Intranasal Vasopressin Treatment in Children With Autism
Phase: PHASE2
Conditions: Autism, Autism Spectrum Disorder, ASD
Sponsor: Stanford University

Intranasal Vasopressin Treatment in Children 
with Autism 
Study Protocol 
NCT03204786 
 
 27MAR2020 
Antonio Y. Hardan, M.D., Principal Investigator 
Karen J. Parker, Ph.D., Principal Investigator 
Stanford University 
Stanford, California 94305 
 
 

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1. 
PURPOSE OF THE STUDY 
a. 
Brief Summary 
We will test the safety and efficacy of intranasal arginine vasopressin (hereafter referred 
to as vasopressin) treatment for social deficits in children with autism spectrum disorder 
(ASD). This research also aims to identify those individuals who stand to benefit most 
from this drug intervention. Vasopressin treatment has enormous potential for enhancing 
quality of life in people with ASD through improved social cognition and more 
meaningful social relationships. If efficacious, vasopressin will considerably reduce the 
emotional and financial burden of ASD on patients, family members, and society. 
b. 
Objectives 
Vasopressin is one of the most promising candidate drugs to treat the presently 
intractable social deficits of ASD. This will be the first large-scale clinical trial to test the 
efficacy of intranasal vasopressin treatment to enhance social abilities in individuals with 
ASD. Inclusion of female participants is a strength of this study, because their exclusion, 
which frequently occurs in ASD treatment studies, may jeopardize optimal testing of 
effective pharmacotherapies. Evidence from both preclinical and clinical studies has 
shown that differences in neuropeptide biology and/or pre-treatment social functioning 
are associated with treatment response outcomes. Our proposed project therefore will also 
test whether neuropeptide measurements and pre-treatment social functioning contribute 
to individual differences in vasopressin treatment efficacy. 
c. 
Rationale for Research in Humans 
The purpose of the study is to test the tolerability and efficacy of intranasal vasopressin 
administration in children with ASD. 
 
2. 
STUDY PROCEDURES 
a. 
Overview and Design 
Using a quadruple-blind (participant, care provider, investigator, and outcomes assessor), 
randomized, placebo-controlled design, we will test the efficacy of 8-week intranasal 
vasopressin on social functioning in children with ASD (aged 6-17 years). Following a 
gold-standard Sequential Parallel Comparison Design (SPCD), participants will be 
randomized into one of three treatment allocations. The treatment allocations are: 1) 
drug-drug, in which participants will be on active vasopressin for the entire 8-week 
dosing period, 2) placebo-drug, in which participants will be on placebo for four weeks 
and then switch to active vasopressin for the remaining four weeks, and 3) placebo-
placebo, in which participants will be on placebo for the entire 8-week dosing period. At 
the completion of the study, participants in the placebo-placebo group will be given the 
option of switching to active vasopressin for a four-week open-label dosing period. The 
ratio of participants in the three groups is 1:2:2 (drug-drug: placebo-drug: placebo-
placebo). Consent by parents (and assent by participants aged 7-17 years) will be 
obtained before initiating any study procedures.  
 

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After obtaining informed consent, participants will be screened at Visit 1. If the 
participant so desires, Visit 1 can be split into two shorter clinic visits.  
 
During Visit 1, participants will undergo: 
• 
Medical and psychiatric history assessments 
• 
A physical exam 
• 
ASD diagnostic screening using the Autism Diagnostic Observation Schedule, 
2nd edition (ADOS-2) or the Childhood Autism Rating Scale, 2nd Edition (CARS-
2), and the Autism Diagnostic Interview-Revised (ADI-R) 
• 
Intellectual ability assessment using the Stanford Binet, 5th Edition or the 
Wechsler Intelligence Scale for Children, 5th Edition (WISC-V) 
• 
Demographics questionnaire 
• 
Clinical Global Impressions Scale – Severity (CGI-S) ratings 
• 
Overt Aggression Scale (OAS) ratings 
• 
The Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
The Social Responsiveness Scale, 2nd edition (SRS-2) 
• 
Side effects ratings using the Dosage Record and Treatment Emergency 
Symptom Scale (DOTES) 
• 
Concomitant medications information 
• 
Electrocardiogram (EKG) recordings 
• 
Blood samples (up to 30 mL) for clinical evaluation and safety monitoring (urea 
nitrogen, sodium, potassium, chloride, CO2, anion gap, glucose, creatinine, 
calcium, and osmolality) 
• 
Urine samples (up to 5mL) for clinical evaluation and safety monitoring 
(osmolality; females of childbearing age [12.5 years and older] or females with a 
history of menstruating will undergo urine pregnancy testing at screening and as 
needed in later visits)  
• 
Vital signs (including heart rate, blood pressure, and temperature) 
• 
Height and weight measurements 
 
Biological samples for research purposes will also be collected. These samples will be 
obtained at the same time as the clinical samples mentioned above. These samples will 
include blood, saliva, buccal cells, and urine. 
 
Whole blood samples for research purposes will be processed and banked. Plasma-borne, 
DNA, and RNA biomarkers of treatment response will be evaluated. Because limitations 
to how much blood can be drawn depend on the participant's weight, peripheral blood 
mononuclear cells (PBMCs) will only be obtained at Visit 1 from participants who meet 
the weight requirements.  
 
Saliva and buccal cell samples for research purposes will also be collected, to evaluate 
biomarkers of treatment response. For every sample collection, participants are asked to 
fast for one hour prior to saliva and buccal cell sample collection. Participants will also 
be instructed to rinse their mouths prior to saliva and buccal cell collection. This 
procedure applies for all future visits at which saliva and buccal cell samples are 
collected. As much as 4 mL of saliva will be collected. For participants who enroll in the 

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trial after the implementation of COVID-19 protocol changes, saliva and buccal cell 
samples will not be collected.  
 
Urine samples will also be collected for research purposes, to evaluate biomarkers of 
treatment response. Urine samples for research purposes will not be collected for 
participants enrolled after the implementation of the COVID-19 protocol changes.  
 
Participants’ tissues, cells, or other materials derived from these biospecimens may be 
kept for many years and may be used by researchers at Stanford or by researchers at 
entities outside Stanford in future studies, which are not foreseeable now. They may 
include research that involves genetic manipulation as well as those that involve induced 
pluripotent stems cells (iPSCs) and iPSC-derived neurons and organoids. 
 
Prior to Visit 2, inclusion and exclusion criteria (as outlined in section 8h) will be 
assessed. One to six weeks later, participants will return to the clinic or schedule a Zoom 
visit for Visit 2 (Baseline and Randomization).  
 
The following information will be obtained at this time point: 
• 
Clinical Global Impressions Scale – Severity (CGI-S) ratings 
• 
Dosage Record and Treatment Emergency Symptom Scale (DOTES) ratings 
• 
Concomitant medications information 
• 
Vital signs 
• 
Height and weight measurements   
 
 
 
Parent ratings on the following will also be obtained at this time point: 
• 
Social Responsiveness Scale, 2nd edition (SRS-2) 
• 
Wing Subgroup Questionnaire (WSQ) 
• 
Vineland Adaptive Behavior Scales 3: Social Skills and Relationships Domain 
(VABS-3) 
• 
Repetitive Behaviors Scale – Revised (RBS-R) 
• 
Stanford Social Motivation Scale, also known as the Stanford Social Dimensions 
Scale (SSDS) 
• 
Spence Children’s Anxiety Scale (SCAS) 
• 
Parent Rated Anxiety Scale-ASD (PRAS-ASD) 
• 
Pediatric Quality of Life (PedsQL) Inventory 
• 
Child's Sleep Habits Questionnaire (CSHQ) 
 
We will also perform an optional high-density electroencephalogram (EEG) to detect the 
participant's brain activity. Resting-state EEG will be recorded from participants 
comfortably seated with their eyes open during each visit. Participants will be 
familiarized with all experimental materials prior to recording and provided with an 
explicit visual schedule to diminish any undue stress associated with novel environments, 
equipment (e.g., electrode caps), or support staff. A practice cap will also be made 
available for participants should further familiarization be requested. Data will be 
collected using a 64-channel Ag/AgCl electrode cap (ANT North America, Madison, WI) 
and continuously digitized at 500Hz with an asalab Turnkey System (Madison, WI). 

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Placement of electrodes will conform to the International 10–20 System. MNE-Python 
will be used to pre-process data and monitor impedances to be less than 10kOhms. 
Approximately 5 minutes of continuous EEG will be recorded as participants sit with 
eyes open. Offline processing will also be performed using the MNE neuroimaging suite 
and includes (but is not limited to) re-referencing to linked-ear mastoids, correction of 
DC drift, and the removal of eye-blink artifacts.  
 
The EEG, vital signs, and height and weight measurements at this time point will not be 
collected from participants who enroll in the trial after the COVID-19 protocol changes.  
 
Participants will undergo experimental assessments measuring social behavior and 
cognition to facilitate the analysis of post-treatment changes in functioning by accounting 
for any pre-existing individual differences. These assessments will include: the Reading 
the Mind in the Eyes Test, NEPSY-II Theory of Mind Test, Diagnostic Analysis of 
Nonverbal Accuracy, 2nd edition: Child Voices (DANVA-2), and Facial Emotion 
Recognition Test. We will also record participants' eye gaze using eye-tracking 
technology while the participants view emotional faces (Eye Gaze Assessment). 
 
Participants who enroll in the trial after the COVID-19 protocol changes will complete 
the social behavior and cognition assessments via Zoom. The Eye Gaze Assessment will 
no longer be performed.  
 
Participants will then be randomized in a blinded fashion to a treatment condition 
(vasopressin or placebo). Stratification will be based on gender and age. Participants will 
receive 32 IU (16 IU BID) of vasopressin or placebo. Parents will be given a dosing 
schedule that they will be required to follow and sign each day. Participants will continue 
vasopressin or placebo administration for 4 weeks at home and their parents will be 
responsible for reporting any adverse events to research staff. Participants will be 
screened for excessive water intake and will be informed to maintain an average water 
intake to decrease the potential occurrence of hyponatremia and water intoxication during 
the treatment period.  
 
One week after starting the nasal spray, research staff will contact families to check in 
and inquire about side effects.  
 
Two weeks after starting the nasal spray, participants will return to the clinic for Visit 3. 
For participants who enroll in the trial after the COVID-19 protocol changes, Visit 3 will 
be conducted remotely, with the physician visit completed via Zoom.  
 
The following will be obtained at this time point: 
• 
Clinical Global Impressions Scale – Severity (CGI-S) ratings  
• 
Clinical Global Impressions Scale—Improvement (CGI-I) ratings 
• 
Overt Aggression Scale (OAS) ratings 
• 
Dosage Record and Treatment Emergency Symptom Scale (DOTES) ratings 
• 
Concomitant medications information 
• 
Vital signs 
• 
Height and weight measurements 

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• 
Optional PBMC collection 
• 
Social Responsiveness Scale, 2nd edition (SRS-2) ratings 
 
For participants who enroll in the trial after the COVID-19 protocol changes, vital signs 
and height and weight measurements will not be obtained at Visit 3 unless instructed by 
the study physician.  
 
Three weeks after starting the nasal spray, research staff will contact families to check in 
and inquire about side effects.  
 
Four weeks after starting the nasal spray, participants will return to the clinic for Visit 4 
or complete a portion of the visit locally through the primary physician’s office (an 
option instituted after the COVID-19 pandemic).  
 
During Visit 4, the following information will be obtained:  
• 
Clinical Global Impressions Scale – Severity (CGI-S) ratings 
• 
Clinical Global Impressions Scale – Improvement (CGI-I) ratings 
• 
Overt Aggression Scale (OAS) ratings 
• 
The Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
Dosage Record and Treatment Emergency Symptom Scale (DOTES) ratings 
• 
Concomitant medications information 
• 
EKG recordings 
• 
Optional EEG recordings 
• 
Vital signs 
• 
Height and weight measurements 
• 
Clinical blood and urine samples 
• 
Research biological samples (e.g., blood, urine, saliva, buccal cells) 
 
Parent ratings on the following will also be obtained: 
• 
Social Responsiveness Scale, 2nd edition (SRS-2) 
• 
Vineland Adaptive Behavior Scales 3: Social Skills and Relationships Domain 
(VABS-3) 
• 
Repetitive Behaviors Scale – Revised (RBS-R) 
• 
Stanford Social Motivation Scale, also known as the Stanford Social Dimensions 
Scale (SSDS) 
• 
Spence Children’s Anxiety Scale (SCAS) 
• 
Parent Rated Anxiety Scale-ASD (PRAS-ASD) 
• 
Pediatric Quality of Life (PedsQL) Inventory 
• 
Child's Sleep Habits Questionnaire (CSHQ) 
 
For participants who enroll in the trial after the implementation of the COVID-19 
protocol changes, the research saliva, buccal cell, and urine samples will not be collected.  
 
If participants choose to complete the blood draw locally through the primary physician’s 
office, research blood samples will not be obtained. Participants who opt to complete the 

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visit through the primary physician’s office must obtain and send to the study team the 
EKG recording, vital signs, and height and weight measurements. 
 
Participants will undergo experimental assessments including:  
▪ 
Eye Gaze Assessment 
▪ 
Reading the Mind in the Eyes Test 
▪ 
NEPSY-II Theory of Mind Test 
▪ 
Diagnostic Analysis of Nonverbal Accuracy, 2nd edition  (Child Voices) 
▪ 
Facial Emotion Recognition Test  
 
For participants who enroll in the trial after the COVID-19 protocol changes, the Eye 
Gaze Assessment will not be performed.  
 
At this time point, participants who were in the placebo group will either continue on 
blinded placebo or be switched in a blinded manner to the active vasopressin for the 
remaining 4 weeks. Participants who were taking the active vasopressin will continue 
taking the drug in a blinded fashion for the remainder of the study.  
 
Five weeks after starting the nasal spray, research staff will contact families to check in 
and inquire about side effects.  
 
Six weeks after starting the nasal spray, participants will return to the clinic for Visit 5. 
For participants who enroll in the trial after the COVID-19 protocol changes, Visit 5 will 
be conducted remotely, with the physician visit completed via Zoom.  
 
The following information will be obtained at this time point: 
• 
Clinical Global Impressions Scale – Severity (CGI-S) ratings 
• 
Clinical Global Impressions Scale – Improvement (CGI-I) ratings 
• 
Overt Aggression Scale (OAS) ratings 
• 
Dosage Record and Treatment Emergency Symptom Scale (DOTES) ratings 
• 
Concomitant medications information 
• 
Vital signs 
• 
Height and weight measurements  
• 
Optional PBMC collection 
• 
Social Responsiveness Scale, 2nd edition (SRS-2) ratings 
 
For participants who enroll in the trial after the COVID-19 protocol changes, vital signs 
and height and weight measurements will not be obtained at Visit 5 unless instructed by 
the study physician. If the required blood volume for optional PBMC collection was not 
obtained at Visit 3 due to the participant's weight, additional blood samples may be 
obtained at Visit 5. As much as 30 mL of blood will be collected. 
 
Seven weeks after starting the nasal spray, research staff will contact families to check in 
and inquire about side effects.  
 

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Eight weeks after starting the nasal spray, participants will return to the clinic for Visit 6 
or complete a portion of the visit locally through the primary physician’s office (an 
option instituted after the COVID-19 pandemic).  
 
The following information will be obtained at this time point: 
• 
Clinical Global Impressions Scale – Severity (CGI-S) ratings 
• 
Clinical Global Impressions Scale – Improvement (CGI-I) ratings 
• 
Overt Aggression Scale (OAS) ratings 
• 
The Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
Dosage Record and Treatment Emergency Symptom Scale (DOTES) ratings 
• 
Concomitant medications information 
• 
EKG recordings 
• 
Optional EEG recordings 
• 
Vital signs 
• 
Height and weight measurements 
• 
Clinical blood and urine samples 
• 
Research blood, urine, saliva, and buccal cell samples  
 
Parent ratings on the following will also be obtained:  
• 
Social Responsiveness Scale, 2nd edition (SRS-2) 
• 
Vineland Adaptive Behavior Scales 3: Social Skills and Relationships Domain 
(VABS-3) 
• 
Repetitive Behaviors Scale – Revised (RBS-R) 
• 
Stanford Social Motivation Scale, also known as the Stanford Social Dimensions 
Scale (SSDS) 
• 
Spence Children’s Anxiety Scale (SCAS) 
• 
Parent Rated Anxiety Scale-ASD (PRAS-ASD) 
• 
Pediatric Quality of Life (PedsQL) Inventory 
• 
Child's Sleep Habits Questionnaire (CSHQ)   
 
For participants who enroll in the trial after the implementation of the COVID-19 
protocol changes, saliva, urine, and buccal cell samples will not be collected.  
 
If the participant chooses to complete the blood draw locally through the primary 
physician’s office, research blood samples will not be obtained. Participants who opt to 
complete the visit locally must also obtain and send to the study team the EKG recording, 
vital signs, and height and weight measurements obtained through the primary 
physician's office.  
 
Participants will undergo experimental assessments including:  
• 
Eye Gaze Assessment 
• 
Reading the Mind in the Eyes Test 
• 
NEPSY-II Theory of Mind Test 
• 
Diagnostic Analysis of Nonverbal Accuracy, 2nd edition (Child Voices) 
• 
Facial Emotion Recognition Test 
 

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For participants who enroll in the trial after the COVID-19 protocol changes, the Eye 
Gaze Assessment will not be performed.  
 
After completion of the blinded 8-week treatment period, participants will be informed of 
their treatment group. Participants in the placebo-placebo group will have the option of 
participating in a 4-week open-label vasopressin treatment extension period.  
 
One week after starting open-label vasopressin treatment, research staff will contact 
families in this open-label extension period to check in and inquire about side effects.  
 
Two weeks after starting open-label vasopressin treatment, participants in this open-label 
extension period will return to the clinic for Visit 7. Participants who enroll in the trial 
after the COVID-19 protocol changes will complete Visit 7 remotely, with the physician 
visit completed via Zoom.  
 
The following information will be obtained at this time point: 
• 
Clinical Global Impressions Scale – Severity (CGI-S) ratings 
• 
Clinical Global Impressions Scale – Improvement (CGI-I) ratings 
• 
Overt Aggression Scale (OAS) ratings 
• 
Dosage Record and Treatment Emergency Symptom Scale (DOTES) ratings 
• 
Concomitant medication information 
• 
Vital signs 
• 
Height and weight measurements  
• 
Optional PBMC collection 
• 
Social Responsiveness Scale, 2nd edition (SRS-2) ratings 
 
For participants who enroll in the trial after the COVID-19 protocol changes, vital signs 
and height and weight measurements will not be obtained at Visit 7 unless instructed by 
the study physician. 
 
Three weeks after starting open-label vasopressin treatment, research staff will contact 
families in the open-label period to check in and inquire about side effects.  
 
Four weeks after starting open-label vasopressin treatment, participants in the open-label 
phase will return to the clinic for Visit 8 or complete this visit locally through the primary 
physician’s office (an option instituted after the COVID-19 pandemic).  
 
The following information will be obtained at this time point: 
• 
Clinical Global Impressions Scale – Severity (CGI-S) ratings 
• 
Clinical Global Impressions Scale – Improvement (CGI-I) ratings 
• 
Overt Aggression Scale (OAS) ratings 
• 
The Columbia-Suicide Severity Rating Scale (C-SSRS) 
• 
Dosage Record and Treatment Emergency Symptom Scale (DOTES) ratings 
• 
Concomitant medication information 
• 
EKG recordings 
• 
Optional EEG recordings 

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• 
Vital signs 
• 
Height and weight measurements  
• 
Clinical blood and urine samples 
• 
Research blood, urine, saliva, and buccal cell samples 
 
Parent ratings will be obtained on the following at this time point: 
• 
Social Responsiveness Scale, 2nd edition (SRS-2) 
• 
Vineland Adaptive Behavior Scales 3: Social Skills and Relationships Domain 
(VABS-3) 
• 
Repetitive Behaviors Scale – Revised (RBS-R) 
• 
Stanford Social Motivation Scale, also known as the Stanford Social Dimensions 
Scale (SSDS) 
• 
Spence Children’s Anxiety Scale (SCAS) 
• 
Parent Rated Anxiety Scale-ASD (PRAS-ASD) 
• 
Pediatric Quality of Life (PedsQL) Inventory 
• 
Child's Sleep Habits Questionnaire (CSHQ)   
 
For participants who enroll in the trial after the implementation of the COVID-19 
protocol changes, saliva, buccal cell, and urine samples will not be collected. If the 
participant chooses to complete the blood draw locally through the primary physician’s 
office, research blood samples will not be obtained. Participants who opt to complete the 
visit locally must send to the study team the EKG recording, vital signs, and height and 
weight measurements obtained through the primary physician's office.  
 
Participants will undergo experimental assessments including: 
• 
Eye Gaze Assessment 
• 
Reading the Mind in the Eyes Test 
• 
NEPSY-II Theory of Mind Test 
• 
Diagnostic Analysis of Nonverbal Accuracy, 2nd edition (Child Voices) 
• 
Facial Emotion Recognition Test  
 
For participants who enroll in the trial after the COVID-19 protocol changes, the Eye 
Gaze Assessment will not be performed.  
 
For participants in all 3 treatment allocation groups, research staff will contact families 4 
weeks after completion of the last vasopressin dose to ask them to complete the Social 
Responsiveness Scale, 2nd edition.  
 
b. 
Procedure Risks 
Given that this research is some of the first to determine the effects of intranasal 
vasopressin for the treatment of social deficits in children with ASD, we have chosen 
doses and a treatment duration that we believe will prove both safe and effective. 
Participants will receive 32 IU vasopressin (16 IU bid). If severe side effects occur, the 
study physician may lower the dose or instruct the participant to discontinue the nasal 
spray. 

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Safety monitoring: A medical and psychiatric history will be obtained, and a physical 
examination conducted during the screening phase, prior to randomization. All 
participants will be in good general medical health. Additional evaluations will be 
conducted at later visits. Seizure history will be reviewed carefully during the screening 
visit and, as stated in the protocol’s exclusion criteria, children with seizure disorder, or a 
history of seizure-like activity, will be excluded. Drug side effects will be evaluated with 
the Dosage Record and Treatment Emergent Symptom Scale at each visit. The Dosage 
Record and Treatment Emergency Symptom Scale is a general rating scale published by 
the Early Clinical Drug Evaluation Unit of the National Institute of Mental Health. The 
scale has been widely used clinically for children and adults to assess many central 
nervous system side effects as well as some behavioral side effects. We have modified 
the original version of the Dosage Record and Treatment Emergency Symptom Scale to 
include specific questions related to potential side effects that might be related to 
vasopressin, such as hyponatremia/water intoxication. Vital signs (heart rate/blood 
pressure and temperature) will be assessed at each visit. Height and weight will also be 
assessed at each visit.  In order to increase safety monitoring, blood and urine safety 
measurement will be conducted during the screening phase and at Visits 3, 4, 5, and 6. 
Clinical blood work will consist of a basic metabolic panel of blood urea nitrogen, 
sodium, potassium, chloride, CO2, anion gap, glucose, creatinine, calcium). Osmolality 
(urine, blood) will also be assessed. In order to determine the impact of vasopressin on 
heart function, EKG recordings will be obtained at screening and Visits 3, 4, 5, and 6.  
 
After treating more than 40 pediatric participants with vasopressin using a conservative 
monitoring plan, we have concluded that the drug has been well tolerated with minimal 
side effects. Therefore, we have decreased the number of safety monitoring points during 
this trial, which will allow us to collect fewer venous blood samples, urine samples, and 
EKGs. We received Stanford Institutional Review Board (IRB) approval on 01FEB2019 
for these changes to the frequency of safety monitoring points. We also received approval 
for this change from the Food and Drug Administration (FDA) and the National Institute 
of Child Health and Human Development. We will keep the safety blood draws and 
EKGs performed at Visit 1 (screening), Visit 2 (baseline), Visit 4 (4 weeks after 
baseline), Visit 6 (8 weeks after baseline), and Visit 8 (12 weeks after baseline for 
participants in the open-label extension phase). We have removed the safety blood draws 
and EKGs performed at Visit 3 (2 weeks after baseline), Visit 5 (6 weeks after baseline), 
and Visit 7 (10 weeks after baseline for participants in the open-label extension phase).  
 
For participants who enroll in the trial after the COVID-19 protocol changes, vital signs 
and height and weight measurements, EKG readings, and blood and urine safety 
measurement will be obtained at screening and Visits 4 and 6.  
 
In light of the recent evidence linking psychotropic medications to suicidal behaviors, 
closely monitoring the mental well-being of individuals taking these psychotropic 
medications is important. Therefore, assessment of suicidal ideation/behaviors will be 
completed during Visit 1 and will be monitored during the trial at Visits 4, 6, and 8 (if 
applicable). 
 

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Finally, based on preclinical animal studies, some evidence to suggests that vasopressin 
may be involved in the expression of aggressive behavior. Although the relationship 
between vasopressin and aggression in humans is currently unknown, we will take every 
precaution to assess such behavioral changes throughout the study. The Overt Aggression 
Scale will be administered at screening and Visits 3, 4, 5, and 6. The Overt Aggression 
Scale is designed to assess observable aggressive or violent behavior and has been used 
in children with different neuropsychiatric disorders. Identical safety measures as 
outlined above will be performed during the optional 4-week open-label extension study. 
 
Procedures for handling adverse events: Outpatient dosing phase: For any adverse events, 
families will be instructed to contact the research coordinator directly during business 
hours, and through the Stanford page operator after hours and during weekends/holidays. 
(A project coordinator will be available 24 hours per day/7 days per week to respond to 
safety concerns.) If the adverse event is life threatening, participants will be asked to call 
911 or to visit the nearest emergency room. If the adverse event is not life threatening, the 
study coordinator will contact the study physician who will contact the family directly 
and inquire about the adverse event. If the study physician judges the side effects as 
minor or benign, a decision will be made as to whether the participant will continue in the 
study. If side effects are judged to be severe and potentially related to vasopressin, the 
participants will be asked to stop the medication immediately and invited to come to the 
clinic within 24 hours for a direct evaluation and potential termination of their 
participation in the study. If the study physician ascertains that the adverse event requires 
immediate medical attention, parents will be instructed to contact 911 or go to the nearest 
emergency room. The study physician will also have the ability to break the blind if 
doing so is in the best interest of the participant’s health.  
 
Any serious adverse events will be reported to the Data and Safety Monitoring Board and 
Stanford IRB within 24 hours and to the FDA within 7 calendar days.  
c. 
Use of Deception in the Study 
No deception will be used. 
d. 
Use of Audio and Video Recordings 
Audio and video recordings will be used during the Autism Diagnostic Observation 
Schedule, 2nd Edition, Childhood Autism Rating Scale, 2nd Edition, and the Autism 
Diagnostic Interview – Revised assessments. A senior clinical psychologist (Dr. Jennifer 
Phillips or Dr. Cristiana Vattuone) will supervise diagnostic testing. Video recording will 
be used in order to quantify the participant’s social mimicry while they view videos of 
people yawning and laughing. Two independent raters will study the videos to assess for 
mimicry behavior.  
 
The analyses of these recordings can be shared for scientific purposes, shown in 
classrooms to students for educational purposes, shown in public presentations to non-
scientific groups, and submitted for public distribution (sold on a DVD). However, audio 
and video recordings will not be used for any other purpose or shown outside of the 
research group unless explicit written permission is obtained in the consent form. 

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e. 
Alternative Procedures or Courses of Treatment 
An alternative is not participating in this study. No standard treatment will be withheld. 
Participants would remain on their regular medications. 
f. 
Will it be possible to continue the more (most) appropriate therapy for the 
participant(s) after the conclusion of the study? 
Yes. 
g. 
Study Endpoint(s) 
Primary Outcome Measure:   
 
1. Change from baseline in parent rated Social Responsiveness Scale, 2nd edition (SRS-
2) Total scores during treatment. [Time Frame: 4-week; 8-week] 
 
Secondary Outcome Measures:  
 
2. Change from baseline in Clinical Global Impression (CGI) scores during treatment. 
[Time Frame: 4-week; 8-week] 
3. Change from baseline on Reading the Mind in the Eyes Test (RMET) during treatment. 
[Time Frame: 4-week; 8-week] 
4. Change from baseline on the Facial Emotion Recognition Test during treatment. 
[Time Frame: 4-week; 8-week] 
5. Change from baseline in parent rated Repetitive Behavior Scale Revised (RBS-R) 
scores during treatment. 
[Time Frame: 4-week; 8-week] 
6. Change from baseline in parent rated Spence Children's Anxiety Scale (SCAS) during 
treatment. 
[Time Frame: 4-week; 8-week] 
7. Change from baseline on electrocardiogram (EKG) P Duration during treatment. 
[Time Frame: 4-week; 8-week] 
8. Change from baseline on electrocardiogram (EKG) PR Interval during treatment. 
[Time Frame: 4-week; 8-week] 
9. Change from baseline on electrocardiogram (EKG) QRS Interval during treatment. 
[Time Frame: 4-week; 8-week] 
10. Change from baseline on electrocardiogram (EKG) QT Interval during treatment. 
[Time Frame: 4-week; 8-week] 
11. Change from baseline on blood clinical labs (Sodium) during treatment. 
[Time Frame: 4-week; 8-week] 
12. Change from baseline on blood clinical labs (Potassium) during treatment. 
[Time Frame: 4-week; 8-week] 
13. Change from baseline on blood clinical labs (Chloride) during treatment. 
[Time Frame: 4-week; 8-week] 
14. Change from baseline on blood clinical labs (CO2) during treatment. 
[Time Frame: 4-week; 8-week] 
15. Change from baseline on blood clinical labs (Anion Gap) during treatment. 
[Time Frame: 4-week; 8-week] 

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16. Change from baseline on blood clinical labs (Glucose) during treatment. 
[Time Frame: 4-week; 8-week] 
17. Change from baseline on blood clinical labs (Creatinine) during treatment. 
[Time Frame: 4-week; 8-week] 
18. Change from baseline on blood clinical labs (Urea Nitrogen) during treatment. 
[Time Frame: 4-week; 8-week] 
19. Change from baseline on blood clinical labs (Calcium) during treatment. 
[Time Frame: 4-week; 8-week] 
20. Change from baseline on blood clinical labs (Osmolality) during treatment. 
[Time Frame: 4-week; 8-week] 
21. Change from baseline on urine clinical labs (Osmolality) during treatment. 
[Time Frame: 4-week; 8-week] 
22. Change from baseline on vital signs (systolic blood pressure) during treatment. 
[Time Frame: 4-week; 8-week] 
23. Change from baseline on vital signs (diastolic blood pressure) during treatment. 
[Time Frame: 4-week; 8-week] 
24. Change from baseline on vital signs (pulse) during treatment. 
[Time Frame: 4-week; 8-week] 
25. Change from baseline on height during treatment. 
[Time Frame: 4-week; 8-week] 
26. Change from baseline on weight during treatment. 
[Time Frame: 4-week; 8-week] 
27. Change from baseline on the Dosage Record Treatment Emergent Symptom Scale 
(DOTES) during treatment. 
[Time Frame: 2-week, 4-week; 6-week, 8-week] 
28. Change from baseline in Overt Aggression Scale (OAS) during treatment. 
[Time Frame: 2-week, 4-week; 6-week, 8-week] 
29. Baseline vasopressin concentration predicting primary and secondary behavioral 
outcome measures. 
[Time Frame: 4-week; 8-week] 
 
Other Pre-specified Outcome Measures: 
 
30. Change from baseline in Vineland Adaptive Behavior Scales, 3rd edition (VABS-3) - 
Social Skills and Relationships Domain during treatment. 
[Time Frame: 4-week; 8-week] 
31. Change from baseline in parent rated Pediatric Quality of Life (PedsQL) inventory 
scores during treatment. 
[Time Frame: 4-week; 8-week] 
32. Change from baseline on Eye Gaze Assessment (eye tracking) during treatment. 
[Time Frame: 4-week; 8-week] 
33. Change from baseline on the Developmental Neuropsychological Assessment, 2nd 
edition (NEPSY-II) Theory of Mind Test during treatment. 
[Time Frame: 4-week; 8-week] 
34. Change from baseline the Diagnostic Analysis of Nonverbal Accuracy, 2nd edition 
(DANVA-2) Child Voices Prosody Test during treatment. 
[Time Frame: 4-week; 8-week] 

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35. Change from baseline in parent rated Stanford Social Motivation Scale (also known 
as the Stanford Social Dimensional Scale) Total scores during treatment. 
[Time Frame: 4-week; 8-week] 
36. Change from baseline in Parent Rated Anxiety Scale - Autism Spectrum Disorder 
(PRAS-ASD) score during treatment. 
[Time Frame: 4-week; 8-week]  
37. Change from baseline in parent rated Social Responsiveness Scale, 2nd edition (SRS-
2) Social Avoidance Factor Score during treatment. 
[Time Frame: 4-week; 8-week] 
38. Change from baseline in parent rated Social Responsiveness Scale, 2nd edition (SRS-
2) Emotion Recognition Factor Score during treatment. 
[Time Frame: 4-week; 8-week] 
39. Change from baseline in parent rated Social Responsiveness Scale, 2nd edition (SRS-
2) Interpersonal Relatedness Factor Score during treatment. 
[Time Frame: 4-week; 8-week] 
40. Change from baseline in parent rated Social Responsiveness Scale, 2nd edition (SRS-
2) Insistence On Sameness Factor Score during treatment. 
[Time Frame: 4-week; 8-week] 
41. Change from baseline in parent rated Social Responsiveness Scale, 2nd edition (SRS-
2) Repetitive Mannerisms Factor Score during treatment. 
[Time Frame: 4-week; 8-week] 
42. Change from baseline in parent rated Social Responsiveness Scale, 2nd edition (SRS-
2) Attachment and Affiliation Factor Score during treatment. 
[Time Frame: 4-week; 8-week] 
43. Change from baseline in parent rated Social Responsiveness Scale, 2nd edition (SRS-
2) Non-facial Communication Production Factor Score during treatment. 
[Time Frame: 4-week; 8-week] 
44. Change from baseline in parent rated Social Responsiveness Scale, 2nd edition (SRS-
2) Facial Communication Production Factor Score during treatment. 
[Time Frame: 4-week; 8-week] 
45. Change from baseline in parent rated Social Responsiveness Scale, 2nd edition (SRS-
2) Mental States Understanding Factor Score during treatment. 
[Time Frame: 4-week; 8-week] 
46. Change from baseline in parent rated Child's Sleep Habits Questionnaire (CSHQ) 
Score during treatment. 
[Time Frame: 4-week; 8-week] 
47. Change from baseline on spectral power in the alpha, theta, and gamma frequencies 
as measured by electroencephalogram (EEG) during treatment. 
[Time Frame: 4-week; 8-week] 
 
3. 
BACKGROUND  
Impact and relevance. ASD is a pervasive developmental disorder characterized by core deficits 
in social behavior and communication, and the presence of repetitive or stereotyped behaviors. 
ASD affects an estimated 1 in 68 children in the US [1]. Individuals with ASD demonstrate 
diminished eye gaze, abnormal facial and emotion processing, and impaired social judgment. 

27MAR2020 
 
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These deficits jeopardize the development of appropriate social skills and maintenance of social 
relationships [2-4]. Although several medications are approved for the treatment of ASD (i.e., the 
atypical antipsychotics risperidone and aripiprazole), none are effective in ameliorating the 
characteristic social deficits. Moreover, these medications have unfavorable side effects (e.g., 
lethargy, weight gain). Identifying the underlying pathophysiology of the core social deficits 
associated with ASD and developing new medications that target these impairments is clearly an 
important challenge [5]. The proposed project leverages promising preclinical findings to test 
whether intranasal administration of the neuropeptide vasopressin enhances social functioning in 
children, particularly males, with ASD. Vasopressin represents enormous potential for enhancing 
an individual’s quality of life through improved social cognition and more meaningful social 
relationships. The discovery of effective novel therapeutics provides an outstanding opportunity 
to reduce the emotional and financial burden of ASD on patients, family members, and society.  
 
Preclinical findings: Vasopressin and oxytocin regulate social behavior and show translational 
promise as pharmacotherapies to treat social impairments. The neurobiological systems critical 
for normative social functioning are arguably the most promising candidates by which to identify 
“druggable” targets to treat ASD [5,6]. Two such candidates are vasopressin and oxytocin [8]. 
Vasopressin and oxytocin are primarily synthesized in the hypothalamus and released into the 
brain via distributed neural pathways and systemic circulation via the posterior pituitary [7]. 
Vasopressin and oxytocin are nearly structurally identical nonapeptides and likely evolved due to 
duplication of a common ancestral gene [6]. Extensive animal research during four decades has 
demonstrated the importance of both vasopressin and oxytocin in social functioning. Specifically, 
brain vasopressin and oxytocin systems promote social behavior (e.g., partner preference 
formation, parenting behavior) and social cognition (e.g., learning and memory for social 
information) in a variety of mammalian species [8]. In contrast, vasopressin and oxytocin peptide 
and receptor impairments induced by pharmacological or genetic manipulations produce 
numerous social deficits in animals [9-12].  
 
Clinical findings: The behavioral effects of intranasal vasopressin and oxytocin administration in 
neurotypical and patient populations and gaps in our knowledge. On the basis of these promising 
preclinical findings, multiple investigators have begun to test the potential of these neuropeptides 
as therapeutic agents to enhance social functioning in people. These studies have mostly focused 
on the prosocial effects of intranasal oxytocin on social functioning in both neurotypical 
individuals and individuals with various psychiatric disorders (e.g., anxiety, schizophrenia, ASD) 
[13-25]. Several independent groups have recently demonstrated that single doses of oxytocin 
administered to teenage and adult males with ASD improve the processing and retention of social 
information [20], improve emotion recognition when viewing the eye region of faces [15], and 
increase trust and preference for social partners during a computer simulated ball-toss game [14]. 
Several groups, including our own, are now testing the effects of longer-term oxytocin 
administration to younger individuals, inclusive of boys and girls, with ASD.  
 
In contrast to oxytocin, only a handful of studies have investigated the effects of intranasal 
vasopressin on social functioning in humans. These studies have shown that vasopressin enhances 
memory for happy and angry faces [26], increases recognition of positively and negatively 
valenced social words [27], and enhances neural activity in known vasopressin brain circuitry 
during a cooperation task [28]. Single intranasal doses of vasopressin or analogs have also been 
shown to enhance speech and word formation in patients with post-stroke aphasia and improve 

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short and long-term memory in patients with central diabetes insipidus suggesting potential 
cognitive enhancing properties of this hormone [29,30]. In humans, intranasally administered 
vasopressin results in elevated cerebrospinal fluid levels of measured vasopressin, strongly 
suggesting that it achieves access to the brain [31].  
 
Intranasally administered vasopressin and its analogs (e.g., desmopressin) are well tolerated in 
humans with no significant side effects reported in any of the studies outlined above. Vasopressin 
and its analogs have been used for more than 30 years in both children and adults to treat central 
diabetes insipidus, nocturnal enuresis, and varying states of shock. It has caused very few side 
effects given that precautions are adhered to (e.g., water restriction to prevent hyponatremia/water 
intoxication) [32-36]. Despite a growing body of evidence documenting the prosocial effects of 
vasopressin, and the relevance of this system to ASD [37,38], no studies have tested whether 
vasopressin administration enhances social functioning in this disorder. Given the research effort 
now directed toward testing oxytocin as a treatment for the social deficits in ASD, there is an 
obvious need to investigate the treatment potential of this closely related neuropeptide in order to 
ameliorate the social deficits in individuals with ASD.  
 
Why is a vasopressin treatment trial critically needed in people with ASD? In addition to its 
structural and functional similarity to oxytocin, vasopressin merits investigation as a candidate 
drug for use in ASD for several other reasons. First, preclinical findings from genetically 
modified and wild type animals suggest that important aspects of social cognition are mediated 
through vasopressin V1a receptors. In oxytocin receptor (OXTR) null (Oxtr-/-) mice, central 
administration of either oxytocin or vasopressin directly in to the brain improves sociability 
deficits, enhances exploration of social novelty, and reverses cognitive flexibility deficits [39]. 
Pre-treatment with a selective V1a receptor antagonist prior to central oxytocin administration 
almost completely attenuates the prosocial and cognitive enhancing effects of oxytocin, indicating 
that V1a receptors mediate this effect. Experiments using wild-type mice, rats, and voles likewise 
show that administration of selective V1a antagonists in the presence of normal brain oxytocin 
signaling impairs social functioning [40,41]. These findings are particularly evident in males, in 
which vasopressin has been shown to selectively regulate social functioning. An intriguing and 
important aspect of vasopressin and oxytocin physiology is that they exert largely sexually 
dimorphic behavioral effects as determined by a series of influential pharmacological and 
autoradiographical studies [42-44]. These studies have shown that, whereas oxytocin 
preferentially regulates pair bond formation, reproductive physiology (e.g., parturition and 
lactation), and parental care in females, vasopressin preferentially regulates mating behavior, pair 
bond formation, and parental care in males [45].  
 
Second, recent genetic association studies indicate that several single nucleotide polymorphisms 
and their haplotypes in the OXTR gene increase risk for ASD [46,47]. Genome-wide scans 
likewise indicate that the 3p25 region, which contains the OXTR gene, may be a linkage site for 
ASD [48]. These findings suggest the intriguing supplementary hypothesis that in people with 
OXTR impairments, vasopressin treatment may be even more efficacious than oxytocin 
administration. Although both vasopressin and oxytocin ligands show high affinity for all four 
receptors (i.e., vasopressin: V1a, V1b, V2; and oxytocin: OXTR, respectively), they bind with 
greatest affinity to their own receptor(s) [49]. This hypothesis is further supported by evidence 
that Oxtr-/- mice have higher vasopressin V1a receptor expression in the brain than do wild-type 
mice, which suggests that these animals may be more sensitive to vasopressin administration than 

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oxytocin [39,50]. These findings clearly highlight the need for careful studies that clarify the 
underlying neurobiological actions of these neuropeptides as pharmacotherapeutic agents in 
individuals with ASD [50]. To address this larger research question, we must first test whether 
intranasal vasopressin administration improves social functioning in individuals with ASD, and 
whether this medication is more efficacious in males than females.  
 
Factors that contribute to treatment response efficacy. In addition to gender differences in 
treatment response, most vasopressin and oxytocin pharmacology studies have found treatment 
responders and non-responders. For example, previous preclinical research conducted by our 
group, led by Dr. Karen Parker, has shown that baseline social phenotype significantly influences 
the efficacy of vasopressin treatment to induce or enhance prosocial behaviors in male rodents 
[51]. Similarly, a single-dose oxytocin treatment study in male adults with ASD provides 
preliminary evidence for enhanced social functioning post-treatment in a subgroup of individuals 
who show higher social motivation at baseline [14]. Another recent study using transcutaneous 
electrical acupoint stimulation therapy demonstrated enhanced social functioning post-treatment, 
which was associated with higher plasma vasopressin levels in children with ASD. Treatment 
benefits and higher vasopressin levels were most pronounced in children with “passive” and 
”aloof,”, but not “active but odd” behavioral phenotypes as assessed by the Wing Subgroup 
Questionnaire at baseline [52]. These findings suggest that individual differences in pre-treatment 
social impairments may contribute to treatment response efficacy and that these changes are 
associated with increased plasma neuropeptide levels. This intriguing hypothesis will be explored 
in the present study.  
 
Innovation. Vasopressin is one of the most promising candidate drugs to treat the presently 
intractable social deficits of ASD. This large-scale clinical trial will to test the efficacy of 
vasopressin treatment to enhance social abilities in individuals with ASD. Inclusion of female 
participants is a strength of this study. Female exclusion, which frequently occurs in ASD 
treatment studies, may jeopardize optimal testing of effective pharmacotherapies, and preclude 
identification of disease mechanisms. Our inclusion of females is particularly important because 
preclinical evidence suggests that males may respond more robustly to vasopressin treatment than 
females [53]. Findings from both preclinical and clinical studies have shown that differences in 
pre-treatment social functioning and/or neuropeptide biology are associated with vasopressin and 
oxytocin treatment response outcomes. Ours will be the first study to test concomitantly whether 
pre-treatment social measurements and baseline neuropeptide levels contribute to individual 
differences in vasopressin treatment response efficacy.  
 
The use of both eye-tracking methodology to assess change in social abilities and an automated 
prosody assessment in this trial represent crucial steps toward objective assessment of core 
symptoms of ASD and generalization of treatment. No clear biologically-based marker, such as 
eye tracking, has yet been used extensively in published controlled trials of children with ASD in 
order to test treatment effects and moderators of response.  
 
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2 
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Hammock, E. A. & Young, L. J. Oxytocin, vasopressin and pair bonding: Implications 
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Guastella, A. J. et al. Intranasal oxytocin improves emotion recognition for youth with 
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Guastella, A. J. et al. A randomized controlled trial of intranasal oxytocin as an adjunct to 
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Ditzen, B. et al. Intranasal oxytocin increases positive communication and reduces 
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Domes, G. et al.  Oxytocin improves "mind-reading" in humans. Biological Psychiatry 
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Guastella, A. J., Mitchell, P. B. & Dadds, M. R. Oxytocin increases gaze to the eye 
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20 
Hollander, E. et al. Oxytocin increases retention of social cognition in autism. Biological 
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21 
Kirsch, P. et al. Oxytocin modulates neural circuitry for social cognition and fear in 
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Kosfeld, M. et al. Oxytocin increases trust in humans. Nature 435, 673-676 (2005).  
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Rimmele, U. et al. Oxytocin makes a face in memory familiar. Journal of Neuroscience 
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24 
Theodoridou, A. et al. Oxytocin and social perception: oxytocin increases perceived 
facial trustworthiness and attractiveness. Hormones and Behavior 56, 128-132 (2009).  
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Guastella, A. J. et al. Intranasal arginine vasopressin enhances the encoding of happy and 
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27 
Guastella, A. J. et al. Arginine Vasopressin selectively enhances recognition of sexual 
cues in male humans. Psychoneuroendocrinology 36, 294-297 (2011).  
28 
Rilling, J. K. et al. Effects of intranasal oxytocin and vasopressin on cooperative behavior 
and associated brain activity in men. Psychoneuroendocrinology 37, 447-461 (2012).  
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Laczi, F. et al. Effects of lysine-vasopressin and 1-deamino-8-D-arginine-vasopressin on 
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Tsikunov, S. G. & Belokoskova, S. G. Psychophysiological analysis of the influence of 
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Born, J. et al. Sniffing neuropeptides: A transnasal approach to the human brain. Nature 
Neuroscience 5, 514-516 (2002).  
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Vande Walle, J. et al. Desmopressin 30 years in clinical use: A safety review. Current 
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34 
Vande Walle, J., Van Herzeele, C. & Raes, A. Is there still a role for desmopressin in 
children with primary monosymptomatic nocturnal enuresis?: A focus on safety issues. Drug 
Safety 33, 261-271 (2010).  
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Meyer, S. et al. Arginine-vasopressin in catecholamine-refractory septic versus non-
septic shock in extremely low birth weight infants with acute renal injury. Critical Care 10, Epub 
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Kim, R. J. et al. Vasopressin and desmopressin in central diabetes insipidus: Adverse 
effects and clinical considerations. Pediatric endocrinology Reviews: PER 2 Suppl 1, 115-123 
(2004).  
37 
Tansey, K. E. et al. Functionality of promoter microsatellites of arginine vasopressin 
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Insel, T. R. The challenge of translation in social neuroscience: A review of oxytocin, 
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Sala, M. et al. Pharmacologic rescue of impaired cognitive flexibility, social deficits, 
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Donaldson, Z. R., Spiegel, L. & Young, L. J. Central vasopressin V1a receptor activation 
is independently necessary for both partner preference formation and expression in socially 
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Nephew, B. C. & Bridges, R. S. Arginine vasopressin V1a receptor antagonist impairs 
maternal memory in rats. Physiology and Behavior 95, 182-186 (2008).  
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Cho, M. M. et al. The effects of oxytocin and vasopressin on partner preferences in male 
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Carter, C. S. et al. Consequences of early experiences and exposure to oxytocin and 
vasopressin are sexually dimorphic. Developmental Neuroscience 31(4):332-341 (2009).  
44 
Carter, C. S. Sex differences in oxytocin and vasopressin: Implications for autism 
spectrum disorders? Behavioural Brain Research 176, 170-186 (2007).  
45 
Young, L. J. Being human: Love: Neuroscience reveals all. Nature 457(7226):148 
(2009).  
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Wermter, A. K. et al. Evidence for the involvement of genetic variation in the oxytocin 
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Journal of Medical Genetics Part B: Neuropsychiatric Genetics 153B, 629-639 (2010).  
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Wu, S. et al. Positive association of the oxytocin receptor gene (OXTR) with autism in 
the Chinese Han population. Biological Psychiatry 58, 74-77 (2005).  
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Liu, X. et al. Association of the oxytocin receptor (OXTR) gene polymorphisms with 
autism spectrum disorder (ASD) in the Japanese population. Journal of Human Genetics 55, 137-
141 (2010).  
49 
Manning, M. et al. Peptide and non-peptide agonists and antagonists for the vasopressin 
and oxytocin V1a, V1b, V2 and OT receptors: Research tools and potential therapeutic agents. 
Progress in Brain Research 170, 473-512 (2008).  
50 
Ring, R. H. A complicated picture of oxytocin action in the central nervous system 
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51 
Parker, K. J., Kinney, L. F., Phillips, K. M. & Lee, T. M. Paternal behavior is associated 
with central neurohormone receptor binding patterns in meadow voles (Microtus 
pennsylvanicus). Behavioral Neuroscience 115, 1341-1348 (2001).  
52 
Zhang, R. Transcutaneous electric acupoint stimulation in children with autism and its 
impact on plasma levels of arginine-vasopressin and oxytocin: a prospective single-blinded 
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53 
Keverne, E. B. & Curley, J. P. Vasopressin, oxytocin and social behaviour. Current 
opinion in neurobiology 14, 777-783 (2004). 
4. 
RADIOISOTOPES OR RADIATION MACHINES 
a. 
Standard of Care (SOC) Procedures 
Identify Week/Month of Study 
Name of Exam 
Identify if SOC or Research 
NA 
NA 
NA 
b. 
Radioisotopes 
i. 
Radionuclide(s) and chemical form(s) 
NA 
ii. 
Total number of times the radioisotope and activity will be administered (mCi) and 
the route of administration for a typical study participant 
NA 
iii. 
If not FDA approved: dosimetry information and source documents (package insert, 
Medical Internal Radiation Dose [MIRD] calculation, and peer reviewed literature) 
NA 

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Page 22 of 48 
c. 
Radiation Machines – Diagnostic Procedures 
i. 
Examination description (well-established procedures) 
NA 
ii. 
Total number of times each procedure will be performed (typical study participant) 
NA 
iii. 
Setup and techniques to support dose modeling 
NA 
iv. 
FDA status of the machine and information on dose modeling (if procedure is not 
well-established) 
NA 
d. 
Radiation Machines – Therapeutic Procedures 
i. 
Area treated, dose per fraction/number of fractions, performed as part of normal 
clinical management or due to research participation (well-established procedures) 
NA 
ii. 
FDA status of the machine, basis for dosimetry, area treated, dose per fraction and 
number of fractions (if procedure is not well-established) 
NA 
 
5. 
DEVICES USED IN THE STUDY 
a. 
Investigational Devices (Including Commercial Devices Used Off-Label) 
Investigational Device 1 
Name: 
NA 
 
b. 
IDE-Exempt Devices 
IND-Exempt Device 1 
Name: 
NA 
 
6. 
DRUGS, BIOLOGICS, REAGENTS, OR CHEMICALS USED IN THE STUDY 
a. 
Investigational Drugs, Biologics, Reagents, or Chemicals 
Investigational Product 1 
Name: 
Vasopressin Injection, USP 
 
Dosage: 
16 IU BID 
Administration Route: 
Intranasal 
b. 
Commercial Drugs, Biologics, Reagents, or Chemicals 

27MAR2020 
 
Page 23 of 48 
Commercial Product 1 
Name: 
NA 
 
 
 
 
7. 
DISINFECTION PROCEDURES FOR MEDICAL EQUIPMENT USED ON BOTH HUMANS AND 
ANIMALS 
NA 
 
8. 
PARTICIPANT POPULATION 
a. 
Planned Enrollment 
All participants will be enrolled at Stanford. We plan to enroll and screen as many as 200 
children to meet our target of a minimum of 100 randomized participants. 
b. 
Age, Gender, and Ethnic Background 
The participants will be between the ages of 6 and 17 years (maximum 17 years and 11 
months). Males and females from all racial and ethnic backgrounds will be eligible to 
participate in this study. 
 
c. 
Vulnerable Populations 
We are recruiting a minimum of 100 potentially decisionally impaired children (ages 6 to 
17 years) with ASD. This study is specifically directed at children with ASD in order to 
test the tolerability and efficacy of vasopressin in this population. 
d. 
Rationale for Exclusion of Certain Populations 
NA 
e. 
Stanford Populations 
NA 
f. 
Healthy Volunteers 
NA 
g. 
Recruitment Details 
Potential participants will be identified from the Autism and Developmental Disorders 
Clinic at Stanford and from the Autism and Developmental Disorders Research Registry 
participants (eProtocol #9345; PI: Antonio Hardan). An email letter and flyers will be 
distributed to the Autism and Developmental Disorders Research Registry participants.  
 
Participants may also be recruited via the Simons Foundation Powering Autism Research 
for Knowledge (SPARK). SPARK will inform families about our study via email.  
 

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Flyers will be posted  throughout the community in public places and also on craigslist, 
Facebook, Berkeley Parent Network, and various websites such as the Stanford Autism 
Research website (PI: Antonio Hardan), the Stanford Autism Center website, the 
Stanford Social Neuroscience Research Program (PI: Karen Parker), the Stanford 
Department of Psychiatry Recruitment website, the Bay Area Autism Consortium 
website, ClinicalTrials.gov, resourcesmatch.org, the Stanford Clinical Trials website, and 
centerwatch.com. 
 
Additionally, participants may be recruited via the Interactive Autism Network (IAN). 
The Interactive Autism Network Project will inform families about our study in two 
distinct ways: via email (for Interactive Autism Network Research families meeting our 
study criteria) and via the Interactive Autism Network Community Research 
Opportunities Bulletin Board (for the public at large). If participants are interested in 
participating, they can fill out an online survey with basic contact information, or call the 
research staff who will explain the study using the advertisement phone script. If 
participants remain interested in participating, the research staff will obtain their 
informed consent as outlined above. The same process outlined above will be used for 
participants recruited from the flyers and email letters. 
 
h. 
Eligibility Criteria 
i. 
Inclusion Criteria 
All participants will meet the following:  
a) Medically healthy outpatients between 6 and 17 years of age; 
b) Diagnostic and Statistical Manual 5th edition (DSM-5) criteria for Autism 
Spectrum Disorder on the basis of clinical evaluation, confirmed with the Autism 
Diagnostic Interview Revised and Autism Diagnostic Observation Schedule, 2nd 
edition or the Childhood Autism Rating Scale, 2nd Edition; 
c) Males and females; 
d) IQ of 40 and above; 
e) Rating of 4 or higher on the Social Communication domain of the Clinical Global 
Impressions Severity; 
f) Social Responsiveness Scale, 2nd edition Total score of 70 and above; 
g) Care provider who can reliably bring participant to clinic visits, provide 
trustworthy ratings, and interact with participant on a regular basis; 
h) Stable concomitant psychotropic medications or medications potentially affecting 
vasopressin for at least 4 weeks (with the exception of fluoxetine, 6 weeks); 
i) No planned changes in psychosocial and biomedical interventions during the trial; 
j) Willingness to provide blood samples and ability to participate in key study 
procedures (i.e., diagnostic assessments and laboratory safety measurements). 
ii. 
Exclusion Criteria 
Participants will be excluded if one or more of the following are met:  
a) DSM-5 diagnosis of schizophrenia, schizoaffective disorder, or psychotic disorder; 
b) Regular nasal obstruction or nosebleeds; 

27MAR2020 
 
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c) Unstable medical conditions such as migraine, asthma attacks, or seizures, and 
significant physical illness (e.g., serious liver disease, renal dysfunction, or cardiac 
pathology); 
d) Clinically significant abnormal EKG reading; 
e) History of hypersensitivity to vasopressin, its analogs, or compounding 
preservatives (e.g., chlorobutanol); 
f) Evidence of a genetic mutation known to cause ASD or intellectual disability (e.g., 
Fragile X Syndrome); or metabolic or infectious etiology for ASD on the basis of 
medical history, neurologic history, and available tests for inborn errors of 
metabolism and chromosomal analysis; 
g) Significant hearing or vision impairments; 
h) Habitually drinks large volumes of water; 
i) Pregnant or sexually active females not using a reliable method of contraception; 
j) Current use of any medications known to interact with vasopressin including: 1) 
carbamazepine (i.e., Tegretol); chlorpropamide; clofibrate; urea; fludrocortisone; 
tricyclic antidepressants (all of which may potentiate the antidiuretic effect of 
vasopressin when used concurrently); 2) demeclocycline; norepinephrine; lithium; 
heparin; alcohol (all of which may decrease the antidiuretic effect of vasopressin 
when used concurrently); 3) ganglionic blocking agents including benzohexonium, 
chlorisondamine, pentamine (all of which may produce a marked increase in 
sensitivity to the pressor effects of vasopressin); 
k) Previous participation in a vasopressin clinical trial or current use of vasopressin; 
l) Current use of desmopressin (DDAVP) or oxytocin.  
iii. 
Screening Procedures: 
Consent will be obtained before any screening procedures can begin. A review of the 
medical and psychiatric history of participants will occur during the screening 
procedures in order to determine study eligibility. Clinically significant abnormal 
vital signs, EKG readings, and clinical chemistry labs will be determined according 
to Lucile Packard Children’s Hospital standards and expert opinion from trained 
physicians. 
i. 
Participation in Multiple Protocols 
Participants will not be allowed to be enrolled in any other medication or behavioral trials 
during their participation in the current research study. 
j. 
Payments to Participants 
Participants will be paid $60 for the first visit and $30 for each additional completed visit. 
k. 
Costs to Participants 
There will be no costs charged to the participants. 
l. 
Planned Duration of the Study 
The entire study will last as long as six years to complete and will be followed by a 
period of 6 months of data analysis. A participant could be in the study for approximately 
14 weeks including the initial screening period, the 8-week blinded treatment trial. The 

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optional open-label extension study (only for those participants randomized to the 
placebo-placebo group) will take an additional 4 weeks to complete. 
 
9. 
RISKS 
a. 
Potential Risks 
i. 
Investigational devices 
NA 
ii. 
Investigational drugs 
Vasopressin side effects: There is presently no readily available list of side effects 
based on a common-rare continuum for vasopressin. There are several routes of 
administration for vasopressin: intramuscular (IM), subcutaneous (SC), intravenous 
(IV), and intranasal (IN). In the present study, the intranasal administration route will 
be used. There are limited side effects associated with the intranasal route of 
administration for vasopressin. However, as discussed below, there are a number of 
potential side effects observed when vasopressin is administered by injection (i.e., 
intramuscular, subcutaneous, intravenous). It is crucial to differentiate between the 
side effects specifically associated with different routes of administration.  
 
Intranasal administration: Information regarding the safety profile of intranasal 
vasopressin administration comes mostly from several clinical trials examining the 
efficacy of vasopressin for enhancing neurocognitive functioning. Additionally, 
although the typical administration route for treatment of central diabetes insipidus 
(CDI) is some form of vasopressin injection, some patients (including children) have 
primarily used a nasal route of administration to treat their disease, or use a 
vasopressin nasal spray as an adjunct to vasopressin injections [1-4]. Importantly, a 
large number of studies have provided convincing evidence for intranasal vasopressin 
being very well tolerated [1-13]. As mentioned, the majority of these studies have 
aimed to investigate the impact of intranasal vasopressin on neurocognitive 
processes.  
 
Given the relatively large size of vasopressin (>1 kD), injections of this polypeptide 
are not considered to reach the brain in significant quantities due to the restrictions of 
the blood-brain barrier (BBB) [14]. Nasal routes of administration are purported to 
overcome the restrictions of the blood-brain barrier for large molecule peptides, 
including vasopressin, making it a preferred administration route for targeted central 
nervous system treatment. Born et al. [15] provided convincing evidence of this by 
showing that intranasal vasopressin (40 and 80 IU) administered to healthy adult 
males and females significantly increased cerebrospinal fluid concentrations of the 
peptide compared to placebo administration; vasopressin levels had not returned to 
baseline at the end of the 80-minute sampling period. Blood concentrations of 
vasopressin also increased but were only slightly (non-significantly) correlated with 
cerebrospinal fluid levels. The nasal route of administration is generally considered 
much safer than injections of vasopressin for multiple reasons. Not only is the risk of 

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local infection or transfer of contagious blood borne disease substantially reduced, far 
fewer peripheral effects are noted with intranasal administration of vasopressin [5-
13]. For example, several recent studies have outlined the ability of intranasal 
vasopressin (20 and 40 IU) to enhance complex psychosocial functioning and 
associated brain activity when given in single-doses to healthy adults [5,6,11-13]. 
Only minor and transient side effects (relaxation/tiredness, headache, dizziness, bitter 
taste, nasal irritation, increased diastolic blood pressure) were reported by a small 
number of participants and were experienced following both administration of 
vasopressin and placebo.  
 
Chronic dosing with intranasal vasopressin, as proposed in the current study, has also 
been shown in several studies to be very well tolerated [8-10]. In a study of 26 
elderly individuals utilizing a blinded, randomized, placebo-controlled, 10-week trial 
of intranasal vasopressin administration (20 IU, bid) for treatment of sleep 
disturbances, no major side effects were reported across multiple safety measures 
[10]. A self-rating scale of complaints did not reveal any side effects of the intranasal 
vasopressin treatment. Cardiovascular monitoring revealed a systolic blood pressure 
that was slightly elevated 60 minutes after vasopressin administration, but not 8-12 
hours later. Measurements of diastolic blood pressure and heart rate did not indicate 
any treatment effects. Examination of blood pressure and heart rate on a weekly basis 
during the 10-week study period revealed values in the normal range and no 
treatment related differences. At the end of the trial, measurement of sodium, 
osmolality, and hematocrit did not reveal any treatment effects, and values were 
entirely within the normal range.  
 
In our pilot intranasal vasopressin trial, minimal side effects were reported, including 
fever, cough, body aches, excitement/agitation, increased motor activity, insomnia, 
headache, decreased motor activity, akathisia, depressive affect, drowsiness, head 
banging, nasal congestion, blurred vision, dry mouth, decreased appetite/anorexia, 
nausea/vomiting, constipation, increased urination, bed wetting, skin rash, bug bite, 
lethargy/tiredness, feeling emotional, bloody nose, stinging sensation in the nose, and 
burning sensation in the throat.  
 
Taken together, the studies outlined above suggest that intranasal vasopressin 
administration at the doses proposed here is very well tolerated. Below is a list of 
side effects reported from a small number of participants following intranasal 
vasopressin (and placebo) treatment.  
 
In our prior pilot vasopressin trial at Stanford, sneezing, gagging, and sore throat, 
have also been reported.  
 
Reported side effects following intranasal vasopressin (and placebo) administration 
(NB: These side effects were all minor and transient):  
• 
Relaxation or tiredness  
• 
Headache  
• 
Dizziness  
• 
Increased systolic blood pressure  

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• 
Increased diastolic blood pressure  
• 
Bitter taste  
• 
Nasal irritation  
 
Vasopressin administered by injection: Ten IU of vasopressin (0.5 mL) given 
intramuscularly will usually elicit full physiologic response in adult patients. The 
manufacturer recommends that in the average postoperative adult, an initial 5 IU 
dose, increased to 10 IU, if necessary, should be given intramuscularly every 3 to 4 
hours for treating abdominal distention. In preparation for roentgenography, the 
average patient will require two intramuscular injections of 10 IU given two hours 
and one half-hour, respectively, before films are exposed. For treating central 
diabetes insipidus, vasopressin may be administered subcutaneously or intranasally. 
The dose of injection is 5 to 10 IU repeated two or three times daily as needed. When 
vasopressin is administered intranasally for treating central diabetes insipidus, the 
dosage and interval should be adjusted for each patient [16].  
 
Many of the side effects listed by the manufacturer are associated with injections of 
vasopressin and result from its vasoconstrictive properties mediated by vasopressin 
V1a receptors. These side effects include cardiac arrest and/or shock, circumoral 
pallor, arrhythmias, decreased cardiac output, angina, myocardial ischemia, and 
peripheral vasoconstriction. Gastrointestinal side effects may include abdominal 
cramps, diarrhea, intestinal hyperactivity, nausea and vomiting. Bronchial 
constriction, tremor, vertigo and “pounding” in the head have also been reported. 
Skin changes may also occur following vasopressin injection and include sweating, 
urticarial (rash), and cutaneous gangrene. Additionally, some individuals may 
experience a severe hypersensitivity to vasopressin or its excipients (e.g., 
chlorobutanol as preservative) (see Kim et al. [17] for a review of vasopressin side 
effects). In recent years, an increase has been noted in the use of intravenous 
vasopressin treatment for hemodynamically unstable infants and children following 
cardiothoracic surgery [18].  
 
This treatment has been associated with reports of water intoxication/hyponatremia 
associated with prolonged intravenous vasopressin. Careful monitoring of 
cardiovascular parameters and serum sodium values is important when vasopressin is 
given to intensive care patients or to those with underlying cardiovascular pathology 
or a known sensitivity to the drug or its excipients. For outpatients, drinking a glass 
of water when taking vasopressin is reported to reduce some of the skin and 
gastrointestinal effects. However, close monitoring of fluid intake and output should 
also be considered during vasopressin treatment. Less free water should be given in 
cases where hyponatremia may be a concern. Several studies have shown that 
regulation of fluids and close monitoring of electrolyte balance substantially reduce 
the risk of hyponatremia in children treated with intravenous vasopressin [19,20].  
 
Reported side effects following injections (intramuscular, subcutaneous, intravenous) 
of vasopressin:  
• 
Abdominal cramps  
• 
Diarrhea  

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• 
Intestinal hyperactivity  
• 
Nausea  
• 
Vomiting  
• 
Passage of gas  
• 
Blanching of skin  
• 
Sweating  
• 
Tremor  
• 
Vertigo  
• 
“Pounding” in head  
• 
Bronchial constriction  
• 
Urticarial  
• 
Circumoral pallor  
• 
Cutaneous gangrene  
• 
Anaphylaxis (cardiac arrest and/or shock)  
• 
Arrhythmias  
• 
Decreased cardiac output  
• 
Angina  
• 
Myocardial ischemia  
• 
Peripheral vasoconstriction  
• 
Gangrene  
• 
Hyponatremia/water intoxication (possibly resulting in seizure or coma)  
 
FDA indications for vasopressin administration: The formulation of vasopressin to be 
used in the proposed research is VasostrictTM (Vasopressin Injection, USP; 
manufactured by PAR Pharmaceutical, an Endo International Company, Chestnut 
Ridge, NY). The drug has FDA marketing approval for increasing blood pressure in 
adults with vasodilatory shock. This study is a Phase II clinical trial that aims to 
investigate both the efficacy and tolerability of intranasal vasopressin treatment for 
social, cognitive, and behavioral problems in children with ASD. Several other US 
research groups have received FDA approval to investigate the effects of intranasal 
vasopressin administration for enhancing neurocognitive functioning in both healthy 
adults and people with ASD (e.g., see NCT01327027, NCT01566539, 
NCT01680718, NCT01093768).  
 
Contraindications and precautions for vasopressin administration: The safety 
concerns listed in the section above for vasopressin injections are considered rare if 
precautions are adhered to. The package insert for Vasopressin Injection, USP lists 
several precautions and contraindications associated with this drug. Contraindications 
for the use of vasopressin include anaphylaxis or hypersensitivity to the drug or its 
components (e.g., chlorobutanol as a preservative). This drug is not recommended for 
use in patients with vascular disease, especially disease of the coronary arteries, 
except with extreme caution. In such patients, even small doses may precipitate 
angina pain; with larger doses, the possibility of myocardial infarction should be 
considered. Vasopressin may also produce hyponatremia/water intoxication and is 
contraindicated in patients who habitually drink large volumes of water (e.g., habitual 
or psychogenic polydipsia). For this reason, the early signs of drowsiness, 
listlessness, and headaches should be recognized to prevent terminal coma and 

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convulsions. Vasopressin should also be used with caution in the presence of 
epilepsy, migraine, asthma, heart failure, or any state in which a rapid addition to 
extracellular water may produce hazards for an already overburdened system. These 
contraindications are reflected in the extensive exclusion criteria and safety 
monitoring used in this study. Research utilizing vasopressin treatment in children 
provides convincing evidence for vasopressin being well tolerated if fluid intake is 
monitored closely during the treatment period [e.g., 20].  
 
An additional concern with using vasopressin is the potential for increased 
aggression. This concern is based on specific preclinical animal studies; however, to 
the investigators’ knowledge no evidence has demonstrated that vasopressin 
increases aggressive behavior when administered to humans. Research on 
vasopressin and aggression in rodents has generally shown that vasopressin increases 
aggression in: 1) non-monogamous adult male residents when an adult male intruder 
is introduced into his “territory” (i.e., home cage), and 2) monogamous adult male 
residents when an adult male intruder is introduced into his territory, which 
sometimes includes the mate and pups [21,22]. One can argue that increased 
aggression in these behavioral assays is adaptive. In the context of the second 
example, increased aggression in the presence of mate/pups in the home territory is a 
protective response that is prosocial in nature, at least regarding the resident male’s 
family. Nevertheless, we acknowledged that monitoring aggression in children in our 
pilot treatment trial was an important precaution. We found no evidence that blinded 
vasopressin treatment increased aggression in our pilot vasopressin trial. We will 
continue to regularly inquire about aggressive behavior throughout this larger phase 
II study.  
 
No reliable data are available on the developmental risks of vasopressin 
administration in children. The main purpose of our study is to determine the safety 
and efficacy of intranasal vasopressin administration in children with ASD. We will 
report any serious adverse events to the IRB and FDA according to law and will 
detail this information in published articles and presentations.  
 
References 
1 
Chirman, S. B. & Kinsell, L. W. Diabetes insipidus. Treatment with 8-lysine 
vasopressin in a nasal spray. California Medicine 101, 1-3 (1964).  
2 
Dashe, A. M. et al. Synthetic vasopressin nasal spray in treatment of diabetes 
insipidus. Journal of the American Medical Association 190, 1069-1071 (1964).  
3 
Moses, A. M. Synthetic lysine vasopressin nasal spray in treatment of diabetes 
insipidus. Clinical Pharmacology & Therapeutics 5, 422-427 (1964).  
4 
Hung, W. Treatment of diabetes insipidus in children with synthetic lysine-8-
vasopressin nasal spray. Medical Annals of the District of Columbia 36, 400-401 
(1967).  
5 
Guastella, A. J. et al. Intranasal arginine vasopressin enhances the encoding of 
happy and angry faces in humans. Biological Psychiatry 67, 1220-1222 (2010).  
6 
Guastella, A. J. et al. Arginine Vasopressin selectively enhances recognition of 
sexual cues in male humans. Psychoneuroendocrinology 36, 294-297 (2011).  

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7 
Laczi, F. et al. Effects of lysine-vasopressin and 1-deamino-8-D-arginine-
vasopressin on memory in healthy individuals and diabetes insipidus patients. 
Psychoneuroendocrinology 7, 185-193 (1982).  
8 
Perras, B. et al. Verbal memory after three months of intranasal vasopressin in 
healthy old humans. Psychoneuroendocrinology 22, 387-396 (1997).  
9 
Perras, B. et al. Beneficial treatment of age-related sleep disturbances with 
prolonged intranasal vasopressin. Journal of Clinical Psychopharmacology 19, 28-36 
(1999).  
10 Perras, B. et al. Improvement of sleep and pituitary-adrenal inhibition after 
subchronic intranasal vasopressin treatment in elderly humans. Journal of Clinical 
Psychopharmacology 23, 35-44 (2003).  
11 Rilling, J. K. et al. Effects of intranasal oxytocin and vasopressin on cooperative 
behavior and associated brain activity in men. Psychoneuroendocrinology 37, 447-
461 (2012).  
12 Zink, C. F. et al. Vasopressin modulates social recognition-related activity in the 
left temporoparietal junction in humans. Translational Psychiatry 1(4):e3 (2011).  
13 Zink, C. F. et al. Vasopressin modulates medial prefrontal cortex-amygdala 
circuitry during emotion processing in humans. Journal of Neuroscience 30, 7017-
7022 (2010).  
14 Ermisch, A. et al. On the blood-brain barrier to peptides: accumulation of 
labelled vasopressin, DesGlyNH2-vasopressin and oxytocin by brain regions. 
Endocrinologia Experimentalis 19, 29-37 (1985).  
15 Born, J. et al. Sniffing neuropeptides: a transnasal approach to the human brain. 
Nature Neuroscience 5, 514-516 (2002).  
16 American Regent (N.Y.). Vasopressin Injection, USP Package Insert. (2011).  
17 Kim, R. J. et al. Vasopressin and desmopressin in central diabetes insipidus: 
Adverse effects and clinical considerations. Pediatric Endocrinology Reviews: PER 2 
Suppl 1, 115-123 (2004).  
18 Davalos, M. C. et al. Hyponatremia during arginine vasopressin therapy in 
children following cardiac surgery. Pediatric Critical Care Medicine 14(3) 290-297 
(2013).  
19 Mishra, G. & Chandrashekhar, S. R. Management of diabetes insipidus in 
children. Indian Journal of Endocrinology and Metabolism 15 Suppl 3, S180-187 
(2011).  
20 Wise-Faberowski, L. et al. Perioperative management of diabetes insipidus in 
children. Journal of Neurosurgical Anesthesiology 16, 220-225 (2004).  
21 Albers, H. E. The regulation of social recognition, social communication and 
aggression: Vasopressin in the social behavior neural network. Hormones and 
Behavior 61, 283-292 (2012).  
22 Young, L. J., Wang, Z. X. & Insel, T. R. Neuroendocrine bases of monogamy. 
Trends in Neurosciences 21, 71-75 (1998). 
 
iii. 
Commercially available drugs, biologics, reagents or chemicals 
NA 
iv. 
Procedures 

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Screening measures  
Medical and psychiatric screening will be conducted under the supervision of Dr. 
Antonio Hardan, a board-certified child and adolescent psychiatrist, to determine 
participants’ eligibility to take part in the trial. A physical examination will be 
completed on all participants. Parents and children will be interviewed to determine 
relevant information pertaining to the child’s lifetime medical and psychiatric health.  
 
The Clinical Global Impression Scale (CGI) [1] consists of 3 subscales: severity of 
illness (CGI-S), global improvement (CGI-I), and therapeutic index. The severity of 
the illness is scored from 1= normal to 7= extremely ill. The patient's improvement is 
scored on a 7-point scale which ranges from markedly improved (1), to no change 
(4), and to very much worse (7). The Clinical Global Impressions Scale – Severity 
has been widely used in psychopharmacological studies and has been shown as 
highly sensitive to medication effects [2]. Consistent with the Research Unit on 
Pediatric Psychopharmacology (RUPP) Autism Network, a score of 3 (mildly ill) on 
the severity of illness scale will be assigned to participants based upon the core 
features of ASD. Higher scores will be assigned based on the presence of other, 
secondary behaviors. The Clinical Global Impressions Scale – Improvement is a 
subscale scored from 1 (very much improved) to 7 (very much worse). A score of 4 
reflects no change. Positive response is defined by a score of 2 (much improved) or 1 
(very much improved) at week 4. The scores on the severity of illness and 
improvement scale will be based on parent interview, parent-completed behavior 
problem checklists, as well as direct observation of the child. The CGI-S will be used 
as a screening tool and as an outcome measure. CGI-I will be used as an outcome 
measure to assess improvement observed during the trial that is due to vasopressin 
treatment.  
 
The Autism Diagnostic Interview-Revised (ADI-R) [3] is a reliable and well 
validated research diagnostic instrument administered to participants’ parents and 
consists of 88 items that are informed by the ICD-10 and DSM-5 diagnostic criteria 
for ASD. To meet these criteria, the participant must have a score higher than a pre-
specified cut-point in the three symptom areas of the ICD-10 diagnostic system, and 
must also have an age of onset prior to 3 years.  
 
The Autism Diagnostic Observation Schedule, 2nd edition (ADOS-2) [4,5] is a 
reliable and well validated semi-structured clinical and research diagnostic 
instrument that allows assessment through behavioral observations during specific 
play, social, and language tasks. The ADOS-2 provides empirically-based thresholds 
for diagnoses of autism and autism spectrum. The ADI-R and  ADOS-2 will be used 
in conjunction with expert clinical opinion guided by DSM-5 criteria to assess for the 
presence of a diagnosis of ASD.  
 
The Childhood Autism Rating Scale, 2nd Edition (CARS-2) is a clinician-rated 
questionnaire that allows for ASD diagnosis assessment through behavioral 
observations and additional information such as parent and/or teacher reports [6]. 
CARS-2 consists of 15 items that cover social, emotional, adaptive, communicative, 
and cognitive functions. CARS-2 (standard form) is “for use with individuals 

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younger than 6 years of age and those with communication difficulties or below-
average estimated IQs” and CARS-2-HF (high functioning) is used for “assessing 
verbally fluent individuals, 6 years of age and older, with IQ scores above 80”. The 
Childhood Autism Rating Scale, 2nd edition will be used as an alternative to the 
ADOS-2 for participants who enroll in the trial after the COVID-19 protocol 
changes; CARS-2 can be administered via Zoom.   
 
The Stanford Binet, 5th edition (SB-5) [7] will be administered to determine 
intellectual functioning. Participants must have an IQ of 40 or higher to meet 
inclusion criteria. The SB-5 provides an overall (Full Scale) IQ score, as well as 
Verbal and Nonverbal IQ scores. Tasks are broken into five domains of cognitive 
functioning: Fluid Reasoning, Knowledge, Quantitative Reasoning, Visual-Spatial 
Processing, and Working Memory. Age-referenced standard scores, as well as raw 
scores for cognitive domains, are available. If participants have already undergone 
previous IQ testing with a different instrument, such as one of the Weschler scales, 
the research team will review the assessment report to determine its suitability in 
place of the SB-5.  
 
The Wechsler Intelligence Scale for Children, 5th Edition (WISC-V) is an 
individually administered, comprehensive clinical instrument that will be 
administered to assess intelligence [8]. The primary index scores represent 
intellectual functioning in five cognitive areas: Verbal Comprehension Index, Visual 
Spatial Index, Fluid Reasoning Index, Working Memory Index, and the Processing 
Speed Index. The assessment also includes a Full-Scale IQ composite score 
representing general intellectual ability. The WISC-V will be used as an alternative to 
the SB5 for participants who enroll in the trial after the COVID-19 protocol changes; 
the WISC-V can be administered in a modified manner via Zoom, following 
publisher guidelines.  
 
Phenotyping measures:  
The Wing Subgroups Questionnaire (WSQ) [9] will be administered to classify 
participants into distinct social subtypes to test whether social phenotype affects 
treatment efficacy. The three subtypes are: active-but-odd (actively seeks social 
interaction with others but does so in an awkward manner); passive (does not engage 
in social approach but responds when approached and will remain socially engaged); 
or aloof (fails to approach others and withdraws if approached). The Wing Subgroup 
Questionnaire has criterion-referenced validity and internal consistency [10].  
 
Safety measures  
Clinical chemistry labs, including  blood urea nitrogen sodium, potassium, chloride, 
CO2, anion gap, glucose, creatinine, calcium, and blood and urine osmolality, will be 
conducted at screening prior to participants being allocated to treatment groups to 
determine eligibility status and Visits 4 and 6 to assess for drug safety. Blood 
samples will be collected at the Lucile Packard Children’s Hospital phlebotomy lab 
or locally through the participant’s primary care physician’s office. As much as 
30mL of blood will be collected (including the blood collected for research 
biomarker measures).  

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An EKG will be performed at screening prior to participants being allocated to 
treatment groups to determine eligibility status and at Visits 4 and 6 to assess for drug 
safety. A trained investigator will place the leads for measurement of basal cardiac 
function.  
 
Vital signs including heart rate, blood pressure, and body temperature will be 
assessed at each visit. Participants enrolled in the trial after the COVID-19 protocol 
changes will have the above assessed at Visits 1, 4, 6, and 8 (if applicable).  
 
Height and weight will be measured at each visit. Participants enrolled in the trial 
after the COVID-19 protocol changes will have height and weight measured at 
screening, Visit 4, Visit 6, and Visit 8 (if applicable). Fluctuations in weight can 
provide important information on the diuretic effects of vasopressin and will be used 
to determine alterations in weight gain or loss potentially related to changes in 
appetite/metabolism resulting from the treatment.  
 
The Dosage Record and Treatment Emergent Symptom Scale (DOTES) will be used 
to assess general physical and psychiatric side effects. The Dosage Record and 
Treatment Emergency Symptom Scale is a general rating scale published by the 
Early Clinical Drug Evaluation Unit of the National Institute of Mental Health [11]. 
The scale has been widely used clinically for children and adults to assess many 
central nervous system side effects as well as some behavioral side effects [12]. We 
have modified the Dosage Record and Treatment Emergency Symptom Scale to 
include relevant questions regarding hydration status.  
 
The Overt Aggression Scale (OAS) will be administered to determine changes in 
aggressive behavior throughout the study. The Overt Aggression Scale is designed to 
assess observable aggressive or violent behavior and has been used in children with 
different neuropsychiatric disorders [13,14].  
 
All safety assessments outlined above will be repeated during the optional open-label 
vasopressin treatment extension period. We will also perform pharmacokinetics 
analysis during the open-label treatment period as outlined previously.  
 
Urine pregnancy tests will be administered to all female participants of childbearing 
age. Females, who are at least 12.5 years old or have a history of menstruating, must 
have a negative pregnancy test before participating in this study.  
 
 
 
 
Primary outcome measure 
 
The Social Responsiveness Scale, 2nd edition (SRS-2) [15-17] is a norm-referenced 
questionnaire developed to measure social behavior in both clinical and non-clinical 
populations. The Social Responsiveness Scale, 2nd edition provides age- and gender-

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referenced scores, as well as raw scores for the following domains: Total score, 
Receptive, Cognitive, Expressive, and Motivational aspects of social behavior, and 
Autistic preoccupations. The psychometric properties were tested in younger and 
older participants [15,18]. The Social Responsiveness Scale, 2nd edition Total score 
was continuously distributed within each group and minimally correlated with IQ. 
Post-treatment parent Social Responsiveness Scale, 2nd edition  ratings will be used 
as the primary outcome measure in each treatment arm, and pre-treatment parent 
Social Responsiveness Scale, 2nd edition ratings will be used to assess whether social 
deficit severity affects treatment response efficacy.  
 
Secondary outcome measures  
 
The Clinical Global Impressions Scale – Severity (CGI-S) and Clinical Global 
Impressions Scale – Improvement (CGI-I) are included as secondary outcome 
measures. Please see above for more details about this instrument.  
 
The Repetitive Behavior Scale – Revised (RBS-R) [19] is a rating tool used to 
capture the breadth of repetitive behavior in ASD. The Repetitive Behaviors Scale – 
Revised contains 43 items that are drawn from other instruments and grouped 
theoretically based on the authors’ clinical experience. The Repetitive Behaviors 
Scale – Revised consists of five subscales: 1) Rituals/Sameness; 2) Self-injurious 
behavior; 3) Stereotypical behavior; 4) Compulsive behavior; and 5) Restricted 
interests. Items are rated on a four-point Likert scale ranging from (0) ‘‘behavior 
does not occur’’ to (3) ‘‘behavior occurs and is a severe problem.” Raters are asked 
to refer to the previous month when completing the scale. The Repetitive Behaviors 
Scale – Revised has been validated for use in young children with ASD.  
 
The Spence Children’s Anxiety Scale (SCAS) [20] assesses the frequency with which 
children experience symptoms relating to obsessive-compulsive disorder, separation 
anxiety, social phobia, panic/agoraphobia, generalized anxiety/overanxious disorder, 
and fears of physical injury. The Spence Children’s Anxiety Scale has high internal 
consistency for the total score and factor scores, acceptable for 6-month test-retest 
reliability. Results of both confirmatory and exploratory factor analyses were 
supportive of the DSM-IV constructs of anxiety disorders.  
 
The Reading the Mind in the Eyes Test (RMET) [21] will be used to test participants’ 
ability to determine the emotions of others. The Reading the Mind in the Eyes Test is 
a widely used test of theory of mind that assesses individuals’ ability to infer 
complex emotions from the eye region of faces. We will use the child version of the 
test, which consists of 28 images and has modified answer options for ease of use in 
pediatric populations.  
 
The Facial Emotion Recognition Test will be used to assess participants’ ability to 
identify facial emotions of others. The Facial Emotion Recognition Test was derived 
from the NimStim Set of Facial Expressions that required participants to identify the 
correct facial emotion displayed by each face stimulus [22]. Participants are required 
to select an emotion from a list of seven possible emotions (angry, calm, disgusted, 

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happy, sad, scared, and surprised) and are administered a total of 42 face stimuli per 
test session. 
 
Optional high-density EEG: Outcome measures will include spectral power in the 
alpha, theta, and gamma frequencies. The exploratory outcome measure includes 
EEG coherence. Resting-state EEG will be recorded from participants comfortably 
seated with their eyes open during each visit at which EEG is collected. Participants 
will be familiarized with all experimental materials prior to recording and provided 
with an explicit visual schedule to diminish any undue stress associated with novel 
environments, equipment (e.g., electrode caps), or support staff. A practice cap will 
also be made available for participants should further familiarization be requested. 
Data will be collected using a 64-channel Ag/AgCl electrode cap (ANT North 
America, Madison, WI) and continuously digitized at 500Hz with an asalab Turnkey 
System (Madison, WI). Placement of electrodes will conform to the International 10–
20 System. MNE will be used to pre-process data and monitor impedances to be less 
than 10kOhms. Approximately 5 minutes of continuous EEG will be recorded as 
participants sit with eyes open. Offline processing will be performed using the MNE 
neuroimaging suite and includes (but is not limited to) re-referencing to linked-ear 
mastoids, correction of DC drift, and the removal of eye-blink artifacts. For 
participants who enroll in the trial after the COVID-19 protocol changes, the EEG 
will not be available. 
 
Other outcome measures 
 
The Vineland Adaptive Behavior Scales, 3rd edition: Social Skills and Relationships 
Domain (VABS-3) will be administered to measure behavioral functioning [23]. The 
participants’ level of expressive and receptive speech will be used as a covariable 
when examining performance on tasks that require adequate language and 
communication skills. The Vineland Adaptive Behavior Scales 3: Social Skills and 
Relationships Domain is a norm-referenced, standardized, parent report/interview 
that measures developmental and behavioral abilities in the areas of socialization, 
communication, daily living skills, and motor skills. This instrument was developed 
for use in people with developmental disabilities, has been used frequently in 
individuals with ASD, and maintains strong psychometric properties [24,25]. 
 
The Pediatric Quality of Life (PedsQL) [26] inventory is a 23-item brief parent 
proxy-report designed not only to measure core dimensions of health as delineated by 
the World Health Organization, but also to capture information about an individual’s 
functioning in educational settings. The inventory has 4 subscales including physical, 
emotional, social, and school functioning. The Pediatric Quality of Life distinguishes 
between healthy children and children with acute and chronic health conditions and 
also distinguishes disease severity within a chronic health condition. 
The NEPSY-II [27] is a widely used and highly validated norm-referenced measure 
of child (3-16 years old) neurocognitive processes. The Theory of Mind subtest will 
be used to assess social perception abilities. This test consists of participants being 
read various scenarios and then asked questions that require knowledge of another 
person’s point of view to answer correctly. 

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Eye Gaze to social cues will be measured while participants view the emotional faces 
presented in the Facial Emotion Recognition assessment using a corneal reflection 
eye tracker. Eye tracking is routinely used with infants and children; it is no different 
from being videotaped with a camera that produces no sensation. For coding of eye 
gaze, four standard a priori regions of interest (the whole face, the eyes, the nose and 
mouth, and the forehead and cheeks) will be created on each face [28]. Data will be 
extracted for these regions of interest and analyzed for levels of gaze duration (total 
amount of time fixating on a region of interest) and fixation counts (number of gaze 
fixations toward a region of interest). The NimStim Set of Facial Expressions has 
been standardized for use with eye tracking and has been used in previous eye gaze 
studies in pediatric participants [29]. For participants who enroll in the trial after the 
COVID-19 protocol changes, the Eye Gaze Assessment will not be performed. 
 
The Child’s Sleep Habits Questionnaire (CSHQ) is the most frequently employed 
measure assessing the quality and type of sleep experienced by children as reported 
by parents/caregiver [30,31]. Thirty-three items are grouped into 8 subscales: 
bedtime resistance, sleep onset delay, sleep duration, sleep anxiety, night 
awakenings, parasomnias, sleep disordered breathing, and daytime sleepiness. To 
calculate subscale scores, each item is rated on a scale from 1 to 3; a higher score 
reflects more sleep disturbance.  Owen et al., (2000) [30] demonstrated internal 
consistency and validity of the Child’s Sleep Habits Questionnaire comparing a 
community sample and a clinical sample. 
 
The Diagnostic Analysis of Nonverbal Accuracy-2 (DANVA-2) is a standardized 
measure that includes child vocal emotion recognition subtests.  Diagnostic Analysis 
of Nonverbal Accuracy-2 scores are associated with subclinical characteristics of 
ASD in non-autistic individuals [32], and are widely utilized to evaluate emotional 
recognition in individuals with ASD [33-35]. The scores reflect the number of errors 
made in identifying the displayed emotion, with a lower score indicating stronger 
performance. 
 
The Stanford Social Motivation Scale, also known as the Stanford Social 
Dimensional Scale (SSDS) [36] was developed by researchers from the Stanford 
Autism Center to enable detailed assessment of key social processes and skills that, if 
impaired, can impede one’s ability to navigate the complexities of the social world. 
The Stanford Social Motivation Scale is a 71-item questionnaire measure. The first 
58 items are appropriate for any child of any language level and have been factor 
analyzed. An additional 13 are language-based items suitable for verbal individuals. 
The  Stanford Social Motivation Scale is a dimensional, quantitative measure 
designed to capture individual differences in social motivation, affiliation, social 
communication, and recognition, as well as unusual social approach in both 
normative and clinical populations. 
 
The Parent Rated Anxiety Scale-ASD (PRAS-ASD) [37] is a 25-item, parent-
reported measure of anxiety symptoms in youth with ASD (age 5-17 years). Parents 
rate the frequency and impairment of anxiety symptoms on a 4-point scale (0 = not 

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present; 1 = present sometimes, not a real problem; 2 = often present and a problem; 
3 = very frequent and a major problem) during the past two weeks.  
 
The Social Responsiveness Scale, 2nd edition (SRS-2) subscales: Five subscales have 
been proposed by the SRS manual and include Social Awareness, Social Cognition, 
Social Communication, Social Motivation, and Restricted Repetitive behaviors. 
Subsequent factor analysis indicated the presence of additional domains including 
Social Avoidance, Emotion Recognition, Interpersonal Relatedness, Insistence On 
Sameness, and Repetitive Mannerisms [38]. A factor analytic analysis that was based 
on the Research Domain Criteria (RDoC) revealed the following social domains: 
Attachment and Affiliation, Non-facial Communication Production, Facial 
Communication Production, and Understanding Mental States [39]. 
 
Biological measurements 
Plasma vasopressin concentrations, as well as related biological measures, will be 
quantified using techniques validated for use in humans. Blood samples for 
measuring plasma-based biomarkers will be collected once pre-treatment and at 
Visits 4 and 6 (for participants in open-label period, Visit 8 as well). Blood collection 
will take place at the Lucile Packard Children’s Hospital phlebotomy lab. The blood 
samples will be immediately placed on wet ice and centrifuged at 1600g for 15 mins 
at 4°C. The plasma layer will be aliquoted, and stored at -80°C in Dr. Parker’s lab. 
As much as 30 mL of blood will be collected (including the blood collected for 
clinical chemistry measurements).  
 
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1 
Guy, W. ECDEU Assessment manual for psychopharmacology-revised (DHEW 
Publ No ADM 76-338). Rockville, MD, U.S. Department of Health, Education, and 
Welfare, Public Health Service, Alcohol, Drug Abuse, and Mental Health 
Administration, NIMH Psychopharmacology Research Branch, Division of 
Extramural Research Programs, 1976, pp 218–222. (2000).  
2 
Campbell, M. & Palij, M. Measurement of side effects including tardive 
dyskinesia. Psychopharmacology Bulletin 21, 1063-1080 (1985).  
3 
Lord, C., Rutter, M. & Le Couteur, A. Autism diagnostic interview-revised: A 
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Lord, C. et al. The autism diagnostic observation schedule-generic: A standard 
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Lord, C. et al. Autism Diagnostic Observation Schedule-WPS. (Western 
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6  Moon, S. J. et al.  Accuracy of the childhood autism rating scale: A systematic 
review and meta‐analysis. Developmental Medicine and Child Neurology 61(9), 
1030-1038 (2019). 
7 
Roid, G. H. Stanford Binet's Intelligence Scales, 5th ed., Technical Manual 
(Riverside Publishing, 2003).  

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8  Pearson Assessments. WISC-V Interpretive Considerations for Sample Report 
(10/20/2020). NCS Pearson, Inc. 
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Castelloe, P. & Dawson, G. Subclassification of children with autism and 
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scheme. Journal of Autism and Development Disorders 23, 229-241 (1993).  
10 O'Brien, S. K. The validity and reliability of the Wing Subgroups Questionnaire. 
Journal of Autism and Development Disorders 26, 321-335 (1996).  
11 Guy, W. ECDEU assessment manual for psychopharmacology. Rev. Rockville, 
MD: U.S. National Institute of Health, Psychopharmacology Research Branch. 
(1976).  
12 Garvey, C. A., Gross, D. & Freeman, L. Assessing psychotropic medication side 
effects among children. A reliability study. Journal of Child and Adolescent 
Psychiatric Mental Health Nursing 4, 127-131 (1991).  
13 Dittmann, S. et al. Cognitive functioning in euthymic bipolar I and bipolar II 
patients. Bipolar Disorders 10, 877-887 (2008).  
14 Martin Fernandez-Mayoralas, D. et al. Treatment with paliperidone in children 
with behavior disorders previously treated with risperidone: An open-label trial. 
Clinical Neuropharmacology 35, 227-230 (2012).  
15 Constantino, J. N. et al. Validation of a brief quantitative measure of autistic 
traits: Comparison of the social responsiveness scale with the autism diagnostic 
interview- revised. Journal of Autism and Development Disorders 33, 427-433 
(2003).  
16 Constantino, J. N. et al. Reciprocal social behavior in children with and without 
pervasive developmental disorders. Journal of Development and Behavioral 
Pediatrics 21, 2-11 (2000).  
17 Constantino, J. N. & Todd, R. D. Autistic traits in the general population: A twin 
study. Archives of General Psychiatry 60, 524-530 (2003).  
18 Pine, E. et al. Quantitative assessment of autistic symptomatology in 
preschoolers. Autism 10, 344-352 (2006).  
19 Bishop, S. L. et al. Subcategories of restricted and repetitive behaviors in 
children with autism spectrum disorders. Journal of Autism and Developmental 
Disorders  43(6), 1287-1297 (2013).  
20 Spence, S. H., Barrett, P. M. & Turner, C. M. Psychometric properties of the 
Spence Children's Anxiety Scale with young adolescents. Journal of Anxiety 
Disorders 17, 605-625 (2003).  
21 Baron-Cohen, S. et al. The "Reading the Mind in the Eyes" test revised version: 
A study with normal adults, and adults with Asperger syndrome or high-functioning 
autism. Journal of Child Psychology and Psychiatry 42, 241-251 (2001).  
22 Tottenham, N. et al. The NimStim set of facial expressions: Judgments from 
untrained research participants. Psychiatry Research 168, 242-249 (2009).  
23 Sparrow, S., Balla, D. A. & Cichetti, D. Vineland Adaptive Behavior Scales, 2nd 
ed., (Pearson Education, Inc., 2005).  
24 Park, C. J. et al. Brief report: The relationship between language skills, adaptive 
behavior, and emotional and behavior problems in pre-schoolers with autism. Journal  
of Autism and Developmental Disorders 42(12), 2761-2766 (2012).  
25 Kjellmer, L. et al. Language and communication skills in preschool children with 
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and adaptive functioning to the variability. Research in Developmental Disabilities. 
33, 172-180 (2012).  
26 Varni, J. W., Seid, M. & Rode, C. A. The PedsQL: Measurement model for the 
pediatric quality of life inventory. Medical Care 37, 126-139 (1999).  
27 Korkman, M., Kirk, U. & Kemp, S. L. NEPSY II. Administrative manual. San 
Antonio, TX: Psychological Corporation (2007).  
28 Guastella, A. J., Mitchell, P. B. & Dadds, M. R. Oxytocin increases gaze to the 
eye region of human faces. Biological Psychiatry 63, 3-5 (2008).  
29 Amso, D. et al. Visual exploration strategies and the development of infants' 
facial emotion discrimination. Frontiers in Psychology 1:180 (2010).  
30  Owens JA, Spirito A, McGuinn M. The children’s sleep habits questionnaire 
(CSHQ): Psychometric properties of a survey instrument for school-aged children. 
Sleep, 23(8):1043-51 (2000). 
31 Markovich AN, Gendron MA and Corkum PV. Validating the Children’s Sleep 
Habits Questionnaire against polysomnography and actigraphy in school-aged 
children. Front. Psychiatry 5:188 (2015).  
32 Ingersoll, B. Broader autism phenotype and nonverbal sensitivity: Evidence for an 
association in the general population. Journal of Autism and Developmental 
Disorders 40, 590–598 (2010).  
33 Berard, N. et al. Executive function, social emotional learning, and social 
competence in school-aged boys with autism spectrum disorder. Canadian Journal of 
School Psychology, 32(3-4), 265-281 (2017).  
34 Hudepohl, M. B. et al. The role of emotion perception in adaptive functioning of 
people with autism spectrum disorders. Autism, 19(1), 107-112 (2015). 
35 Rosen, T.E., Lerner, M.D. Externalizing and internalizing symptoms moderate 
longitudinal patterns of facial emotion recognition in autism spectrum disorder. 
Journal of Autism and Developmental Disorders 46, 2621–2634 (2016).  
36 Phillips, J. M. et al. Development of the Stanford Social Dimensions Scale 
(SSDS): Initial validation in autism spectrum disorder and in neurotypicals. 
Molecular Autism, 10:48 (2019). 
37 Scahill L, et al. Development of the parent-rated anxiety scale for youth with 
autism spectrum disorder. Journal of the American Academy of Child and 
Adolescent Psychiatry, 58, 887–896 (2019). 
38 Frazier, T.W. et al. Confirmatory factor analytic structure and measurement 
invariance of quantitative autistic traits measured by the social responsiveness scale-
2. Autism, 18(1), 31-44 (2014). 
39 Uljarevic, M. et al. Mapping the research domain criteria social processes 
constructs to the Social Responsiveness Scale. Journal of the American Academy of 
Child Adolescent Psychiatry, 59(11):1252-1263 (2020). 
v. 
Radioisotopes/radiation-producing machines 
NA 
vi. 
Physical well-being 
Vasopressin and its analogs have been used for more than 30 years, in both pediatric 
and adult patient groups, to treat central diabetes insipidus, nocturnal enuresis, and 
varying states of shock with very few serious adverse effects, given that simple 

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precautions are adhered to (e.g., water restriction to prevent hyponatremia and water 
intoxication). See above for a comprehensive discussion of potential risks associated 
with vasopressin administration. Obtaining blood can cause bruising and hurt briefly, 
which applying a topical anesthetic can minimize. 
vii. 
Psychological well-being 
There are minimal risks to individuals from interviewing, testing measures, and blood 
draws other than loss of time at school and parental work. The risks associated with 
the testing measures are minimal and are limited to performance anxiety or fatigue. 
There will be an attempt to schedule appointments for assessments at times that 
minimize loss of time from the child's school schedule and caregiver's work. Parents 
may experience some discomfort in responding to questions asked during the initial 
interview or to items on the various measures. Blood collection can also cause stress 
and anxiety for some individuals. Trained pediatric phlebotomists, who have 
extensive experience working with children with ASD, will collect blood at the  
Lucile Packard Children’s Hospital Phlebotomy Clinic. 
 
As detailed above in 9a, there is preclinical data showing that vasopressin can induce 
aggression in several rodent species, under specific circumstances. Although we did 
not observe an increase in aggression in children enrolled in our pilot vasopressin 
trial, we nevertheless will monitor aggression in children in the present trial as a 
precaution. We will regularly inquire about aggressive behavior throughout the study.  
viii. 
Economic well-being 
Low to almost no risk 
ix. 
Social well-being 
Low to almost no risk  
x. 
Overall evaluation of risk 
Medium – therapy with chemotherapy, antibodies, or a non-FDA approved 
potentially toxic drug, invasive procedures such some organ biopsies or catheter 
procedures, and some studies using biological agents 
b. 
International Research Risk Procedures 
NA 
c. 
Procedures to Minimize Risk 
Every precaution will be taken to use the safest and most gentle procedures.  
 
Cognitive and behavioral assessments and paper-and-pencil tests: The risk of the 
cognitive and behavioral tests are minimal and are limited to performance anxiety or 
fatigue. To minimize these problems, testing will not begin until the participant is 
comfortable with the testing environment and the tester. Staff experienced in working 
with children with disabilities will administer the tests, provide breaks as needed, and 
adjust the length of the test sessions to each individual. Participants will be provided with 

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frequent positive feedback and will receive certificates in recognition of their 
participation. Each examiner will be attentive to participant fatigue and provide breaks 
accordingly. Parents/legal guardians may experience discomfort in revealing personal 
information regarding psychiatric and medical status; therefore, we will provide support 
and assure that personal information is kept in a locked cabinet with no personal 
identifiers on the forms except for a participant ID number.  
 
Scheduling during school/caregiver work: Attempts will be made to schedule 
appointments for research assessments at times that minimize absence of the child from 
school and the caregiver from work.  
 
Blood draws: Obtaining blood may hurt briefly and cause bruising, but will be minimized 
by both applying a topical anesthetic and having experienced staff draw blood samples. 
All Lucile Packard Children’s Hospital laboratory staff have considerable experience 
working with children. The phlebotomists are trained to work with youth of a wide age 
range and different neuropsychiatric disorders, including ASD.  
 
Vasopressin side effects: As discussed above, the use of intranasal vasopressin in several 
research studies has been associated with limited side effects. However, in light of the 
young age of participants, the lack of experience with intranasal vasopressin in 
individuals with ASD, and the theoretical pharmacological effects, a series of protective 
measures will be applied to minimize risk and increase monitoring. Briefly (see above for 
full list):  
1. 
Vital signs (heart rate/blood pressure, temperature) monitoring will be conducted 
at each visit. Participants enrolled in the trial after the COVID-19 protocol 
changes will have vital signs measured at screening, Visit 4, Visit 6, and Visit 8 
(if applicable). 
2. 
Height and weight will be measured at each visit. Participants enrolled in the trial 
 
after the COVID-19 protocol changes will have height and weight measured at 
 
screening, Visit 4, Visit 6, and Visit 8 (if applicable). 
3. 
Dosage Record and Treatment Emergency Symptom Scale side effects report 
will be collected at each visit.  
4.  
Overt Aggression Scale will be collected at screening and Visits 3, 4, 5, 6, 7, and 
8 (if applicable). 
5. 
EKG monitoring will be conducted at screening and Visits 4, 6, and 8 (if 
applicable). 
6. 
Clinical chemistry labs will be conducted at screening and Visits 4, 6, and 8 (if 
applicable). 
7. 
A study investigator will be available 24 hours a day to respond to adverse 
events.  
8. 
Participants and their families will be briefed on procedures for responding to 
potential adverse events (see Procedures for Handling Adverse Events section 
below).  
 
All safety procedures will be repeated during the optional open-label extension period.  
 
Procedures for Handling Adverse Events:  

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Outpatient dosing phase: For any adverse events, families will be instructed to contact the 
research coordinator directly during business hours, and through the Stanford page 
operator after hours and during weekends/holidays. (A project coordinator will be 
available 24/7 to respond to safety concerns.) If the adverse event is life threatening, 
participants will be asked to call 911 or referred to the nearest emergency room. If the 
adverse event is not life threatening, the study coordinator will contact the study 
physician who will contact the family directly and inquire about the adverse event. If the 
study physician judges the side effects as minor or benign, a decision will be made 
whether the participant will continue in the study. If side effects are judged as severe and 
might be related to vasopressin, the participants will be told to stop the study drug 
immediately. They will be invited to the clinic within 24 hours for a direct evaluation and 
termination of their participation in the study. If the study physician believes that the 
adverse event requires immediate medical attention, parents will be instructed to contact 
911 or go to the nearest emergency room. The study physician will also have the ability 
to break the blind if it is felt that doing so is in the best interest of the participants’ health.  
 
Any serious adverse events will be reported to the Data Safety and Monitoring Board and 
Stanford IRB within 24 hours and to the FDA within seven calendar days.  
 
Data Safety and Monitoring Board: A Data and Safety Monitoring Board will be 
established to monitor the proposed clinical trial that will be registered with, and receive 
approval from, the FDA as an Investigational New Drug. (This study will also be listed 
on clinicaltrials.gov and on Stanford University’s Clinical Trials Directory.) The Data 
and Safety Monitoring Board will include several physicians who are not involved in the 
research and will be chaired by Glen Elliott, M.D., PhD. The Data and Safety Monitoring 
Board will meet every three months to assess data quality and timeliness, participant 
recruitment, accrual and retention, participant risk-versus-benefit (including review of all 
adverse reactions and SAEs), and any breaches of confidentiality. Reports will be 
submitted to the Stanford University IRB every 3 months, as part of the annual IRB 
review process, as well as for the annual report. We will also submit annual reports to the 
FDA.  
 
Confidentiality: All information from the evaluation and assessment of all participants 
are subject to standard confidentiality procedures followed at Stanford as mandated by 
the IRB. Information will not be released to any party, except with the written consent of 
participants and parents/legal guardians. Participants’ identity will be concealed in data 
records and files by assigned ID codes. Research data will be maintained in locked 
storage cabinets in a locked file room. Only project staff will be allowed in this room. 
The screening, diagnostic, and neuropsychological tests are maintained in folders for 
each participant, stored in locked cabinets, in locked rooms, within a locked suite. When 
data are transferred to data summary sheets, only the participant number will appear on 
the sheet and entered alone into the database.  
 
We will continuously monitor both our procedures and our data to ensure compliance 
with confidentiality guidelines. Research staff members are carefully trained concerning 
both the critical nature of participants’ confidentiality and also the procedures for 

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respecting and maintaining it. They are instructed to file data immediately after 
collection, never to leave unlocked or opened data files unattended, never to discuss 
participants’ behavior outside of the research study, and never to mention the name(s) of 
participants except to other research staff on this project. They are also instructed on the 
procedures for assigning ID numbers and for filing data separately from participant-
identification information. All staff members complete training modules on human 
subjects’ protection and take an examination to obtain certification.  
 
Data and safety monitoring by PIs: Drs. Parker and Hardan will oversee all data and 
safety monitoring. They will hold weekly meetings with staff to discuss progress of the 
research study (data quality, timeliness, and participant recruitment); outcome and 
adverse event data and changes to the benefit-to-risk ratio that would change the design 
of the experiment; and issues related to confidentiality, ensuring that procedures for 
obtaining information in a private manner were performed and that documentation was 
stored in the appropriate locked file cabinets. The PIs will also hold separate monthly 
educational meetings to discuss any new information relevant to this study. They will be 
responsible for reporting any serious and unexpected adverse reactions to the IRB and 
Data and Safety Monitoring Board within 24 hours and also to the FDA within seven 
calendar days. Any identifying information collected from participants in this study will 
be kept strictly confidential. As mentioned above, the participants will be assigned an ID 
code for all data, and all information in research files will be coded using that number 
rather than participants’ names. A name log will be kept in a locked desk in a locked 
office at all times. All data will be entered onto a secured database. Scientifically trained 
and properly authorized employees of the FDA and/or Stanford University may inspect 
the relevant records. We are committed to complying with FDA and IRB policies for 
reporting serious and unexpected adverse events.  
 
For maximal benefit to the field, de-identified data will be made available to other 
investigators through the National Database for Autism Research (NDAR) and related 
information will be included in our consent form.  
 
Columbia-Suicide Severity Rating Scale: Because recent evidence has linked 
psychotropic medications to suicidal behaviors, closely monitoring the mental well-being 
of patients taking these psychotropic medications is important. During Visit 1, suicidal 
ideation/behaviors will be assessed using the Columbia-Suicide Severity Rating Scale, 
and will continue to be administered throughout the trial. The Columbia-Suicide Severity 
Rating Scale is an interview that prospectively assesses suicidal ideation and behavior 
using a semi-structured interview to probe participant responses. Determining the 
presence of suicidal ideation and/or behavior depends on the judgment of the individual 
administering the scale. A trained investigator will administer the Columbia-Suicide 
Severity Rating Scale. Parents/caregivers will complete the interview for participants. 
The study physician will proactively assess participants for suicidality and mood 
disturbances through discussions with the participant and/or parent. Any positive 
responses will be further investigated, and appropriate medical treatment will be initiated. 
The Columbia-Suicide Severity Rating Scale will be completed at baseline, at the end of 
the blinded phase, and at the end of the open-label phase. For baseline, the scale will 
evaluate the last 12 months and for subsequent time points, it will assess any changes 

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from the previous visit. If the study physician determines that the participant should be 
monitored more closely, the scale may be added as needed throughout the study. If, at 
any assessment, the Suicidal Ideation (questions #1-5) score is a 4 or higher, or the 
patient (or parents) answers “yes” to any Suicidal Behavior item (actual attempt, 
interrupted attempt, aborted attempt, preparatory acts or behavior, or suicidal behavior), a 
mental health care professional will further assess and/or treat. Once the participant has 
started study medication, the decision about whether the participant should be withdrawn 
from study treatment will be determined by the protocol director and study physician. To 
note, any study investigator or research staff can refer a participant to the designated 
mental health professional for any concerns about suicidality, even if the participant does 
not meet the criteria detailed above. The participant should not be allowed to leave the 
study center until the results of the Columbia-Suicide Severity Rating Scale are reviewed 
and the participant is not considered to be at risk. If there is doubt about whether a 
participant is at risk, the investigator should obtain appropriate psychiatric consultation 
prior to releasing the participant. 
 
d. 
Study Conclusion 
Outpatient dosing phase: For any adverse events, families will be instructed to contact the 
research coordinator directly during business hours, and through the Stanford page 
operator after hours and during weekends/holidays. (A project coordinator will be 
available 24 hours a day/7 days a week to respond to safety concerns.) If the adverse 
event is life threatening, participants will be told to call 911 or referred to the nearest 
emergency room. If the adverse event is not life threatening, the study coordinator will 
contact the study physician who will contact the family directly and inquire about the 
adverse event. If the study physician judges the side effects as minor or benign, a 
decision will be made whether the participant will continue in the study. If side effects 
are judged as severe and might be related to vasopressin, the participants will be told to 
stop the study drug immediately. They will be asked to come to the clinic within 24 hours 
for a direct evaluation and termination of their participation in the study. If the study 
physician ascertains that the adverse event requires immediate medical attention, parents 
will be instructed to contact 911 or go to the nearest emergency room. The study 
physician will also have the ability to break the blind if it is felt that doing so is in the 
best interest of the participants’ health.  
 
Any serious adverse events will be reported to the Data and Safety Monitoring Board  
and Stanford IRB within 24 hours, and to the FDA within seven calendar days. 
 
 
e. 
Data Safety Monitoring Plan 
i. 
Data and/or events subject to review 
1. Vital signs (Heart Rate/Blood Pressure, temperature) monitoring will be 
conducted at each visit.  
2. Height and weight will be measured at each visit.  

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3. Dosage Record and Treatment Emergency Symptom Scale side effects report 
will be conducted at each visit.  
4.  Overt Aggression Scale will be measured at screening and Visits 3, 4, 5, and 6.  
5. EKG monitoring will be conducted at screening and Visits 4 and 6 
6. Clinical chemistry labs will be conducted at screening and Visits 4 and 6.  
 
All safety assessments outlined above will be repeated during the optional open-label 
extension period. 
ii. 
Person(s) responsible for Data and Safety Monitoring 
A Data and Safety Monitoring Board will be established to monitor the proposed 
clinical trial that will be registered with, and will receive approval from, the FDA as 
an Investigational New Drug. (This study will also be listed on clinicaltrials.gov and 
on Stanford University’s Clinical Trials Directory.) The Data and Safety Monitoring 
Board will include several physicians who are not involved in the research 
investigations and will be chaired by Glen Elliott, M.D., PhD. The Data and Safety 
Monitoring Board will meet every three months to assess data quality and timeliness, 
participant recruitment, accrual and retention, participant risk-versus-benefit 
(including review of all adverse reactions and Serious Adverse Events [Serious 
Adverse Events]), and any breaches of confidentiality. Reports will be submitted to 
the Stanford University IRB every six months, as part of the annual IRB review 
process, as well as for the annual report. We will also submit annual reports to the 
FDA. 
iii. 
Frequency of Data and Safety Monitoring Board meetings 
The Data and Safety Monitoring Board will meet every three months to assess data 
quality and timeliness, participant recruitment, accrual and retention, participant risk 
versus benefit (including review of all adverse reactions and Serious Adverse 
Events), and any breaches of confidentiality. Reports will be submitted to the 
Stanford University IRB every six months, as part of the annual IRB review process, 
as well as for the annual report. We will also submit an annual report to the FDA. 
iv. 
Specific triggers or stopping rules 
The study will end if a serious adverse event is related to the study medication 
resulting in hospitalization or emergency room visit or death. A serious adverse 
reaction is an untoward medical occurrence that at any dose: results in death; is life-
threatening; requires inpatient hospitalization; results in persistent or significant 
disability/incapacity; or is an otherwise important medical event. An important 
medical event may not be immediately life-threatening or result in death or 
hospitalization but, based upon appropriate medical and scientific judgment, may 
jeopardize the patient/participant or may require intervention (e.g., medical, surgical) 
to prevent one of the other serious outcomes. Cancer/Overdose: All cases of cancer 
and overdose will be reported immediately. 
v. 
DSMB Reporting 

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Any serious adverse events will be reported to the Data and Safety Monitoring Board 
and Stanford IRB within 24 hours and to the FDA within seven calendar days. 
vi. 
Will the Protocol Director be the only monitoring entity? (Y/N) 
N 
vii. 
Will a board, committee, or safety monitor be responsible for study monitoring? 
(Y/N) 
Y 
f. 
Risks to Special Populations 
Research involving greater than minimal risk but presenting the prospect of direct benefit to the 
individual subjects. The research presents more than minimal risk to children, but holds out the 
prospect of direct benefit for the individual subject or is likely to contribute to the subject's well-
being. Please provide rationale that: (a) the risk is justified by the anticipated benefit to the 
subjects; (b) the relation of the anticipated benefit to the risk is at least as favorable to the subjects 
as that presented by available alternative approaches; and (c) adequate provisions are made for 
soliciting the assent of the children and permission of their parents or guardians. 
 
Rationale for category selected above: 
a) ASD is a pervasive developmental disorder characterized by core deficits in social behavior 
and communication, and the presence of repetitive/stereotyped behaviors. Recent prevalence rates 
estimate that 1 in 68 children in the US meet criteria for ASD. Good evidence now exists for the 
potential of vasopressin treatment to improve social functioning and relieve other symptoms in 
patients with ASD. Importantly, in the present study vasopressin treatment occurs during 
childhood when the brain is most plastic, and when pharmacotherapies may be maximally 
beneficial.  
 
b) Although several medications are approved for ASD (i.e., the antipsychotics risperidone and 
aripiprazole), none are effective in ameliorating the characteristic social deficits and often result 
in unfavorable side effects (e.g., lethargy and weight gain). No effective pharmacological or 
behavioral treatments are currently available for the core social deficits exhibited in people with 
ASD. Vasopressin is overall a very well tolerated agent with minimal risks if simple precautions 
are adhered to (e.g., water restriction to prevent hyponatremia and water intoxication).  
 
c) Parents of participants will be consented in a private room by a trained investigator. All 
participants who are older than 7 years of age, and also capable of understanding the consenting 
process, will be assented by a trained investigator, in a private room, in the presence of the parent. 
Both parents of participants and the participants themselves will have ample opportunity to ask 
questions and to discuss the risks and potential benefits with Dr. Hardan and the other 
investigators. 
10. 
BENEFITS 
As of now, no effective intervention strategy is aimed at targeting the core symptoms of ASD and 
curbing the long course and guarded prognosis of ASD. Outcome studies indicate that about 2/3 
of autistic adults remain severely handicapped and live in complete dependence or semi-

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dependence. Available agents do aim at controlling associated behavioral features such as 
aggression, agitation and compulsive behaviors. Agents that treat underlying chronic 
neurobiological abnormalities are lacking. The suggested innovative agent (vasopressin), if 
shown to be effective, will lead to the development of new strategies to treat individuals with 
ASD. 
11. 
PRIVACY AND CONFIDENTIALITY 
All participant information and specimens are handled in compliance with the Health Insurance 
Portability and Accountability Act (HIPAA) and privacy policies of Stanford University, Stanford 
Health Care, and Stanford Children’s Health.