A Pharmaco-imaging Approach to Predicting Social Functioning and Clinical Responses to Oxytocin Administration in Schizophrenia
Phase: PHASE2
Conditions: Schizophrenia
Sponsor: VA Office of Research and Development

Protocol; Joshua Woolley, MD, PhD Confidential 
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JOSHUA WOOLLEY, M.D., PH.D. 
CLINICAL RESEARCH PROTOCOL 
A PHARMACO-IMAGING APPROACH TO PREDICTING SOCIAL FUNCTIONING 
AND CLINICAL RESPONSES TO OXYTOCIN ADMINISTRATION IN 
SCHIZOPHRENIA 
Protocol Number: 
v1.5 
Version Date: 
1/25/2023 
Investigational Product: 
Syntocinon (oxytocin) 
IND Number: 
121113 
Development Phase: 
Feasibility, mechanism of action 
Sponsor: 
Joshua Woolley, M.D., Ph.D. 
Funding Organization: 
VA Clinical Science Research & Development Merit Award 
Principal Investigator: 
Name: Joshua D. Woolley 
Telephone: (415)-221-4810 x24117 
Fax: N/A 
E-mail: josh.woolley@ucsf.edu 
Medical Monitor: 
Name: Joshua D. Woolley 
Telephone: (415)-221-4810 x24117 
Fax: N/A 
E-mail: josh.woolley@ucsf.edu 
Coordinating Center: 
If applicable 
 
 
Approval: 
 
 
 
PI or Sponsor Signature (Name and Title) 
Date 
 
This confidential information about an investigational product is provided for the exclusive 
use of investigators of this product and is subject to recall at any time. The information in 
this document may not be disclosed unless federal or state law or regulations require such 
disclosure. Subject to the foregoing, this information may be disclosed only to those 
persons involved in the study who have a need to know, with the obligation not to further 
disseminate this information. 

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TABLE OF CONTENTS 
 
PROTOCOL SYNOPSIS ....................................................................................................................................................... 6 
1 
BACKGROUND ....................................................................................................................................................... 10 
2 
STUDY RATIONALE ................................................................................................................................................. 10 
2.1 
RISK / BENEFIT ASSESSMENT ......................................................................................................................................... 10 
3 
STUDY OBJECTIVES ................................................................................................................................................ 11 
3.1 
PRIMARY OBJECTIVE .................................................................................................................................................... 11 
3.2 
SECONDARY OBJECTIVES ............................................................................................................................................... 11 
4 
STUDY DESIGN ....................................................................................................................................................... 11 
4.1 
STUDY OVERVIEW ....................................................................................................................................................... 11 
5 
CRITERIA FOR EVALUATION ................................................................................................................................... 12 
5.1 
PRIMARY EFFICACY ENDPOINT ....................................................................................................................................... 12 
5.2 
SECONDARY EFFICACY ENDPOINTS .................................................................................................................................. 12 
5.3 
SAFETY EVALUATIONS .................................................................................................................................................. 12 
5.4 
OTHER EVALUATIONS (INCLUDE ONLY IF APPLICABLE) ......................................................................................................... 12 
6 
SUBJECT SELECTION ............................................................................................................................................... 13 
6.1 
STUDY POPULATION .................................................................................................................................................... 13 
6.2 
INCLUSION CRITERIA .................................................................................................................................................... 13 
6.3 
EXCLUSION CRITERIA .................................................................................................................................................... 13 
7 
CONCURRENT MEDICATIONS ................................................................................................................................. 14 
7.1 
ALLOWED MEDICATIONS AND TREATMENTS ..................................................................................................................... 14 
7.2 
PROHIBITED MEDICATIONS AND TREATMENTS .................................................................................................................. 14 
8 
STUDY TREATMENTS .............................................................................................................................................. 14 
8.1 
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS ................................................................................................ 14 
8.2 
BLINDING .................................................................................................................................................................. 15 
8.3 
FORMULATION OF TEST AND CONTROL PRODUCTS ............................................................................................................. 15 
8.4 
SUPPLY OF STUDY DRUG AT THE SITE ............................................................................................................................... 16 
8.5 
STUDY DRUG ACCOUNTABILITY ...................................................................................................................................... 17 
8.6 
MEASURES OF TREATMENT COMPLIANCE ......................................................................................................................... 18 
9 
STUDY PROCEDURES AND GUIDELINES .................................................................................................................. 21 
9.1 
CLINICAL ASSESSMENTS ................................................................................................................................................ 21 
9.1.2 
DEMOGRAPHICS ..................................................................................................................................................... 21 
9.1.3 
MEDICAL HISTORY .................................................................................................................................................. 21 
9.2 
CLINICAL LABORATORY MEASUREMENTS .......................................................................................................................... 22 
10 
EVALUATIONS BY VISIT ...................................................................................................................................... 22 
10.1 
VISIT 1 (DAY 1, REMOTE VISIT) ...................................................................................................................................... 22 
10.2 
VISIT 2 (WEEK 1) ........................................................................................................................................................ 23 
10.3 
VISIT 3 (WEEK 2) ........................................................................................................................................................ 23 
10.4 
VISIT 4 (WEEK 3) ........................................................................................................................................................ 23 

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10.6 VISIT 5 (WEEK 6) ............................................................................................................................................................. 24 
10.7 EARLY WITHDRAWAL VISIT ................................................................................................................................................. 24 
11 
DISCONTINUATION AND REPLACEMENT OF SUBJECTS ........................................................................................ 24 
11.1 
EARLY DISCONTINUATION OF STUDY DRUG ....................................................................................................................... 24 
12.3 
WITHDRAWAL OF SUBJECTS FROM THE STUDY .................................................................................................................. 25 
12.4 
REPLACEMENT OF SUBJECTS .......................................................................................................................................... 25 
12 
STATISTICAL METHODS AND CONSIDERATIONS ................................................................................................. 26 
12.1 
DATA SETS ANALYZED .................................................................................................................................................. 26 
12.2 
DEMOGRAPHIC AND BASELINE CHARACTERISTICS ............................................................................................................... 26 
12.4 
ANALYSIS OF SECONDARY ENDPOINTS .............................................................................................................................. 26 
12.5 
INTERIM ANALYSIS ....................................................................................................................................................... 26 
12.6 
SAMPLE SIZE AND RANDOMIZATION ................................................................................................................................ 26 
13 
DATA COLLECTION, RETENTION AND MONITORING ........................................................................................... 26 
13.1 
DATA COLLECTION INSTRUMENTS ................................................................................................................................... 26 
13.2 
DATA MANAGEMENT PROCEDURES ................................................................................................................................ 27 
13.3 
DATA QUALITY CONTROL AND REPORTING ....................................................................................................................... 27 
13.4 
ARCHIVAL OF DATA ...................................................................................................................................................... 28 
13.5 
AVAILABILITY AND RETENTION OF INVESTIGATIONAL RECORDS .............................................................................................. 28 
13.6 
MONITORING ............................................................................................................................................................. 28 
13.7 
SUBJECT CONFIDENTIALITY ............................................................................................................................................ 28 
14 
ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS ............................................................................. 28 
14.1 
PROTOCOL AMENDMENTS ............................................................................................................................................ 29 
14.2 
INSTITUTIONAL REVIEW BOARDS AND INDEPENDENT ETHICS COMMITTEES ............................................................................. 29 
14.3 
INFORMED CONSENT FORM .......................................................................................................................................... 29 
14.4 
PUBLICATIONS ............................................................................................................................................................ 30 
APPENDIX 1. EXAMPLE OF SCHEDULE OF STUDY VISITS ................................................................................................. 31 

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LIST OF ABBREVIATIONS 
 
AE 
adverse event 
CAINS 
Clinical Assessment Interview for Negative Symptoms 
CFR 
Code of Federal Regulations 
CRF 
case report form 
DMC 
Data Monitoring Committee 
DSMB 
Data Safety Monitoring Board 
DSM-V 
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
FACES 
Facial Expression Coding System 
FDA 
Food and Drug Administration 
fMRI 
Functional Magnetic Resonance Imaging 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
IU 
International Unit 
OT 
Oxytocin 
PI 
Principal Investigator 
rTPJ 
Right Temporal Parietal Junction 
SAE 
Serious Adverse Experience 
SFS 
Social Functioning Scale 
ToM 
Theory of Mind 

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PROTOCOL SYNOPSIS 
 
TITLE 
A pharmaco-imaging approach to predicting social functioning and 
clinical responses to oxytocin administration in schizophrenia 
SPONSOR 
Joshua Woolley, M.D., Ph.D. 
FUNDING 
ORGANIZATION 
VA Clinical Science Research and Development Program 
NUMBER OF SITES 
2 
RATIONALE 
The purpose of this project is to investigate the neural mechanisms of 
oxytocin’s (OT) prosocial effects in patients with schizophrenia. 
Schizophrenia is a prevalent disorder that severely impacts social 
function in affected individuals – it deprives patients of precious 
relationships, undermines lifelong occupational function, and causes 
great stress for families and caregivers. Current treatments for 
schizophrenia are inadequate and have substantial side effects. Thus, 
novel pharmacologic interventions that target key neurophysiological 
deficits in the disease are desperately needed. 
Patients with schizophrenia have significant social cognitive deficits 
including impaired theory of mind (ToM; i.e., impaired understanding 
of other peoples’ mental states) as indexed by poor recognition of 
facial emotion [1],[2]. These deficits interfere with social relationships, 
impact community functioning, and are more common and more 
strongly associated with quality of life and functional outcomes than 
“positive” symptoms such as hallucinations and delusions, and “cold 
cognition” such as executive functioning and working memory. 
Abnormal neural responses underlie these social deficits. Current 
antipsychotic medications are ineffective at treating social deficits, 
improving social functioning, or normalizing neural responses in 
patients with schizophrenia. However, oxytocin, a neuropeptide 
involved in attachment, parenting, and sociality in mammals, has 
promise as a treatment for these deficits. Intranasally administered 
oxytocin is safe for humans and has prosocial and beneficial 
neurophysiological effects in healthy and patient populations. The 
investigators propose to use functional magnetic resonance imaging 
(fMRI) to elucidate the neural mechanisms of oxytocin’s prosocial 
effects on critical social cognitive processes. These experiments will: 
1) Provide high-impact data on how oxytocin affects neural 
mechanisms that underlie social cognition in healthy individuals and 
in patients with schizophrenia; and 2) Lead to a deeper understanding 
of how to intervene to improve functioning in these neural systems. 
STUDY DESIGN 
 
 
This is a double-blind, placebo-controlled, counterbalanced order with 
a cross-over design one week apart, followed by a randomized, 

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double-blind, three week (18-24 days) study design. We will also be 
implementing a response adaptive randomization (RAR) design after 
the first 60 participants complete the study. This will change the 
allocation ratio to favor the drug treatment arm with greater 
improvement in social functioning, while keeping adequate statistical 
power in all arms. 
PRIMARY 
OBJECTIVE 
The objective is to clarify how and in whom exogenous oxytocin 
improves social functioning in schizophrenia as measured by acute 
neural response patterns during social cognitive tasks and social 
functioning as measured by the Social Functioning Scale (SFS). 
SECONDARY 
OBJECTIVES 
Social skills will be assessed during the chronic period over the phone 
or video chat. Participants will answer questions about their social 
interactions and experiences. 
Theory of Mind (ToM) will be assessed using the Hinting Task a well 
validated audiovisual tool that incorporates social interferences. 
 
Negative symptoms will be assessed with Clinical Assessment 
Interview for Negative Symptoms (CAINS), comprising two 
subscales reflecting the negative symptom factors. Data will be 
analyzed with manual and computerized approaches. 
NUMBER OF 
SUBJECTS 
100 total participants 
SUBJECT 
SELECTION 
CRITERIA 
Inclusion Criteria: 
18-70 years of age; meet DSM-V criteria for schizophrenia 
schizophreniform, schizoaffective disorder or brief psychotic disorder; 
no medication changes or psychiatric hospitalizations in the past 
month; SFS raw score of no more than 75. 
 
Exclusion Criteria: 
Active substance use disorder in the past month except mild to 
moderate cannabis use disorder, schizoaffective, schizophreniform 
disorder, or brief psychotic disorder; DSM-5 diagnosis other than 
schizophrenia; Significant neurological/medical disorders; a 
  pacemaker; extensive dental work; claustrophobia; deafness; inability 

Protocol; Joshua Woolley, MD, PhD Confidential 
 
 
 
 
to read; current participation in a psychosocial intervention; taking 
high dose testosterone, estrogen/progesterone. Currently pregnant, 
breastfeeding, or unwilling to practice birth control during 
participation. 
TEST PRODUCT, 
DOSE, AND ROUTE 
OF 
ADMINISTRATION 
fMRI phase: Single dose 40 IU of intranasal oxytocin 
Longitudinal phase: Twice-daily for approximately 3 weeks (18- 24 
days) of 40 IU of intranasal oxytocin 
CONTROL 
PRODUCT, DOSE 
AND ROUTE OF 
ADMINISTRATION 
fMRI phase: Single dose of intranasal placebo 
 
Longitudinal phase: Twice-daily for approximately 3 weeks (18-24 
days) of intranasal placebo 
DURATION OF 
SUBJECT 
PARTICIPATION 
AND DURATION OF 
STUDY 
Subjects will be on study for up to 42 days 
 
Screening: The investigators will contact subjects to conduct a phone 
screening interview to verify eligibility. Screening will take at most 
twenty minutes. In order to reduce number of in-person visits, Visit 1 
has been adapted to be completely remote. Participants will verbally 
consent at the start of Visit 1, before completing any study tasks or 
assessments. Clinical diagnosis will be obtained prior to participation 
and will take up to 4 hours. 
 
Written informed consent will be obtained during Visit 2, the first in- 
person visit, before study drug administration. 
 
Treatment: Subjects will participate in the study for up to 7 weeks. 
The first two visits will be separated by at least 1 week. The third and 
fourth visit will be separated by at least 3 weeks (18-24 days). Each 
visit will be between one to four hours. 
 
The total direction of the study is expected to be 5 years. 54 months 
for subject recruitment. 
CONCOMMITANT 
MEDICATIONS 
Allowed: atypical antipsychotic medication of a consistent, 
therapeutic dose 
 
Prohibited: high dose testosterone or estrogen/progesterone 
EFFICACY 
EVALUATIONS 
The epidemiologist will be evaluating social functioning at multiple 
points throughout the study to determine the drug treatment arm with 
greater improvement which will then be implemented in the RAR 
design. Results will remain blinded to the study staff. 
PRIMARY ENDPOINT 
 
• 
Neural activity from fMRI 

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• 
Social Functioning Scale (SFS) 
SECONDARY 
ENDPOINTS 
• 
Social Skills 
• 
Negative Symptoms 
• 
Theory of Mind 
OTHER 
EVALUATIONS 
 
SAFETY 
EVALUATIONS 
No serious adverse effects have been demonstrated in studies 
examining intranasal administration of OT in numerous patient and 
healthy populations. Therefore, we don’t predict any serious adverse 
events to occur during this study. Documented side effects include 
runny, stuffy, or irritated nose, and more rarely, nausea and vomiting. 
Participants may experience distress due to the nature of personal 
questions about mental health, substance use, and life experiences. 
They may also experience anxiety and/or fatigue due to length of the 
study days. 
PLANNED INTERIM 
ANALYSES 
Interim analysis will be conducted after the first 60 participants have 
completed the study and at multiple points over the course of the 
study. Results will remain blinded to all other study staff. 
STATISTICS 
Primary Analysis Plan 
Linear regression analyses with SFS change and rTPJ activation as the 
primary outcomes and drug modeled as a 2-level dummy variable 
comparing the study drug vs. placebo. 
Similar analyses will be conducted for the secondary clinical 
outcomes including social ability, negative symptoms (CAINS and 
Theory of Mind (Hinting Task). 
Rationale for Number 
of Subjects 
All power and effect size estimates were calculated using STATA/SE 
v. 15.1 using 80% power and two-sided alpha=0.05. To be 
conservative, the investigators used the one-way command with two 
or three groups. The proposed sample size of 100 participants enables 
us to detect effect sizes of 0.23 for the primary hypotheses, which is 
clinically meaningful. 

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1 
BACKGROUND 
 
Oxytocin (OT) is a neuropeptide produced in the hypothalamus that promotes affiliative behavior 
in animals1, and is sometimes called “the bonding hormone.” The OT system has multiple 
interactions with dopaminergic reward pathways and this interplay likely mediates social 
behavior, permitting a range of social behaviors including trust, aggression, pair bonding and 
parenting2. 
 
2 
STUDY RATIONALE 
 
Oxytocin plays an important role in social behavior in mammals, including humans, increasing 
prosocial behavior and improving social cognition in healthy and autistic individuals3. Evidence 
from animal and human models suggests that oxytocin may also play a specific role in the social 
deficits of schizophrenia4,5,6,7. For example, peripheral oxytocin levels increase after a trust- 
related interaction in healthy subjects but not in patients with schizophrenia and this lack of 
response predicts negative symptom6,7 severity. Intranasal oxytocin administration has powerful 
prosocial effects and is extremely well tolerated. After intranasal oxytocin administration, 
healthy subjects gaze more at the information-rich eye region of faces8 and have better ToM9. 
These data indicate that exogenous oxytocin selectively improves various aspects of social 
cognition and raises the possibility that exogenous oxytocin may be an effective adjunct 
treatment for improving social deficits in patients with schizophrenia. Indeed, several small 
recent preclinical studies and our own preliminary data demonstrate that oxytocin has positive 
effects on social cognition in schizophrenia, improving ToM 10,11,12. Furthermore, a recent, small 
clinical trial found that three weeks of intranasal oxytocin decreased negative symptoms of 
schizophrenia13. While early work is promising, sample sizes are small and thus far there has 
been no integration of the observed behavioral effects of oxytocin with assessment of neural 
activity in schizophrenia. 
 
2.1 
Risk / Benefit Assessment 
 
Potential side effects of intranasal OT include a runny, stuffy, or irritated nose. Studies using 
intranasal administration of OT of this dosage have reported no side effects 13,14. PintocinÒ and 
SyntocinonÒ are synthetic and injectable forms of naturally occurring OT regularly used to 
induce uterine contractions in labor. The compounds may cause nausea and vomiting. No serious 
adverse effects have been demonstrated in studies examining intranasal administration of OT in 
numerous patient and healthy populations. 
 
To minimize the risk of side effects and discomforts, study participants will be closely monitored 
for any adverse reactions to the intranasal administration of OT. The proper usage of an 
intranasal device will be demonstrated and explained to participants who may not be familiar 
with this type of drug administration. A medically licensed physician will be available by pager 
throughout the study. 

Protocol; Joshua Woolley, MD, PhD Confidential 
 
 
 
The risks associated with intranasal OT use are minimal. However, all study participants will be 
monitored for any physical side effects and will be provided with additional rest, a drink of 
water, or the option to discontinue the study should these effects occur. 
 
3 
STUDY OBJECTIVES 
 
3.1 
Primary Objective 
The primary objective is to clarify how and in whom oxytocin improves social functioning in 
schizophrenia. The study will assess the effects of exogenous oxytocin on social functioning, 
as measured by the Social Functioning Scale (SFS). Neural activation patterns, as measured 
will be measured by fMRI rTPJ responses during well-characterized social cognitive tasks. 
This will help determine if acute fMRI rTPJ responses to single oxytocin administration 
predicts clinical responses to chronic oxytocin treatment in schizophrenia participants. 
 
3.2 
Secondary Objectives 
The secondary objective is to compare the acute effects of a single administration oxytocin vs. 
placebo, to the clinical and behavioral effects of chronic OT treatment vs. placebo in 
schizophrenia participants. The study will assess the effects of exogenous oxytocin on 
laboratory-based social interactions, Theory of Mind (ToM), and negative symptoms in 
participants with schizophrenia. 
 
4 
STUDY DESIGN 
 
4.1 
Study Overview 
 
100 subjects are planned. During the fMRI phase, intranasal oxytocin and placebo will be 
administered to each subject in a randomized, double-blind, counterbalanced order with a cross- 
over design, at least one week apart. Testing will commence 45 minutes after drug administration 
and continue for no longer than 3 hours. 
 
During the longitudinal phase, participants will then be randomized to receive approximately 
three weeks (18-24 day range) of twice daily administration of either OT or placebo. Testing 
will commence on baseline and after three weeks (18 to 24 days) of drug administration. 
 
Screening data will be reviewed to determine subject eligibility. Subjects who meet all inclusion 
criteria and none of the exclusion criteria will be entered into the study. 
 
The following treatment regimens will be used: 
 
• Experimental treatment: Intranasal oxytocin 
• Placebo: Saline solution 
 
Total duration of subject participation will be 15 hours over 2 months. 

Protocol; Joshua Woolley, MD, PhD Confidential 
 
 
 
5 
CRITERIA FOR EVALUATION 
 
5.1 
Primary Efficacy Endpoint 
 
The primary efficacy endpoint will be social functioning measured by the Social Functioning 
Scale (SFS). SFS is one of the most commonly used social functioning measures in 
schizophrenia research, yields good information about abilities and activities, and is reliable, 
valid, and sensible and responsive to change. The endpoint will be assessed from baseline to end 
of the task. We will also assess activation of the rTPJ during social cognitive tasks measured 
with fMRI. 
 
5.2 
Secondary Efficacy Endpoints 
 
• Social skills will be assessed during the chronic period over the phone or video chat. 
Participants will answer questions about their social interactions and experiences. 
• Theory of Mind (ToM) will be assessed using The Hinting Task a well validated 
audiovisual tool that incorporates social inferences. The endpoint will be assessed from 
baseline to end of the task. 
• Negative symptoms will be assessed with Clinical Assessment Interview for Negative 
Symptoms (CAINS), comprising two subscales reflecting the negative symptom factors. 
The endpoint will be assessed from baseline to end of the task. 
 
5.3 
Safety Evaluations 
 
• No serious adverse effects have been demonstrated in studies examining intranasal 
administration of OT in numerous patient and healthy populations. Therefore, we don’t 
predict any serious adverse events to occur during this study. Documented side effects 
include runny, stuffy, or irritated nose, and more rarely, nausea and vomiting. 
Participants may experience distress due to the nature of personal questions about mental 
health, substance use, and life experiences. They may also experience anxiety and/or 
fatigue due to the length of the study days. 
 
5.4 
Other Evaluations (include only if applicable) 
 
• Positive symptoms will be assessed with the 34-item, interview-based, Scale for the 
Assessment of Positive Symptoms, which focuses on hallucinations, delusions, 
disorganized behavior and thought disorder 
• Quality of life will be assessed with the Quality of Life Scale (QLS), a 7-item assessment 
that measures domains such as interpersonal relations, occupation role functioning and 
intrapsychic foundations 

Protocol; Joshua Woolley, MD, PhD Confidential 
 
 
 
• The Experience in Close Relationships (ECR) questionnaire is a 9-item questionnaire that 
will be used to assess attachment style in respect to a variety of close relationships. 
 
6 
SUBJECT SELECTION 
 
6.1 
Study Population 
 
Subjects with a diagnosis of schizophrenia, schizoaffective, schizophreniform disorder, or brief 
psychotic disorder, who meet the inclusion and exclusion criteria will be eligible for participation 
in this study. 
 
6.2 
Inclusion Criteria 
 
1. Veteran 
2. Male or female 18≥70 years of age at Visit 1. 
3. Must comprehend English 
4. Meet DSM-V criteria for schizophrenia, schizophreniform, schizoaffective disorder, or 
brief psychotic disorder. 
5. Clinically stable, no medication changes or psychiatric hospitalizations in past month 
6. Social Functioning Scale raw score ≤75 
7. Written informed consent obtained from subject or subject’s legal representative and 
ability for subject to comply with the requirements of the study. 
 
6.3 
Exclusion Criteria 
 
1. Active substance use disorder in the past month – except Mild to Moderate Cannabis use 
disorder. 
2. Significant neurological/medical disorder 
3. Pacemaker, extensive dental work, or any metal implants 
4. Claustrophobia, deafness, or inability to read 
5. Current participation in a psychosocial intervention 
6. Taking high dose of testosterone, estrogen/progesterone 

Protocol; Joshua Woolley, MD, PhD Confidential 
 
 
 
7. Pregnant, breastfeeding, or unwilling to practice birth control during participation in the 
study. 
8. Presence of a condition or abnormality that in the opinion of the Investigator would 
compromise the safety of the participant or the quality of the data. 
9. Congestion or sinus problems that could interfere with the study as per the opinion of the 
investigator 
 
7 
CONCURRENT MEDICATIONS 
 
All subjects should be maintained on the same medications throughout the entire study period, as 
medically feasible, with no introduction of new chronic therapies. 
 
7.1 
Allowed Medications and Treatments 
Standard therapy for schizophrenia is allowed except for treatments noted in the exclusion 
criteria described above and as noted in the prohibited medications section below. 
 
7.2 
Prohibited Medications and Treatments 
 
The following medications are prohibited during the study and administration will be considered 
a protocol violation. 
 
• High dose testosterone or estrogen/progesterone 
 
8 
STUDY TREATMENTS 
 
8.1 
Method of Assigning Subjects to Treatment Groups 
 
Randomization sequences will be generated using a response adaptive randomization study 
design. Enrollment would end when at least 55 participants have been assigned to the drug 
treatment arm and 40 participants have been assigned to the placebo arm. 

Protocol; Joshua Woolley, MD, PhD Confidential 
 
 
 
8.2 
Blinding 
 
Due to the objectives of the study, the identity of test and control treatments will not be known to 
investigators, research staff, or participants. The following study procedures will be in place to 
ensure double-blind administration of study treatments. 
 
• 
Access to the randomization code will be strictly controlled. 
• 
Packaging and labeling of test and control treatments will be identical to maintain the 
blind. The oxytocin or placebo will be repackaged into smaller bottles containing 1 mL of 
either the oxytocin or placebo. Designated study staff, who will not be present during the 
study sessions and will not be involved with running any of the study sessions, will be 
responsible for repackaging the drugs and keeping track of each bottle’s contents for 
unblinding. 
 
The study blind will be broken on completion of the clinical study and after the study database 
has been locked. 
 
• Investigators will be made aware of their subject treatment assignments at the completion 
of the study. 
 
During the study, the blind may be broken only in emergencies when knowledge of the 
participant’s treatment group is necessary for further participant management. When possible, 
the Investigator should discuss the emergency with the Medical Monitor prior to unblinding. 
During the study, the blind may be broken to the designated unblinded study staff only in 
emergencies when knowledge of the participant’s treatment group is necessary for further 
participant management. 
 
8.3 
Formulation of Test and Control Products 
 
8.3.1 
Formulation of Test Product 
 
Syntocinon is a formulation of oxytocin, developed originally by Novartis Pharmaceuticals, for 
intranasal administration to stimulate of milk ejection and prevent of mastisis. Syntocinon is a 
clear colorless solution that requires no reconstitution. See Table for formulation and measured 
pH of Syntocinon and Placebo. 
 
Oxytocin and placebo will be ordered from one of the following manufacturers/pharmacies 
depending on supply and ability to guarantee prompt and cooled shipment: 
 
1. Wellspring Compounding Pharmacy, Berkeley, CA – licensed pharmacy which produces 
research drugs to many large hospitals and research centers in the San Francisco Bay 
Area. Use of USP pharmaceutical grade chemicals in a State of California licensed sterile 
compounding facility. 
 
If the shipment arrives in larger bottles (not packaged for individual-use), Abbotts Pharmacy, or 
designated study staff will repackage the oxytocin & placebo solution into smaller bottles 

Protocol; Joshua Woolley, MD, PhD Confidential 
 
 
containing 40 IU/1ml of oxytocin or placebo. Abbotts Pharmacy or designated study staff, who 
will not be present during the study sessions and will not be involved with running any of the 
study sessions, will be responsible for repackaging the drugs and keeping track of each bottle’s 
contents for unblinding. All labels indicating that the drug is oxytocin or placebo will be 
removed. 
 
Table 1: Wellspring Pharmacy Formulation and Measured pH of Oxytocin and Placebo 
 
 
Oxytocin 
Placebo 
Active Ingredient, mg/mL 
Oxytocin USP 40 IU/ml 
Water 
Other ingredient, mg/mL 
0.05% methylparaben 
0.025% propylparaben 
Distilled water 
0.05% methylparaben 
0.025% propylparaben 
pH 
4 – 4.5 
 
 
8.3.2 
Formulation of Control Product 
 
A placebo solution will be provided by one of the three manufacturers/pharmacies described 
above in amber glass bottles with a nasal spray pump applicators and caps ready for 
administration. The formation for the placebo is listed in Tables 1 and 2. If the shipment arrives 
in larger bottles (not packaged for individual-use), Wellspring Pharmacy or designated study 
staff will repackage the nasal sprays into individual syringes (to be administered with nasal spray 
atomizers) and remove any labels that the vendors have placed 
 
8.3.3 
Packaging and Labeling 
 
Packaging: Each nasal spray is supplied in glass bottles with nasal spray pump applicator and 
cap. If the shipment arrives in larger bottles (not packaged for individual-use), Abbotts Pharmacy 
or designated study staff will repackage the nasal sprays into 40 IU/1 ml doses in glass bottles 
with nasal spray pump applicators and caps. 
 
Labeling: Wellspring Compounding Pharmacy or designated staff will remove any labels that the 
vendors have placed. 
 
8.4 
Supply of Study Drug at the Site 
 
One of the three pharmacies/manufacturers described above will ship the oxytocin and placebo 
bottles to the investigational site, San Francisco VA Medical Center. The initial study oxytocin 
and placebo shipment will be shipped after site activation (i.e., all required regulatory 
documentation has been received by the Principal Investigator and a contract has been executed). 
Subsequent study drug shipments will be made after initial supply of oxytocin and placebo has 
run low. Care will be taken to ensure that the study drug supplier is never changed during the 
course of an active study. However, unpredictability in obtaining the study drug in a timely 

Protocol; Joshua Woolley, MD, PhD Confidential 
 
 
fashion from the original manufacturer has led us to institute alternative manufacturing options. 
 
 
8.4.1 
Dosage/Dosage Regimen 
 
Oxytocin and placebo (saline) solution will be administered intranasally followed by a resting 
period in a neutral environment. The oxytocin dose is comparable to that used previously in 
human studies of behavior (Davies et. al. 2019). In the first phase of the study, subjects will 
receive one administration of either oxytocin or placebo on two separate sessions at least one 
week apart. No adjustments for weight, age, and meals will be made. In the second phase, 
subjects will self-administer oxytocin or placebo twice daily for three weeks (18-24 days). 
Again, no adjustments for weight, age, and meals will be made. 
 
8.4.2 
Dispensing 
 
The investigator has the authority to dispense the drug. Trained study staff will be instructing 
participants to administer the nasal spray from a safe distance to limit close contact. 
 
8.4.3 
Administration Instructions 
 
It is preferable to sit when using the nasal spray. 
During the acute phase, study staff will administer the nasal spray to participants with these 
instructions: 
 
Remove the flip-off cap. Holding the bottle upright, insert the nozzle into one nostril and actuate 
while the participant gently inhales through nose and exhales through mouth. Switch nostrils and 
repeat. Keep switching nostrils, actuating, inhaling, and exhaling until all the oxytocin or placebo 
solution has been used up. 
 
During the chronic phase, subjects will administer the nasal spray themselves with these 
instructions: 
 
Remove the flip-off cap. Holding the bottle upright, insert the nozzle into one nostril and actuate 
while gently inhaling through nose and exhaling through mouth. Switch nostrils and repeat. Keep 
switching nostrils, actuating, inhaling, and exhaling until all the oxytocin or placebo solution has 
been used up. 
 
8.4.4 
Storage 
 
Study drug should be stored at the study site in a refrigerator (2-8oC). If the temperature of the 
study drug storage exceeds or falls below this range, this should be reported to the Principal 
Investigator and captured as a deviation. Subjects will be instructed to store the medication in 
provided packaging and in a refrigerator. 
 
8.5 
Study Drug Accountability 
 

Protocol; Joshua Woolley, MD, PhD Confidential 
 
 
An accurate and current accounting of the dispensing and return of study drug for each subject 
will be maintained on an ongoing basis by a member of the study site staff. The number of study 
drug dispensed and returned by the subject will be recorded on the Investigational Drug 
Accountability Record. The study monitor will verify these documents throughout the course of 
the study. 
 
8.6 
Measures of Treatment Compliance 
 
Adherence to and administration technique of administering the study drug will be directly 
observed for all groups via secure video calls between participants and study coordinators during 
Video Observed Therapy (VOT) procedure. Participants may use tablets provided by the VA or 
their own devices. 
 
In order to safeguard the well-being of all subjects enrolled in the study, each subject will be 
monitored for the following: 
 
a. Adverse Event: Any untoward medical occurrence in a subject that does not necessarily 
have a causal relationship with the assessment procedures. Will include any unfavorable 
and unintended clinical sign, symptom, or illness temporally associated with the use of 
the assessment, whether or not considered related to it. 
b. Serious Adverse Event: Any adverse experience that results in any of the following 
outcomes: death, a life-threatening experience, acute psychiatric decompensation, 
inpatient hospitalization, or a persistent or significant disability/incapacity. 
c. Unexpected Adverse Event: Any adverse experience the specificity or severity of which 
is not consistent with the risks information described in this study protocol or 
consent/assent document

Protocol; Joshua Woolley, MD, PhD Confidential 
 
 
 
9 
STUDY PROCEDURES AND GUIDELINES 
 
A Schedule of Events representing the required testing procedures to be performed for the 
duration of the study is diagrammed in Appendix 1. 
 
Prior to conducting any study-related activities, written informed consent and the Health 
Insurance Portability and Accountability Act (HIPAA) authorization must be signed and dated 
by the subject. 
 
9.1 
Clinical Assessments 
 
9.1.1 
Concomitant Medications 
 
All concomitant medication and concurrent therapies will be documented at Baseline/Screening 
and at Study Days when applicable. Dose, route, unit frequency of administration, and indication 
for administration and dates of medication will be captured. 
 
9.1.2 Demographics 
 
Demographic information (date of birth, gender, race) will be recorded during the visit. 
 
9.1.3 Medical History 
 
Relevant medical history, including history of current disease, other pertinent respiratory history, 
and information regarding underlying diseases will be recorded during the visit. 
 
9.1.4 
Vital Signs 
 
Blood pressure and pulse will be recorded during the visit. 
 
9.1.5 
fMRI Testing 
 
Subjects will perform theory of mind tasks in the San Francisco Veterans Affairs Medical 
Center’s on-site MRI research facility. Participants are asked to lie in the scanner with only their 
head placed in the fMRI and visual stimuli are presented on a screen. The task administrator is 
able to communicate through an intercom system. Task specific instructions are displayed on a 
computer screen and responses are collected through a button box. 

Protocol; Joshua Woolley, MD, PhD Confidential 
 
 
 
9.1.6 
Social Functioning Test 
 
Subjects will perform social functioning tasks in Dr. Joshua Woolley’s Bonding and Attunement 
in Neuropsychiatric Disorders laboratory. Participants will be asked to complete several 
measures of social functioning, social ability, negative symptoms, and Theory of Mind. 
 
9.1.7 
Adverse Events 
 
Information regarding occurrence of adverse events will be captured throughout the study. 
Duration (start and stop dates and times), severity/grade, outcome, treatment and relation to 
study drug will be recorded on the case report form (CRF). 
 
9.2 
Clinical Laboratory Measurements 
 
9.2.1 
Pregnancy Test 
 
For those who can become pregnant, a urine pregnancy test will be obtained during each in- 
person visit. 
 
10 EVALUATIONS BY VISIT 
 
10.1 Visit 1 (Day 1, Remote Visit) 
 
1. Review the study with the subject (subject’s legal representative) and obtain verbal 
informed consent and HIPAA authorization, if appropriate. 
1. During the covid-19 pandemic, Visit 1 tasks and procedures have been adapted to 
be remote. We will be collecting verbal consent by video call at the beginning of 
this visit. Written informed consent will be obtained during Visit 2, the first in- 
person visit, before study drug administration. 
2. Assign the subject a unique screening number. 
3. Record demographics data. 
4. Record medical history, including a history of psychosis, diagnosis date, and prior 
antipsychotic treatments. 
5. Record concomitant medications. 

Protocol; Joshua Woolley, MD, PhD Confidential 
 
 
 
6. Structured Clinical Interview for DSM-5 (Diagnostic and Statistical Manual of Mental 
Disorders, 5th Edition) 
7. Social functioning assessments. 
8. Schedule subject for Visit 2 in one week from their first visit if visit hasn’t been 
scheduled yet. 
 
10.2 Visit 2 (Week 1) 
 
1. Review the study with the subject (subject’s legal representative) and obtain written 
informed consent and HIPAA authorization, if appropriate. 
2. Urine Pregnancy Test 
3. Oxytocin/placebo administration. 
4. fMRI testing. 
 
10.3 Visit 3 (Week 2) 
 
1. Urine Pregnancy test 
2. Oxytocin/placebo administration. 
3. fMRI testing. 
 
10.4 Visit 4 (Week 3) 
 
1. Urine Pregnancy Test 
2. Record changes to concomitant medications. 
3. Record participant weight 
4. ToM, negative and positive symptoms, and social ability assessments 
5. Oxytocin/placebo administration 
6. Oxytocin self-administration training. 
 
10.5 Chronic Period (Remote procedures between Visit 5 and Visit 6) 
1. VOT 

Protocol; Joshua Woolley, MD, PhD Confidential 
 
 
 
2. Social Functioning assessment 
 
 10.6 Visit 5 (Week 6) 
 
1. Urine Pregnancy test 
2. Record changes to concomitant medications. 
3. Record participant weight 
4. Perform and record vital signs. 
5. Oxytocin/placebo administration. 
6. ToM, negative and positive symptoms, and social ability assessments. 
 
10.7 Early Withdrawal Visit 
1. 
Record any Adverse Experiences and/or Review subject diary for adverse experiences and 
exclusionary medication use. 
2. 
If given, collect and return unused oxytocin to pharmacy. 
 
11 DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
 
11.1 Early Discontinuation of Study Drug 
A subject may be discontinued from study treatment at any time if the subject, the investigator, 
or the Sponsor feels that it is not in the subject’s best interest to continue. The following is a list 
of possible reasons for study treatment discontinuation: (The list should match the Study 
Completion/Discontinuation CRF page.) 
• 
Subject withdrawal of consent (or assent) 
• 
Subject is not compliant with study procedures 
• 
Adverse event that in the opinion of the investigator would be in the best interest of the 
subject to discontinue study treatment 
• 
Protocol violation requiring discontinuation of study treatment 

Protocol; Joshua Woolley, MD, PhD Confidential 
 
 
 
• 
Lost to follow-up 
• 
Sponsor request for early termination of study 
• 
Positive pregnancy test (females) 
If a subject is withdrawn from treatment due to an adverse event, the subject will be followed 
and treated by the Investigator until the abnormal parameter or symptom has resolved or 
stabilized. 
All subjects who discontinue study treatment should come in for an early discontinuation visit as 
soon as possible and then should be encouraged to complete all remaining scheduled visits and 
procedures. 
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals. The reason for the subject’s withdrawal from the study will be specified in the 
subject’s source documents Refer to Section 10 for early termination procedures. 
 
12.3 
Withdrawal of Subjects from the Study 
A subject may be withdrawn from the study at any time if the subject, the investigator, or the Dr. 
Woolley feels that it is not in the subject’s best interest to continue. 
All subjects are free to withdraw from participation at any time, for any reason, specified or 
unspecified, and without prejudice. 
Reasonable attempts will be made by the investigator to provide a reason for subject 
withdrawals. The reason for the subject’s withdrawal from the study will be specified in the 
subject’s source documents. As noted above, subjects who discontinue study treatment early 
(i.e., they withdraw prior to Visit X) should have an early discontinuation visit. Refer to Section 
10 for early termination procedures. Subjects who withdraw after Visit X but prior to Visit X 
should be encouraged to come in for a final visit (and the procedures to be followed would 
include those for their next scheduled visit). 
 
12.4 
Replacement of Subjects 
Subjects who withdraw from the study treatment will be replaced. 
Subjects who withdraw from the study will be replaced. 
 
 
 

Protocol; Joshua Woolley, MD, PhD Confidential 
 
 
 
12 STATISTICAL METHODS AND CONSIDERATIONS 
Prior to the analysis of the final study data, a detailed Statistical Analysis Plan (SAP) will be 
written describing all analyses that will be performed. The SAP will contain any modifications 
to the analysis plan described below. 
 
12.1 Data Sets Analyzed 
All eligible patients who are randomized into the study and receive at least one dose of the study 
drug (the Safety Population) will be included in the safety analysis. 
 
12.2 Demographic and Baseline Characteristics 
 
12.3 Analysis of Primary Endpoint 
 
The investigators will perform linear regression analyses with SFS change as the primary 
outcome and drug modeled as a 2-level dummy variable (drug vs. placebo). Identical analyses 
will be run using accuracy scores for the FBT and PDT instead of rTPJ activity to determine if 
acute OT improves ToM ability versus placebo.  
 
12.4 Analysis of Secondary Endpoints 
Similar analyses as stated in 15.3 will be conducted for the secondary clinical outcomes 
including social ability, negative symptoms (CAINS), and ToM (Hinting Task). 
 
12.5 Interim Analysis 
 
Interim analysis will be conducted after the first 60 participants have completed the study and at 
multiple points after over the course of the study. Results will remain blinded to all other study 
staff. 
 
12.6 Sample Size and Randomization 
 
All power and effect size estimates were calculated using STATA/SE v. 15.1 using 80% power 
and two-sided alpha=0.05. To be conservative, the investigators used the one-way command 
with two or three groups. The proposed sample sizes enable us to detect effect sizes ranging from 
0.23 to 0.27 for the primary hypotheses, which are clinically meaningful and consistent with the 
preliminary data. 
 
13 DATA COLLECTION, RETENTION AND MONITORING 
 
13.1 Data Collection Instruments 
 
The Investigator will prepare and maintain adequate and accurate source documents designed to 
record all observations and other pertinent data for each subject treated with the study drug. 
 
Study personnel will record data corresponding to a subject’s visit on a physical study document. 
Subjects will not be identified by name in the study database or on any study documents to be 

Protocol; Joshua Woolley, MD, PhD Confidential 
 
 
collected by Dr. Woolley (or designee), but will be identified by a subject number. 
 
The Investigator is responsible for all information collected on subjects enrolled in this study. All 
data collected during the course of this study must be reviewed and verified for completeness 
and accuracy by the Investigator. 
 
13.2 Data Management Procedures 
 
The data will be entered into a validated database. The Data Management group will be 
responsible for data processing, in accordance with procedural documentation. Database lock 
will occur once quality assurance procedures have been completed. 
 
All procedures for the handling and analysis of data will be conducted using good computing 
practices meeting FDA guidelines for the handling and analysis of data for clinical trials. 
 
13.3 Data Quality Control and Reporting 
 
After data have been entered into the study database, a system of computerized data validation 
checks will be implemented and applied to the database on a regular basis. Query reports (Data 
Clarification Requests) pertaining to data omissions and discrepancies will be forwarded to the 
Investigators and study monitors for resolution. The study database will be updated in 
accordance with the resolved queries. All changes to the study database will be documented. 

Protocol; Joshua Woolley, MD, PhD Confidential 
 
 
 
13.4 Archival of Data 
 
The database is safeguarded against unauthorized access by established security procedures; 
appropriate backup copies of the database and related software files will be maintained. 
Databases are backed up by the database administrator in conjunction with any updates or 
changes to the database. 
 
At critical junctures of the protocol (e.g., production of interim reports and final reports), data for 
analysis is locked and cleaned per established procedures. 
 
13.5 Availability and Retention of Investigational Records 
 
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee), IRB, and Regulatory Agency (e.g., FDA) inspectors 
upon request. A file for each subject must be maintained that includes the signed Informed 
Consent, HIPAA Authorization and copies of all source documentation related to that subject. 
The Investigator must ensure the reliability and availability of source documents from which the 
information on the CRF was derived. 
 
All study documents (participant files, signed informed consent forms, copies of CRFs, Study 
File Notebook, etc.) must be kept secured for a period of two years following marketing of the 
investigational product or for two years after centers have been notified that the IND has been 
discontinued. There may be other circumstances for which the Sponsor is required to maintain 
study records and, therefore, the Sponsor should be contacted prior to removing study records for 
any reason. 
 
13.6 Monitoring 
 
Monitoring visits will be conducted by VA Personnel according to the U.S. CFR Title 21 Parts 
50, 56, and 312 and ICH Guidelines for GCP (E6). By signing this protocol, the Investigator 
grants permission to the Sponsor (or designee), and appropriate regulatory authorities to conduct 
on-site monitoring and/or auditing of all appropriate study documentation. 
 
13.7 Subject Confidentiality 
 
In order to maintain subject confidentiality, only a subject number will identify all study subjects 
on CRFs and other documentation submitted to the Sponsor. Additional subject confidentiality 
issues (if applicable) are covered in the Clinical Study Agreement. 
 
14 ADMINISTRATIVE, ETHICAL, REGULATORY CONSIDERATIONS 
 
The study will be conducted according to the Declaration of Helsinki, Protection of Human 
Volunteers (21 CFR 50), Institutional Review Boards (21 CFR 56), and Obligations of Clinical 
Investigators (21 CFR 312). To maintain confidentiality, all laboratory specimens, evaluation 
forms, reports and other records will be identified by a coded number and initials only. All study 

Protocol; Joshua Woolley, MD, PhD Confidential 
 
 
 
records will be kept in a locked file cabinet and code sheets linking a participant’s name to a 
participant identification number will be stored separately in another locked file cabinet. Clinical 
information will not be released without written permission of the subject, except as necessary 
for monitoring by the FDA. The Investigator must also comply with all applicable privacy 
regulations (e.g., Health Insurance Portability and Accountability Act of 1996, EU Data 
Protection Directive 95/46/EC). 
 
14.1 Protocol Amendments 
 
Any amendment to the protocol will be written by Dr. Woolley and his research group. Protocol 
amendments cannot be implemented without prior written IRB/IEC approval except as necessary 
to eliminate immediate safety hazards to participants. A protocol amendment intended to 
eliminate an apparent immediate hazard to participants may be implemented immediately, 
provided the IRBs are notified within five working days. 
 
14.2 Institutional Review Boards and Independent Ethics Committees 
 
The protocol and consent form will be reviewed and approved by the IRB of each participating 
center prior to study initiation. Serious adverse experiences regardless of causality will be 
reported to the IRB in accordance with the standard operating procedures and policies of the 
IRB, and the Investigator will keep the IRB informed as to the progress of the study. The 
Investigator will obtain assurance of IRB compliance with regulations. 
 
Any documents that the IRB may need to fulfill its responsibilities (such as protocol, protocol 
amendments, Investigator’s Brochure, consent forms, information concerning participant 
recruitment, payment or compensation procedures, or other pertinent information) will be 
submitted to the IRB. The IRBs written unconditional approval of the study protocol and the 
informed consent form will be in the possession of the Investigator before the study is initiated. 
 
Protocol and/or informed consent modifications or changes may not be initiated without prior 
written IRB approval except when necessary to eliminate immediate hazards to the participants 
or when the change(s) involves only logistical or administrative aspects of the study. Such 
modifications will be submitted to the IRB and written verification that the modification was 
submitted and subsequently approved should be obtained. 
 
The IRB must be informed of revisions to other documents originally submitted for review; 
serious and/or unexpected adverse experiences occurring during the study in accordance with the 
standard operating procedures and policies of the IRB; new information that may affect 
adversely the safety of the participants of the conduct of the study; an annual update and/or 
request for re-approval; and when the study has been completed. 
 
14.3 Informed Consent Form 
 
Informed consent will be obtained in accordance with the Declaration of Helsinki, ICH GCP, US 
Code of Federal Regulations for Protection of Human Subjects (21 CFR 50.25[a,b], CFR 50.27, 

Protocol; Joshua Woolley, MD, PhD Confidential 
 
 
 
and CFR Part 56, Subpart A), the Health Insurance Portability and Accountability Act (HIPAA, 
if applicable), and local regulations. 
 
A properly executed, written, informed consent will be obtained from each subject prior to 
entering the subject into the trial. Information should be given in both oral and written form and 
subjects must be given ample opportunity to inquire about details of the study. 
If a subject is unable to sign the informed consent form (ICF) and the HIPAA authorization, a 
legal representative may sign for the subject. A copy of the signed consent form (and assent) will 
be given to the subject and the original will be maintained with the subject’s records. 
 
14.4 Publications 
 
The preparation and submittal for publication of manuscripts containing the study results shall be 
in accordance with a process determined by mutual written agreement among the study Sponsor 
and participating institutions. The publication or presentation of any study results shall comply 
with all applicable privacy laws, including, but not limited to, the Health Insurance Portability 
and Accountability Act of 1996. 
 
14.5 Investigator Responsibilities 
By signing the Agreement of Investigator form, the Investigator agrees to: 
1. Conduct the study in accordance with the protocol and only make changes after notifying 
the Sponsor (or designee), except when to protect the safety, rights or welfare of subjects. 
2. Personally conduct or supervise the study (or investigation). 
3. Ensure that the requirements relating to obtaining informed consent and IRB review and 
approval meet federal guidelines, as stated in § 21 CFR, parts 50 and 56. 
4. Report to the Sponsor or designee any AEs that occur in the course of the study, in 
accordance with §21 CFR 312.64. 
5. Ensure that all associates, colleagues and employees assisting in the conduct of the study are 
informed about their obligations in meeting the above commitments. 
6. Maintain adequate and accurate records in accordance with §21 CFR 312.62 and to make 
those records available for inspection with the Sponsor (or designee). 
7. Ensure that an IRB that complies with the requirements of §21 CFR part 56 will be 
responsible for initial and continuing review and approval of the clinical study. 
8. Promptly report to the IRB and the Sponsor (or designee) all changes in the research activity 
and all unanticipated problems involving risks to subjects or others (to include amendments 
and IND safety reports). 
9. Seek IRB approval before any changes are made in the research study, except when 
necessary to eliminate hazards to the patients/subjects. 
10. Comply with all other requirements regarding the obligations of clinical investigators and all 
other pertinent requirements listed in § 21 CFR part 312. 

 
Protocol; Joshua Woolley, MD, PhD Confidential 
 
 
 
APPENDIX 1. EXAMPLE OF SCHEDULE OF STUDY VISITS 
 
 
VISIT 1 
(Day/Week/Month #)a 
VISIT 2 
(Day/Week/Month #)a 
VISIT 3 
(Day/Week/Month #)a 
VISIT 4 
(Day/Week/Month #)a 
VISIT 5 
(Day/Week/Month #) 
Verbal Consent 
X 
 
 
 
 
Informed Consent 
X* 
X 
 
 
 
Medical History 
X 
 
 
 
 
Concomitant Medication Review 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
Weight 
 
 
 
X 
X 
Vital Signs 
X 
 
 
X 
 
Urine Tests (pregnancy) 
 
X 
X 
X 
X 
Randomization 
X 
 
 
 
 
Administration of Study Drug 
 
X 
X 
X 
X 
Dispensing of Study Drug 
 
 
 
X 
 
Counting of Returned Study Drug  
 
 
 
X 
fMRI Testing 
 
X 
X 
 
 
Social Functioning Tests 
X 
 
 
X 
X 
Adverse Experiences 
 
 
 
 
 
*written informed consent will be collected during Visit 1 when possible. 
a 
±2 days