to claustrophobia or inability to lie still. If you 
become anxious, you can tell us and we will remove you from the machine.
The MRI magnet is always activated and attracts certain metal objects. Any metal object 
on or inside of your body may heat up, move, and/or improperly function within the 
scanning room. Metal objects in the room can fly through the air toward the machine 
(magnet) and hit those in the area. However, there are many safety measures to prevent or 
reduce these risks.
Stop-Signal Task: There are no known physical risks for this procedure, but you may 
experience temporary embarrassment, frustration, anxiety, or discomfort.
Eye Tracking and EEG Measures:  There are minimal physical risks for this procedure.  
Wearing the Tobii Pro eye glasses and/or the EPOC+ device may cause some temporary 
discomfort.
Mixed Meal Test: The study meal could cause allergic reactions if you eat something to 
which you are allergic. We will carefully screen for food allergies prior to the study visit 
to ensure that the meal is prepared without known allergens. If you feel ill during your 
meal, we will remove the meal and observe you for any symptoms.
Incidental Findings: It is possible that during the course of the study we will find new 
health problems. If this happens, we will discuss them with you and help to review your 
best options with your usual physicians.
Actionable Findings: If your mental and emotional health surveys reveal indications of 
serious mental health problems or suicidal ideation, we may require or recommend 
mental health services.
There may be other risks that are not known at this time. Immediately inform the study 
doctor or a research team member if you experience any problems.
Are there any benefits to participating in this study?
This research study includes procedures that may change the treatment you would 
otherwise receive. The study drug may help reduce excess weight gain. It may also 
improve cognitive and emotional health and quality of life, independent of weight 
changes. Although your condition may improve while participating in this study, this 


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cannot be guaranteed. Future patients with hypothalamic obesity syndrome may benefit 
from the knowledge gained from this clinical trial.
Do you need to give your consent in order to participate? 
If you decide to participate in this study, you must sign this form. A copy will be 
provided to you for your personal records.
What are your responsibilities?
Please consider the study time commitments and responsibilities as a study participant 
when deciding about your participation in this clinical trial. You will need to follow the 
study doctor’s directions, attend all study visits, and take the study drug as instructed.
What happens if you decide not to participate in this study? 
Participation in this study is voluntary. You do not have to participate in order to receive 
care at CHOP.
If you decide not to participate or if you change your mind later there will be no penalties 
or loss of any benefits to which you are otherwise entitled.
Can you stop your participation in the study early?
You can stop participating in the study at any time. You do not have to provide a reason.
Can the study doctor remove you from the study early?
The study doctor may remove you from the study if:

Your condition worsens.

The study is stopped.

The study drug is no longer available.

You no longer meet all the requirements of the study.

New information suggests participating in this study may not be in your best 
interests.
What choices do you have other than this study?
There are options for you other than this study including:

Continuing to receive your usual clinical care

Not participating in this study

You may discuss other options available to you with your doctor.
What about privacy, authorization for use of Personal Health Information (PHI), 
and confidentiality? 
As part of this research, your health information will be collected. This will include 
information from past and present medical records, study procedures/tests, and interviews 
that are part of this research. Information related to your medical care at CHOP will go in 
your medical record. This could include laboratory test results, ECG results and some 
MR images, except for tests that are performed for this research only. Medical records are 


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available to CHOP staff. Staff will view your records only when required as part of their 
job. Staff are required to keep your information private. Information that could identify 
you will not be shared with anyone - unless you provide your written consent, or it is 
required or allowed by law. We will do our best to maintain your privacy and confidential 
status. However, we cannot guarantee absolute confidentiality. Your personal information 
may be disclosed if required by law. 
The results of this study may be shown at academic and medical meetings and published 
in scientific journals to inform other doctors and health professionals. We will not reveal 
your identity in any publication or presentation.
Several people and organizations may review or receive your identifiable information. 
They will need this information to conduct the research, to assure the quality of the data, 
or to analyze the data or samples. These groups include: 

Members of the research team and other authorized staff at CHOP;

People from agencies and organizations that perform independent accreditation 
and/or oversight of research, such as the Department of Health and Human 
Services, Office for Human Research Protections; 

Doris Duke Charitable Foundation who is funding this research; and

The Food and Drug Administration
By law, CHOP is required to protect your health information. The research staff will only 
allow access to your health information to the groups listed above.  By signing this 
document, you are authorizing CHOP to use and/or release your health information for 
this research. Some of the organizations listed above may not be required to protect your 
information under federal privacy laws. If permitted by law, they may be allowed to share 
it with others without your permission.  
There is no set time for destroying the information that will be collected for this study. 
Your permission to use and share the information and data from this study will continue 
until the research study ends and will not expire. Researchers continue to analyze data for 
many years and it is not possible to know when they will be completely done. 
To help us protect your privacy, we have obtained a Certificate of Confidentiality from 
the federal Food and Drug Administration. With this Certificate, the researchers cannot 
be forced to disclose information that may identify you, even by a court subpoena, in any 
federal, state, or local civil, criminal, administrative, legislative, or other proceedings. 
The researchers will use the Certificate to resist any demands for information that would 
identify you, except as explained below.
The Certificate cannot be used to resist a demand for information from personnel of the 
United States Government that is used for auditing or evaluation of Federally funded 
projects or for information that must be disclosed in order to meet the requirements of the 
federal Food and Drug Administration (FDA).
You should understand that a Certificate of Confidentiality does not prevent you or a 
member of your family from voluntarily releasing information about yourself or your 
involvement in this research. If an insurer, medical care provider, or other person obtains 


CHOP IRB#: IRB 16-012730
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Expiration Date: 10/20/2021
Page 12 of 19
your written consent to receive research information, then the researchers will not use the 
Certificate to withhold that information.
The Certificate of Confidentiality does not prevent the researchers from disclosing 
voluntarily, without your consent, information that they are required by law to disclose to 
government authorities. For example, researchers must comply with laws requiring the 
reporting of suspected child abuse and neglect, intent to hurt self or others, and 
communicable diseases.
Can you change your mind about the use of personal information?
You may change your mind and withdraw your permission to use and disclose your 
health information at any time. To revoke your permission, it is preferred that you inform 
the investigator in writing. 
Shana McCormack, MD
The Children’s Hospital of Philadelphia
The Division of Endocrinology and Diabetes
34th Street and Civic Center Boulevard
Philadelphia, PA 19104
In the letter, state that you changed your mind and do not want any more of your health 
information collected. The personal information that has been collected already will be 
used if necessary for the research. No new information will be collected. If you withdraw 
your permission to use your personal health information, you will be withdrawn from the 
study.
You will be informed if changes to the study are needed to protect your health. You will 
be informed of any new information that could affect your willingness to remain in the 
study, such as new risks, benefits or alternative treatments. 
Financial Information 
While you participate in this study, the cost of your usual medical care – clinical 
procedures, medications and doctor visits – will continue to be billed to you or your 
health insurance.
Will there be any additional costs? 
There will be no additional costs to you by participating in this study.
The Doris Duke Charitable Foundation will provide financial support for the following 
research procedures, medications, and study visits: 

The study drug and placebo

Study procedures performed at each visit

Cost of travel, parking and meals
Will you be paid for participating in this study?
The compensation provided at each visit, is designed to cover the cost of travel, parking, 
and meals as well as your time and effort.  Additional compensation will be provided, if 


CHOP IRB#: IRB 16-012730
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Page 13 of 19
Unscheduled Visit(s) or Additional Safety Check Assessment(s) are required during your 
participation.  You and your parent/legal guardian will be compensated according to the 
following study visit schedule:
Study Visits
Participant
Dollar Amount
Parent/Legal 
Guardian 
Dollar Amount
Total
Visit 0: Screening
$75
$25
$100
Visit 1: Block Start
$100
$50
$150
Safety Check
$25
-
$25
Visit 2: Dose Escalation
$50
$25
$75
Safety Check
$25
-
$25
Visit 3: Interim
$50
$25
$75
Safety Check
$25
-
$25
Visit 4: Block End
$100
$50
$150
Visit 5: Block Start
$100
$50
$150
Safety Check
$25
-
$25
Visit 6: Dose Escalation
$50
$25
$75
Safety Check
$25
-
$25
Visit 7: Interim
$50
$25
$75
Safety Check
$25
-
$25
Visit 8: Block End
$100
$50
$150
Total
$ 825
$325
$1,150
Unscheduled Visit 
or
Additional Safety 
Check
$25
-
$25
If you are below 18 years of age (age 10-17), your family will be compensated according 
to the above schedule, however all funds will be placed on a single bank card for you and 
your family.
If you are 18 years of age or older (age 18-35), you will receive a bank card for yourself.  
A separate bank card will be issued to your parent/legal guardian, if applicable  
Adults who enroll individually will receive the compensation amounts as outlined in the 
“Participant Compensation” column above and will not receive the additional 
“Parent/Legal Guardian” compensation.


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Page 14 of 19
If you receive payment with a bank card, the bank will have access to identifiable 
information. The bank will not have access to any medical information.
If you have any questions regarding the payment schedule, we can provide additional 
details in regard to the allocation of family costs, parent/legal guardian compensation, 
and/or subject compensation.
For non-local participants/families, travelling from outside a 100 mile radius of CHOP, 
we will reimburse eligible travel expenses up to a maximum of $1,500 during the course 
of your participation in the study.  We can provide additional details about eligible 
expenses and travel reimbursement guidelines.
Who is funding this research study?
The Doris Duke Charitable Foundation will provide funding to support this study.
Please contact Dr. McCormack if you have any questions about how this study is funded. 
What if you have questions about the study?
If you have questions about the study, contact the study doctor, Dr. McCormack at (215) 
590-3174. You may also talk to your own doctor if you have any questions or concerns.
The Institutional Review Board (IRB) at the Children’s Hospital of Philadelphia has 
reviewed and approved this study. The IRB reviews research studies to protect research 
subjects’ rights and welfare. If you have questions about your rights or if you have a 
complaint, you can contact the IRB Office at (215) 590-2830. 
A description of this clinical trial will be available on http://www.clinicaltrials.gov, as 
required by U.S. law.  This website will not include information that can identify you.  At 
most, the website will include a summary of the study’s results.  You can search this 
website at any time. 
What happens if you are injured during the study?
If you become hurt or sick from any procedure that was done as part of this study, doctors 
at the clinic or hospital can arrange for emergency medical care. The hospital does not 
offer financial compensation or payment for injuries due to participation in this research. 
You and your health insurance company will be billed for the costs of any care or 
injuries. 
If you think you have been injured from participating in this study, contact Dr. 
McCormack at (215) 590-3174. She can review any concerns with you, inform you of 
resources that may be available, and provide information on what you need to do.
In case of injury resulting from this study, you will not lose any legal rights by signing 
this form.


CHOP IRB#: IRB 16-012730
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Expiration Date: 10/20/2021
Page 15 of 19
Optional Consent for Disclosure of Participation and Results to the Participant’s 
Personal Physician for Clinical Use
Please indicate whether you grant permission to have the study disclose your 
participation and results to your personal physician for clinical use by signing next to one 
of the following choices:
__________ (Initials) I agree to the disclosure of my participation and results to my 
personal physician for clinical use.
__________ (Initials) I DO NOT agree to the disclosure of my participation and results to 
my personal physician for clinical use.
Optional Consent for MRI Scan
Please indicated whether you wish to participate in the MRI scans for the study:
__________ (Initials) I agree to complete the study MRIs.
__________ (Initials) I DO NOT agree to complete the study MRIs.
Optional Consent for Eye Tracking and EEG Measures
Please indicated whether you wish to participate in the Eye Tracking and EEG 
Measurements for the study:
__________ (Initials) I agree to complete the Eye Tracking and EEG.
__________ (Initials) I DO NOT agree to complete the Eye Tracking and EEG.


CHOP IRB#: IRB 16-012730
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Optional Consent for Stool Sample Collection and Storage for Future Research
With your permission, we will collect a teaspoon-size amount of fresh stool in a clean 
container.
We may wish to use these samples for analysis in the current study and for future 
microbial testing.  The samples will be given a unique code and will not include 
information that can identify you.  Coded samples will be stored in a secured laboratory 
freezer at CHOP.  Information that can identify you or your stool samples may be kept 
permanently on a secured shared drive at CHOP.  Only the study doctors and authorized 
CHOP personnel will have access to information that could identify you.
Results will not be disclosed to you, but they may contribute to knowledge for future 
research studies. If you leave the study, you can ask to have your samples destroyed.  You 
can also ask us to remove information that identifies you from the samples.
Please indicate whether you grant permission to have the study collect and store your stool 
sample for future microbial testing by signing next to one of the following choices:
__________ (Initials) I agree to the collection and storage of my stool sample for future 
research.
__________ (Initials) I DO NOT agree to the collection and storage of my stool sample 
for future research.
Optional Consent for Blood Sample Collection and Storage for Future Research
As a part of the study, we will collect blood samples.  We may wish to use these samples 
for future analysis related to energy balance and metabolism research studies.  The 
samples will be given a unique code and will not include information that can identify 
you.  Coded samples will be stored in a secured laboratory freezer at CHOP.  Information 
that can identify you or your blood samples may be kept permanently on a secured shared 
drive at CHOP.  Only the study doctors and authorized CHOP personnel will have access 
to information that could identify you.
Results will not be disclosed to you, but they may contribute to knowledge for future 
research studies. If you leave the study, you can ask to have your samples destroyed.  
You can also ask us to remove information that identifies you from the samples.  
Please indicate whether you will allow your blood samples for future research by signing 
next to one of the following choices:
__________ (Initials) I agree to the collection and storage of my specimens for future 
research.
__________ (Initials) I DO NOT agree to the collection and storage of my specimens for 
future research.


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Optional Consent to be Contacted for Future Research Studies
Please indicate whether you grant permission to be contacted for future research studies 
by signing next to one of the following choices:
__________ (Initials) I agree to be contacted for future research studies.
__________ (Initials) I DO NOT agree to be contacted for future research studies.


CHOP IRB#: IRB 16-012730
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Page 18 of 19
Consent to Participate in this Research Study and Authorization to Use and 
Disclose Health Information for the Research
The research study and consent form have been explained to you by:
Person Obtaining Consent
Signature of Person Obtaining Consent
Date
If you, the subject and are consenting to participate in the study: 
By signing this form, you are indicating that you have had your questions answered and you 
agree to take part in this research study. You are also agreeing to let CHOP use and share 
your health information as explained above.
If you, the parent or legal guardian, you are consenting for yourself and to allow your 
child/adult to participate in the study:
By signing this form, you are indicating that you have had your questions answered, you agree to 
take part and to allow your child or the adult to take part in the research study, and you 
are legally authorized to consent to your child’s or the adult’s participation. You are also 
agreeing to let CHOP use and share the health information that will be collected for this 
study, as explained above. If you don’t agree to the collection, use and sharing of health 
information, you cannot participate in this study. NOTE: A foster parent is not legally 
authorized to consent for a foster child’s participation.
Name of Subject
Signature of Subject (18 years or older)
Date
Name of Authorized Representative 
(if different than subject)
Relation to subject:
 Parent  
 Legal Guardian
 Legally Authorized Representative
Signature of Authorized Representative
Date
 


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Child/Adult Assent to Participate in this Research Study
For children (or adults with diminished capacity) capable of providing assent:
I have explained this study and the procedures involved to __________________ in 
terms he/she could understand and that he/she freely assented to participate in this study.
Person Obtaining Assent
Signature of Person Obtaining Assent
Date
This study has been explained to me and I agree to participate.
Signature of Subject
Date
For children (or adults with diminished capacity) unable to assent: 
I certify that __________________ was not capable of understanding the procedures 
involved in the study sufficiently to assent to study participation. 
Person Responsible for Conducting 
Assent
Signature of Person Responsible
Date

Prot_000.pdf: 
 
 
 
 
 
 
 
012730 S. McCormack Protocol AM11v.08/20/2019 
viii
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 


  
 
 
 
 
012730 S. McCormack Protocol AM11v.08/20/2019 
ix
 
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


  
 
 
 
 
012730 S. McCormack Protocol AM11v.08/20/2019 
x
- 
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.  


  
 
 
 
 
012730 S. McCormack Protocol AM11v.08/20/2019 
xi
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. 


 
 
 
 
 
 
 
012730 S. McCormack Protocol AM11v.08/20/2019 
xii
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). 


 
 
 
 
 
 
 
012730 S. McCormack Protocol AM11v.08/20/2019 
xiii
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.  

SAP_001.pdf: 
Title: 
Intranasal oxytocin to promote weight loss in children, adolescents and 
adults with brain tumors and hypothalamic obesity syndrome 
NCT: 
NCT02849743 
Date: 
30-June-2021 
 
 
 


This document describes our plans and rationale for analysis of the intranasal oxytocin (OXT) weight loss 
trial data (NCT02849743). This document has been generated before un-blinding. Specifically, we review 
the a priori defined primary and secondary outcomes, and provide the preplanned analysis including 
sensitivity analyses to support the findings reported in the main text. We offer these details to further the 
goals of reproducible research. Analyses were performed with RStudio (v.1.4.1103).  
1.0. Definition of the Endpoints 
 
1.1. The primary endpoint will be the change in body weight over 8 weeks during OXT versus placebo 
treatment. 
 
1.2. Secondary endpoints will include the following: 
• 
Cognitive restraint (stop-signal task) after monitored dose of OXT versus placebo  
• 
Calories consumed (as a percentage of calories offered) during a test meal after a monitored dose 
of OXT versus after a monitored dose of placebo  
• 
The change in arm circumference, over 8 weeks during OXT versus placebo 
• 
The change in waist circumference, over 8 weeks during OXT versus placebo 
• 
The change in hyperphagia (Hyperphagia Questionnaire), hunger, disinhibition of eating, 
cognitive restraint (Eating Inventory), mental/emotional health and quality of life (Neuro-QOL), 
family function (FAD-GRS) over 8 weeks during OXT versus placebo 
• 
Fat mass, lean mass, and % body fat (DXA) at the conclusion of 8 weeks OXT versus 8 weeks of 
placebo 
• 
Resting energy expenditure (REE) at the conclusion of 8 weeks OXT versus 8 weeks of placebo 
• 
Respiratory quotient (RQ) at the conclusion of 8 weeks OXT versus 8 weeks of placebo 
• 
Usual energy intake (calories/day via self-reported 3-day diet record) at the conclusion of 8 weeks 
OXT versus 8 weeks of placebo 
• 
Change in self-reported physical activity (via BMDCS-PA questionnaire) during 8 weeks of OXT 
versus 8 weeks of placebo 
• 
OXT pulse profiling after exogenous OXT vs placebo 
• 
Safety and tolerability of OXT based on AEs 
 
2.0 Statistical Analysis 
2.1. Primary Analysis:  
For the primary outcome, i.e., the change in body weight during each treatment block, linear mixed-
effects modeling will be performed to assess the effect of OXT on the outcome as compared to placebo. 
The primary model will include the treatment (i.e., OXT vs. PBO), the randomization sequence (OXT-
PBO vs. PBO-OXT), and the starting body weight in each treatment block as a time-varying covariate. 
We will test for a carryover effect by including the interaction of treatment by sequence in the model. 
This interaction term will NOT be included in the primary model if it is not significant (i.e., p > 0.05). 
(Table 4)   
2.2. Secondary Analysis: 
Similar modeling approaches will be applied to the secondary outcomes that are continuous and measured 
in both Blocks as in the Primary Analysis (Supplementary Table).   
2.2.1. Descriptive Analyses  
Standard descriptive statistics will be used to summarize the demographics and baseline clinical 
characteristics of the participants (Table 1), and also to summarize primary and key secondary outcomes 


related to OXT vs. PBO (Table 2). We will describe the retention during the study and adherence to OXT 
or PBO. Waterfall plots will be provided to display the change in body weight for each participant, stratified 
by the treatment (OXT vs. PBO). Additionally, spaghetti plots of the body weight measured at each visit 
will be made to inform the trajectory of body weight change over time during each treatment block. Similar 
plots will be produced for other outcomes of interest.  
 
2.2.2. Adverse Events (AE) 
Treatment-related AEs in each treatment period (OXT vs. PBO) will be summarized and reported as count 
(and %) in tables (Table 3). In this Table, we will include any AE that is at least possibly related to study 
drug, and either occurs in at least 2 participants (with any CTCAE grade for severity) and/or occurs in at 
least 1 participant (with CTCAE Grade 2 or higher).  McNemar test will be performed to compare the 
prevalence of the AEs of interest between OXT and PBO. We will describe changes in ECG parameters 
and in sodium levels/DDAVP use, since cardiovascular and fluid balance considerations are special AEs of 
interest. 
 
 
2.3. Additional Sensitivity Analyses 
We will test the effect of sequentially adding age, gender, as well as the adherence to treatment to the 
primary model as sensitivity analyses to understand the extent to which these may influence the main result. 
Adherence is defined in two ways that capture different dimensions of likely effect: first, the average % of 
doses consumed as compared to prescribed during each treatment block, and second, the % of days during 
each block with complete adherence. In exploratory analyses, we will also test the extent to which 
hypothalamic damage (as reflected by the presence or absence of diabetes insipidus, and by centralized 
MRI-based assessment of hypothalamic damage) impacts response to treatment. 
 
2.4. Power Calculations 
We will perform power calculation based on our current sample size and observed standard deviation (SD) 
of the within-subject difference in the weight loss between OXT and PBO.  Specifically, we will calculate 
the detectable effect size (and 95% CI) of the weight loss difference between OXT and PBO to reach 80% 
power at significance level of 0.05. We then compare this effect size with the observed effect size. Since 
we did not reach the original recruitment goal due to the COVID19 pandemic and new considerations 
regarding risk for QTc interval prolongation, we will do similar calculations and comparisons assuming the 
originally planned sample size.