Randomized, Double Blind, Placebo-Controlled Trial of the Efficacy of Intranasal Oxytocin for the Treatment of Alcohol Use Disorder
Phase: PHASE2
Conditions: Alcohol Use Disorder, Alcohol Misuse
Sponsor: National Institute on Alcohol Abuse and Alcoholism (NIAAA)

Oxytocin for Alcohol Use Disorder 
NCIG, NIAAA, NIH 
Protocol Number: NCIG-007R 
Version 4.0 (5Jul2022) 
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IND Number: 147715 
 
Protocol Number: NCIG-007R 
 
Randomized, Double Blind, Placebo-Controlled Trial of the Efficacy and Safety of 
Intranasal Oxytocin for the Treatment of Alcohol Use Disorder 
 
Sponsor: 
National Institute on Alcohol Abuse and Alcoholism 
(NIAAA) 
National Institutes of Health 
Division of Medications Development 
6700B Rockledge Dr., Rm 1324 
Bethesda MD 20892 
NIAAA Medications 
Development Team 
(Sponsor’s Representative) 
Raye Z. Litten, Ph.D. (Lead) 
Fax: 301-443-8774 
E-mail: rlitten@mail.nih.gov 
 
Daniel E. Falk, Ph.D.  
Tel: (301) 443-0788 
Email: falkde@mail.nih.gov 
Jenica Tapocik Patterson, Ph.D. 
Tel (301) 827-6166 
Jenica.patterson@nih.gov  
Megan Ryan, M.B.A, CCRP 
NIAAA (address above) 
Tel: (301) 443-4225 
Email: mryan1@mail.nih.gov 
Joanne Fertig, Ph.D.  
Tel: (301) 443-0635 
Email: jfertig@mail.nih.gov 
 
Study Coordinating Center: 
Fast-Track Drugs & Biologics, LLC 
20010 Fisher Avenue, Suite G 
Poolesville, MD, 20837 
Janet H. Ransom, Ph.D.  
Project Director 
Tel: (301) 349-2059 
Email: jransom@fasttrackresearch.com  
Charles Scott, Ph.D. 
Tel: (240) 421-7826 
Biostatistician 
Email: cscott@fasttrackresearch.com 
Medical Monitor: 
Bryan Smith, M.D. 
Fast-Track Drugs & Biologics, LLC 
Tel: (301) 807-8548 
Email: bsmith@fasttrackresearch.com 

Oxytocin for Alcohol Use Disorder 
NCIG, NIAAA, NIH 
Protocol Number: NCIG-007R 
Version 4.0 (5Jul2022) 
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Backup Medical Monitor: 
 
Lorenzo Leggio, M.D., Ph.D., M.Sc. 
Chief, Section on Clinical Psychoneuroendocrinology and 
Neuropsychopharmacology, NIAAA DICBR and NIDA IRP 
National Institutes of Health 
10 Center Drive (10CRC/15330) Room 1-5429 
Bethesda, MD 20892-1108 
Mobile: 240-478-1503 
Email: lorenzo.leggio@nih.gov  
 
 
 
This document is a confidential communication of NIAAA. Acceptance of this document 
constitutes agreement by the recipient that no unpublished information contained herein will be 
published or disclosed without NIAAA’s prior written approval, except that this document may 
be disclosed to appropriate Institutional Review Boards under the condition that they are 
requested to keep it confidential. 
 
 
STATEMENT OF COMPLIANCE 
 
The study will be carried out in accordance with Good Clinical Practice (GCP) as required by the 
following: 
 
• United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CRF Part 46, 21 CFR Part 50, 21 CFR Part 56 and 21 CFR Part 312) 
• International Conference on Harmonisation (ICH) E6 
 
All key personnel (all individuals responsible for the design and conduct of this study) have 
completed Human Subjects Protection Training. 
 

Oxytocin for Alcohol Use Disorder 
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Protocol Number: NCIG-007R 
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1. 
Protocol Synopsis 
Name of Sponsor/Company: National Institute on Alcohol Abuse and Alcoholism (NIAAA) 
Name of Investigational Product: Oxytocin Nasal Spray 
Name of Active Ingredient: Oxytocin 
Protocol Number: NCIG-007R 
Study Title: Randomized, Double Blind, Placebo-Controlled Trial of the Efficacy and Safety of Intranasal Oxytocin 
for the Treatment of Alcohol Use Disorder 
NIAAA Principal Investigator: Raye Litten, Ph.D. 
Study Centers: Boston University Medical Center, Johns Hopkins University School of Medicine, University of 
California at Los Angeles, and University of Virginia 
Study Period: ~ 12 months 
Phase of Development: 2 
Objectives: 
Primary: The primary objective of the study is to compare the efficacy of intranasal oxytocin in reducing the 
weekly percentage of heavy drinking days over the 10 weeks of maintenance treatment among subjects with 
moderate to severe Alcohol Use Disorder (AUD). A “heavy drinking day” is 4 or more drinks per drinking day for 
women and 5 or more drinks per drinking day for men.  
Secondary: Secondary objectives include assessment of other measures of the effects of oxytocin compared with 
placebo on reduction of alcohol use as well as effects on psychological assessments, alcohol craving, alcohol-related 
consequences, cigarette smoking and other nicotine use, retention in the study, safety, and application site (nares) 
tolerability throughout the study. 
Methodology: This study is a double-blind, randomized, placebo-controlled, parallel group, multi-site clinical trial 
designed to assess the efficacy of oxytocin compared with placebo to reduce drinking in 100 subjects (50 in each 
group) who report 4 or more Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition (DSM-5™) 
symptoms of AUD. This study will be conducted at 4 clinical sites. If eligible for the study, subjects will be 
randomized using a stratified permuted block randomization procedure with “clinical site” as a stratification variable 
in an approximate 1:1 ratio (targeting 50 subjects per group) to receive either intranasal oxytocin or placebo for 12 
weeks. 
If eligible for the study, subjects will receive blinded intranasal oxytocin at 35 IU once per day or intranasal placebo 
(same volume once per day) for 2 weeks (initial tolerability assessment period), then for the next 10 weeks 
(maintenance period) subjects will receive oxytocin at 35 IU/ twice per day (BID, totally daily dose 70 IU) or 
intranasal placebo (same volume twice per day). 
Subjects will be seen in the clinic at screening visit(s), at randomization and 7 other times during the study (Weeks 
2, 3, 4, 6, 8, 10, and 13). During the Weeks 5, 7, 9, 11, and 12 subjects will be contacted once during the week by 
telephone at non-clinic visit weeks to encourage study drug compliance and to assess withdrawal, adverse events 
(AEs), and concomitant medication use. A final follow-up telephone interview will occur during Weeks 14/15 (1-to-
2 weeks after the end of dosing). 
Enrollment will be halted if more than 2 treatment-related SAEs occur.  If this occurs, a DSMB will be convened 
and a decision in conjunction with the study Sponsor will be made regarding stopping the study.   
Number of Subjects (Planned): Estimated 250 to obtain 100 eligible and randomized. 
Main Inclusion/Exclusion Criteria: Subjects will be male and female at least 21 years of age with 4 or more 
DSM-5™ symptoms of AUD. They must also be seeking treatment for alcohol problems and if male, report drinking 
an average of 28 drinks per week or if female report drinking an average of 21 drinks per week and at least one 
heavy drinking day per week in the 28-day period prior to consent and at least one in the 7-day period prior to 
randomization. 

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Investigational Product, Dosage and Mode of Administration: Oxytocin, 35 IU per dose, intranasally once-daily 
for 2 weeks then twice-daily (BID) (morning and evening) for 10 weeks. Oxytocin is formulated to contain 70 
IU/mL. One dose is defined as intranasal spray of 100 μL per each nostril x 5 sprays in alternating nostrils with a 30 
second wait between sprays for a total dose volume of 500 μL.  
Reference Therapy, Dosage and Mode of Administration: Identically matched placebo administered intranasally 
once-daily for 2 weeks then BID (morning and evening) for 10 weeks. The placebo spray is formulated identically to 
oxytocin without the addition of oxytocin. One dose is defined as intranasal spray of 0.1 mL per each nostril x 5 
sprays in alternating nostrils with a 30 second wait between sprays for a total dose of 0.5 mL. 
Duration of Study: Each subject will participate in the study for up to approximately 17 weeks, including up to 2 
weeks of screening, 12 weeks of treatment (2 weeks for initial tolerability and 10 weeks of maintenance dosing for 
safety and efficacy), one follow-up visit after completing treatment, and a final telephone contact 1-to- 2 weeks after 
completing treatment. 
Criteria for Evaluation: 
Primary: The primary efficacy endpoint is the weekly percentage of heavy drinking days during the 10-week 
maintenance treatment period. A “heavy drinking day” is 4 or more drinks per drinking day for women and 5 or 
more drinks per drinking day for men. Drinking data will be collected by the Timeline Followback (TLFB) method.  
Secondary: Secondary efficacy endpoints will be analyzed over the entire 10-week treatment period including: 
1. Percentage of subjects with no heavy drinking days during treatment 
2. Percentage of subjects abstinent from alcohol during treatment 
3. Percentage of subjects with a World Health Organization (WHO) drinking risk category decrease during 
treatment of: 
a) at least 1-level  
b) at least 2-levels  
4. Endpoints analyzed monthly and with 1- and 2-month grace periods: 
a) Percentage of subjects with no heavy drinking days during the period 
b) Percentage of subjects abstinent from alcohol during the period 
c) Percentage of subjects with WHO drinking risk category decrease during the period of: 
i. 
at least 1 level 
ii. 
at least 2 levels 
5. Percentage of days abstinent from alcohol per week 
6. Weekly mean number of drinks per week 
7. Weekly mean drinks per drinking day 
8. MINI AUD Score at end of study  
9. Cigarettes smoked per week among smokers 
10. Abstinence from cigarette smoking among smokers 
11. Other nicotine product use per week among other nicotine product users 
12. Experiences in Close Relationships—Relationship Structures Questionnaire (ECR-RS) scores 
(attachment-related anxiety) 
13. PROMIS sleep disturbances scores 
14. PROMIS alcohol-related negative consequences scores 
15. PROMIS pain interference scores 
16. Profile of Moods States (POMS) scores (including subscale scores) 
17. Urge to Drink Scores 
Exploratory Endpoint: 
1. Hyperkatifeia Scale 
Safety Endpoints Safety endpoints will be evaluated over the entire treatment and follow-up periods including: 
1. Vital signs 
2. Physical exam of the nasal mucosa 

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Protocol Number: NCIG-007R 
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3. Smell testing with the University of Pennsylvania Smell Identification Test (UPSIT) 
4. Blood chemistries  
5. Urine drug screen results 
6. Blood alcohol concentration (BAC) by breathalyzer  
7. AEs/SAEs 
8. Electrocardiogram (ECG)  
9. Clinical Institute of Withdrawal – Alcohol Revised (CIWA-AR) scores 
10. Frequency of subjects with suicidal ideation at any time during the treatment period –Columbia-Suicide 
Severity Rating Scale (C-SSRS) 
11. Change in appetite – Simplified Nutritional Appetite Questionnaire (SNAQ) scores and percentage of 
subjects with scores ≤14. 
12. Buss-Perry Aggression score 
Compliance: Self report of compliance with study drug self-administration. 
Statistical Methods (Data Analysis):  
Analysis Populations: 
Full Analysis Set: The full analysis set is defined as subjects randomized to participate in the study who took at 
least one dose of investigational product. The full analysis set will be used to evaluate all efficacy and safety 
endpoints. 
Sample Size: With an intake sample of 100 subjects (50 subjects per arm) and 12% attrition, it is projected that the 
sample size for primary endpoint analyses will be 88 (44 subjects per arm). The alpha level for the primary analyses 
will be 0.05, two-tailed. An estimate of the effect size (Cohen’s d) for the investigational products is 0.60. Equal 
variances in both groups are assumed. These assumptions lead to a projected power of 0.80. 
Analysis of the Primary Efficacy Endpoint: The analysis of the primary endpoint, percentage of heavy drinking 
days, will be a mixed-effect model for repeated measures during the last 10 weeks of the treatment period. 
Treatment group, study week, treatment group by study week interaction, clinical site and baseline percentage of 
heavy drinking days will be covariates in the mixed effects model. Additional covariates may be selected as 
specified in the SAP. The primary endpoint will be performed on the Full Analysis Set. A sensitivity analysis will be 
performed using multiple imputation for missing drinking data. Specification of the multiple imputation models will 
be provided in the statistical analysis plan (SAP). Descriptive statistics will be used to present these data during the 
initial 2-week period as well. 
Analysis of the Secondary Efficacy Endpoints: Analysis of the continuous secondary endpoints (weekly mean 
drinks per week, weekly mean drinks per drinking day, percentage of days abstinent, number of cigarettes smoked 
per week, number of days of other nicotine product use per week, POMS scores, ED-RS scores, PROMIS scores, 
Urge to Drink Scores will be analyzed in a similar fashion to that of the primary outcome (except substituting 
baseline equivalent of the outcome as a covariate). Analysis of the dichotomous secondary outcomes (percentage of 
subjects with no heavy drinking days, percentage subjects abstinent from alcohol, percentage of subjects with 1- and 
2-level decreases in WHO drinking categories, and percentage of smokers abstinent from smoking) will be 
conducted via logistic regression of the endpoint measured across the entire treatment period (monthly and with 
grace periods, as specified). Secondary analyses to satisfy statistical hypotheses will be performed on data collected 
during the 10-week maintenance period; however, as appropriate, descriptive statistics will be used to present these 
data during the initial 2-week period as well. Covariate selection beyond treatment group, clinical site, and baseline 
equivalent of the endpoint will be specified in the SAP. No imputation will be used for the analysis of secondary 
endpoints. 
Exploratory Analysis: A number of variables will be tested as potential moderators of the medication treatment 
effect on the percentage of heavy drinking days primary endpoint. Weeks 3-12 will be the period of interest. 
Continuous moderator variables will be dichotomized. The potential moderator variables that will be examined 
include measures of anxiety and depression (ECR-RS subscales of attachment and anxiety, POMS subscales of 
depression and anxiety, Spielberger Trait Anxiety Inventory, and Barratt Impulsiveness Scale), and those suggestive 
of alcohol withdrawal (i.e., withdrawal question on the MINI for alcohol use disorder), and alcohol-related treatment 
goal.  
There is interest in exploring the use of a new Hyperkatifeia Scale as a predictor and moderator of drug response 
Exploratory analyses utilizing Hyperkatifeia Scale scores will include: 1) conducting moderator analyses using total 

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Protocol Number: NCIG-007R 
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score; 2) comparison of change from baseline between treatment groups for total score and subscales. 
Ad Hoc Analyses: Ad hoc analyses may be performed on the Hyperkatifeia Scale as a planned part of exploring the 
utility of this scale including total scores, subscales, and individual items. Ad hoc analyses utilizing Hyperkatifeia 
Scale scores may include: 1) identification of baseline subsets and relationship to drinking outcomes; 2) conducting 
mediator analyses; 3) factor analysis to better understand the underlying dimensions of hyperkatifeia; and, 4) 
validity of the Hyperkatifeia Scale by comparing to other measures (e.g., POMS and PROMIS scales or subscale 
scores). The data from this study could be used for meta-analyses with results of other studies to expand data 
availability for the proposed ad hoc analyses 
Safety Analyses: 
The severity, frequency, and relationship of AEs to investigational product will be presented by Medical Dictionary 
for Regulatory Activities (MedDRA) System Organ Class (SOC) and Preferred Term (PT) grouping. AE summary 
data will be presented by dose (all weeks, first two weeks and last 10 weeks). Listings of each individual AE 
including start date, stop date, severity, relationship, outcome, and duration will be provided. Clinical chemistry, 
urine drug screen results, pregnancy test results, and BAC results, will be reported as summary statistics. Vital signs 
will be presented as summary statistics and change from baseline. The proportions of ECG results considered 
clinically significant will also be provided. In addition, change from baseline (shift tables) will also be presented for 
clinical chemistry data. The numbers and proportion of subjects who reported CIWA-AR scores ≥ 10 at any time 
after the start of dosing will be presented. Buss-Perry Aggression scores and SNAQ scores will be compared using 
repeated measures ANOVA. The numbers and proportions of subjects mild, moderate, severe microsomia or any 
smell loss (anosmia) compared with screening assessment using the UPSIT will also be presented. 
Compliance and Retention Analyses: 
Medication compliance, defined as the amount of investigational product taken as a proportion of the total amount 
prescribed per protocol, will be evaluated for the oxytocin and placebo groups based on subject’s self-report. 
Average amounts of investigational product taken overall and weekly will be reported for the oxytocin and placebo 
groups. In addition to self-reports, the volume self-administered will be determined by weighing each of the bottles 
of investigational product dispensed to the subject before and after use and subtracting the difference. The research 
participation rate, defined as percentage of subjects with complete drinking data, will be compared between 
treatment groups. In addition, the percentage of subjects discontinuing medication or early withdrawal from the 
study and a listing of these reasons for discontinuation will be provided. 
Baseline Descriptive Statistics: 
Summaries of the characteristics of the subjects in each of the study groups at baseline will be prepared. Baseline 
characteristics will be compared between the oxytocin and placebo groups using appropriate statistical methods. 

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2. 
Table of Contents, List of Tables, and List of Figures 
 Table of Contents 
1. 
Protocol Synopsis .................................................................................................................. 3 
2. 
Table of Contents, List of Tables, and List of Figures .......................................................... 7 
3. 
List of Abbreviations and Definition of Terms ................................................................... 12 
4. 
Introduction ......................................................................................................................... 15 
4.1. 
Alcohol Use Disorder ............................................................................................. 15 
4.1.1. Oxytocin .................................................................................................... 15 
4.1.2. Rationale for Studying Oxytocin ............................................................... 15 
4.1.3. Pharmacokinetics in the Natural State (non-drug treated) ......................... 16 
4.1.4. Pharmacokinetics after Intranasal Administration .................................... 17 
4.1.4.1. 
Non-clinical ........................................................................... 17 
4.1.4.2. 
Clinical ................................................................................... 17 
4.1.5. Nonclinical Efficacy .................................................................................. 17 
4.1.5.1. 
Mouse Models........................................................................ 17 
4.1.5.2. 
Rat Models ............................................................................. 18 
4.1.5.3. 
Prairie Vole Models ............................................................... 19 
4.1.5.4. 
Conclusions from Animal Models ......................................... 19 
4.1.6. Clinical Efficacy in Alcohol Use Disorder ................................................ 19 
4.1.7. Clinical Efficacy and/or Safety of Intranasal Oxytocin in Other Substance 
Abuse and Mental Health Disorders .......................................................... 21 
4.1.8. Safety of Single Dose and Multiple Dose Intranasal Oxytocin ................. 22 
4.1.9. Safety of Multiple-Dose Intranasal Oxytocin ............................................ 23 
4.1.10. Rationale for Selection of Doses for this Study ........................................ 26 
4.2. 
Study Design .......................................................................................................... 26 
4.3. 
Benefit/Risk Assessment ........................................................................................ 30 
5. 
Study Objectives .................................................................................................................. 31 
5.1. 
Primary Objective ................................................................................................... 31 
5.2. 
Secondary Objective ............................................................................................... 31 
6. 
Study Interventions .............................................................................................................. 32 
6.1. 
Investigational Products: Oxytocin and Placebo .................................................... 32 
6.2. 
Investigational Product Packaging, Labeling, and Distribution of Drug Kits ........ 32 
6.3. 
Investigational Product Storage .............................................................................. 32 
6.4. 
Investigational Product Dispensing ........................................................................ 32 
6.5. 
Investigational Product Accountability and Compliance ....................................... 33 
6.6. 
Used/Unused Investigational Product Supplies ...................................................... 33 
6.7. 
Investigational Product Administration .................................................................. 33 
6.8. 
Take Control Behavioral Platform ......................................................................... 34 
6.9. 
Concomitant Medications ....................................................................................... 34 
7. 
Study Procedures ................................................................................................................. 36 
7.1. 
Recruitment of Subjects ......................................................................................... 36 
7.2. 
Informed Consent ................................................................................................... 36 
7.3. 
Selection and Withdrawal of Subjects .................................................................... 36 
7.3.1. Inclusion Criteria ....................................................................................... 36 
7.3.2. Exclusion Criteria ...................................................................................... 38 

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7.4. 
Eligibility Screening ............................................................................................... 41 
7.5. 
Baseline and Final Eligibility Assessments ............................................................ 41 
7.6. 
Measures Taken to Minimize/Avoid Bias .............................................................. 43 
7.6.1. Randomization........................................................................................... 43 
7.6.2. Blinding ..................................................................................................... 43 
7.7. 
Interventions on Day 1 ........................................................................................... 44 
7.8. 
Treatment Phase ..................................................................................................... 44 
7.9. 
Telephone Assessments .......................................................................................... 45 
7.10. 
Final Clinic Visit .................................................................................................... 45 
7.11. 
Telephone Follow-up ............................................................................................. 46 
7.12. 
Duration of Subject Participation ........................................................................... 46 
7.13. 
Safety Criteria for Stopping Doses ......................................................................... 46 
7.14. 
Investigational Product Discontinuation ................................................................ 46 
7.15. 
Subject Withdrawal or Discontinuation Procedures ............................................... 47 
7.16. 
Situations Requiring Discontinuation from the Study as well as from 
Investigational Product ........................................................................................... 47 
7.17. 
Study Suspension and/or Termination Criteria ...................................................... 48 
8. 
Study Endpoints .................................................................................................................. 49 
8.1. 
Efficacy Endpoints ................................................................................................. 49 
8.1.1. Primary Efficacy Endpoint ........................................................................ 49 
8.1.2. Secondary Efficacy Endpoints .................................................................. 49 
8.2. 
Exploratory Endpoint ............................................................................................. 50 
8.3. 
Safety Endpoints ..................................................................................................... 50 
8.4. 
Compliance ............................................................................................................. 50 
9. 
Safety Monitoring Plan........................................................................................................ 51 
10. 
Assessment Methods ........................................................................................................... 53 
10.1. 
Alcohol Breathalyzer .............................................................................................. 53 
10.2. 
Adverse Events and Serious Adverse Events ......................................................... 53 
10.2.1. Adverse Event Definition .......................................................................... 53 
10.2.2. Serious Adverse Events and Serious Unexpected Adverse Events 
Definition .................................................................................................. 53 
10.2.3. Methods/Timing for Assessing, Recording, and Analyzing Safety 
Endpoints ................................................................................................... 54 
10.2.4. Clinical Laboratory Abnormalities and Other Abnormal Assessments .... 54 
10.2.5. Classification of Adverse Event Intensity and Relationship to 
Investigational Product .............................................................................. 54 
10.2.6. Outcomes and Actions Taken .................................................................... 55 
10.2.7. Reporting Serious Adverse Events ............................................................ 56 
10.2.7.1. 
24 hour Reporting Requirements (Initial Report) .................. 56 
10.2.7.2. 
3-Day Supporting Documentation Requirements (Follow-up 
Report) ................................................................................... 56 
10.2.7.3. 
Reporting to Advarra IRB ...................................................... 57 
10.3. 
Barrett Impulsiveness Scale ................................................................................... 58 
10.4. 
Buss Perry Aggression Questionnaire – Short Form (BPAQ-SF) .......................... 58 
10.5. 
Cigarette Smoking Quantity-Frequency and Other Nicotine Use .......................... 58 
10.6. 
Clinical Institute Withdrawal Assessment for Alcohol-revised (CIWA-AR) ........ 58 
10.7. 
Clinical Chemistry .................................................................................................. 59 
10.8. 
Columbia Suicide Severity Rating Scale (C-SSRS) ............................................... 59 
10.9. 
Demographics ......................................................................................................... 60 

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10.10. Device Issues/Failures ............................................................................................ 60 
10.11. Drinking Goal ......................................................................................................... 60 
10.12. Brief Drinking Questionnaire ................................................................................. 60 
10.13. ECG ........................................................................................................................ 61 
10.14. Exit Interview ......................................................................................................... 61 
10.15. Experiences in Close Relationships—Relationship Structures Questionnaire (ECR-
RS) .......................................................................................................................... 61 
10.16. Family History of Alcohol Problems ..................................................................... 61 
10.17. Hyperkatifeia Questionnaire ................................................................................... 61 
10.18. Inventory of Drinking Situations (IDS-30) ............................................................ 62 
10.19. Locator Form .......................................................................................................... 62 
10.20. Medical/Surgical History........................................................................................ 62 
10.21. MINI ....................................................................................................................... 63 
10.22. Other Services Used for Alcohol Use Problems .................................................... 63 
10.23. Profile of Mood State (POMS) ............................................................................... 64 
10.24. Pregnancy Test and Birth Control Record .............................................................. 64 
10.25. Prior and Concomitant Medications ....................................................................... 64 
10.26. PROMIS Questionnaires ........................................................................................ 64 
10.26.1. Patient-Reported Outcomes Measurement Information System (PROMIS) 
– Alcohol Use Negative Consequences – Long Form ............................... 64 
10.26.2. PROMIS – Sleep Disturbances – Short From 8b ...................................... 65 
10.26.3. PROMIS – Pain Interference – Short Form 8a .......................................... 65 
10.27. Physical Examination ............................................................................................. 65 
10.28. Screen Failures Documentation .............................................................................. 65 
10.29. Spielberger Trait Anxiety Inventory (STAI) .......................................................... 65 
10.30. Simplified Nutritional Appetite Questionnaire (SNAQ) ........................................ 66 
10.31. Subject Disposition ................................................................................................. 66 
10.32. TLFB Interview ...................................................................................................... 66 
10.33. World Health Organization Drinking Risk Categorical Scale ................................ 67 
10.34. University of Pennsylvania Smell Identification Test ............................................ 68 
10.35. Urge-to-Drink Questionnaire .................................................................................. 68 
10.36. Urine Drug Screen .................................................................................................. 69 
10.37. Vital Signs .............................................................................................................. 69 
11. 
Statistical Methods and Determination of Sample Size ...................................................... 70 
11.1. 
Statistical and Analytical Plans .............................................................................. 70 
11.2. 
Statistical Hypotheses ............................................................................................. 70 
11.3. 
Analysis Populations .............................................................................................. 70 
11.4. 
Description of Statistical Methods ......................................................................... 71 
11.4.1. General Approach ...................................................................................... 71 
11.4.2. Analysis Addressing the Primary Efficacy Endpoint ................................ 71 
11.4.3. Secondary Efficacy Endpoints Analysis ................................................... 71 
11.4.4. Safety Analyses ......................................................................................... 72 
11.4.5. Compliance and Retention Analyses ......................................................... 72 
11.4.6. Baseline Descriptive Statistics .................................................................. 73 
11.4.7. Exploratory Analyses ................................................................................ 73 
11.4.8. Ad Hoc Analyses ....................................................................................... 73 
11.4.9. Adjustment for Covariates ......................................................................... 73 
11.4.10. Interim Analyses and Data Monitoring ..................................................... 73 
11.4.11. Multiple Comparison/Multiplicity............................................................. 73 
11.4.12. Tabulation of Individual Response Data ................................................... 73 

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11.5. 
Determination of Sample Size ................................................................................ 74 
12. 
Quality Control and Quality Assurance............................................................................... 75 
12.1. 
Study Monitoring ................................................................................................... 75 
12.2. 
Audits and Inspections ........................................................................................... 75 
13. 
Ethics ................................................................................................................................... 76 
13.1. 
Central Institutional Review Board ........................................................................ 76 
13.2. 
Ethics Review ......................................................................................................... 76 
13.2.1. Review/Approval of Study Protocol ......................................................... 76 
13.2.2. Protocol Modifications .............................................................................. 76 
13.2.3. Protocol Deviation Reporting Procedures ................................................. 76 
13.3. 
Ethical Conduct of the Study .................................................................................. 76 
13.3.1. Confidentiality ........................................................................................... 77 
13.3.1.1. 
Confidentiality of Data .......................................................... 77 
13.3.1.2. 
Confidentiality of Subject Records ........................................ 77 
13.3.2. Compensation for Participation ................................................................. 77 
13.3.3. Written Informed Consent ......................................................................... 77 
13.3.4. Delegation of Responsibilities and Adequate Resources .......................... 78 
13.3.5. Financial Disclosure .................................................................................. 78 
14. 
Data Handling and Record Keeping .................................................................................... 79 
14.1. 
Subject Identification and Confidentiality .............................................................. 79 
14.2. 
Inspection of Records ............................................................................................. 79 
14.3. 
Retention of Records .............................................................................................. 79 
14.4. 
Trial Registration .................................................................................................... 80 
15. 
Publication Policy ................................................................................................................ 81 
16. 
Protocol Signature Page ...................................................................................................... 82 
17. 
References ........................................................................................................................... 83 
18. 
Appendices .......................................................................................................................... 90 
Appendix A. Example Drug Diary Card ................................................................................................... 90 
Appendix B. Common Terminology Criteria for Adverse Events for Clinical Laboratory Adverse Events 
and Elevated Blood Pressure ............................................................................................... 92 
Appendix C. Hyperkatifia Scale ............................................................................................................... 93 
 
List of Tables 
Table 1:  
Summary of Reported Adverse Events ............................................................................... 22 
Table 2: 
Adverse Events Reported in More than One Subject in More than One Oxytocin Study of 
1-13 Weeks Duration: Percentages of Adverse Events Reported at Selected Cumulative 
Doses of Intranasal Oxytocin .............................................................................................. 25 
Table 3. 
Schedule of Assessments ..................................................................................................... 28 
Table 4: 
Investigational Product Dispensing Plan ............................................................................. 33 
Table 5: 
Standard Drink Unit Definitions ......................................................................................... 67 
Table 6: 
CTCAE Criteria for Clinical Laboratory Adverse Events and Blood Pressure Elevations . 92 

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List of Figures 
Figure 1:  
Overview of Study Design .................................................................................................. 27 
 

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3. 
List of Abbreviations and Definition of Terms 
Abbreviation 
Definition 
5-HT 
 
Serotonin 
AA 
Alcoholics anonymous 
AE 
Adverse event 
AEDs 
Antiepileptic drugs 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
AUD 
Alcohol Use Disorder 
AWSC 
Alcohol Withdrawal Symptom Checklist 
BAC 
Blood alcohol concentration 
BID 
Twice daily 
BIS 
Barratt Impulsiveness Scale 
BPAQ-SF 
Buss Perry Aggression Questionnaire – Short Form 
CAP 
College of American Pathologists 
CeA 
Central nucleus of the amygdala 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Act 
CIWA-AR 
Clinical Institute Withdrawal Assessment for Alcohol-revised 
CoC 
Certificate of confidentiality 
CORT 
Corticosterone 
CrCL 
Creatinine clearance 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
eCRF 
Electronic Case Report Form 
CTCAE 
Common terminology criteria for adverse events 
CSF 
Cerebral spinal fluid 
dL 
Deciliter 
DNA 
Deoxyribonucleic acid 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
ECR-RS 
Experiences in Close Relationships-Relationship Structures 
EDMS 
Electronic data management system 
EDTA 
Ethylenediaminetetraacetic acid 
EMA 
European Medicines Agency 
EOS 
End of study 
EtOH-CPP 
Ethanol-induced conditioned place preference  
FDA 
Food and Drug Administration 
g 
Gram 

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Abbreviation 
Definition 
GABA 
Gamma aminobutyric acid 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability Accountability Act 
hr 
Hour 
ICH 
International Conference on Harmonization 
IDS-30 
Inventory of Drinking Situations – 30 item 
IM 
Intramuscular 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
IWRS 
Interactive web response system 
kg 
Kilogram 
L 
Liter 
MAOI 
Monoamine oxidase inhibitors 
MDMA 
3,4-methylenedioxy-methamphetamine 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter 
μg 
Microgram 
μL 
Microliter 
min 
Minutes 
MINI 
MINI Neuropsychiatric Interview 
mL 
Milliliter 
mm 
Millimeter 
mmol 
Millimole 
mmos 
Milliosmols 
NIAAA 
National Institutes on Alcohol Abuse and Alcoholism 
NIH 
National Institutes of Health 
OTC 
Over-the-counter 
oz 
Ounce 
pg 
Picograms 
PI 
Principal Investigator 
PK 
Pharmacokinetic 
POMS 
Profile of Mood State 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PRN 
when necessary 
PSNHDD 
Percentage of subjects with no heavy drinking days 
PT 
Preferred Term 
PVN 
Paraventricular nuclei 
QID 
Three-times-per-day 
SAE 
Serious adverse event 

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Abbreviation 
Definition 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SDU 
Standard drinking unit 
SOC 
System Organ Class 
SON 
Supraoptic nuclei 
SOS 
Secular organizations for sobriety 
SNAQ 
Simplified Nutritional Appetite Questionnaire 
SNRI 
Serotonin-norepinephrine reuptake inhibitors 
STAI 
Spielberger Trait Anxiety Inventory 
SSRI 
Selective serotonin reuptake inhibitors 
THC 
Tetrahydrocannabinol 
TLFB 
Timeline followback  
TSST 
Trier Social Stress Test 
ULN 
Upper limit of normal 
U 
Units 
UPSIT 
University of Pennsylvania Smell Identification Test 
US 
United States 
WHO 
World Health Organization 

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4. 
Introduction 
4.1. 
Alcohol Use Disorder 
Alcohol use disorder (AUD) is one of the most prevalent substance use disorders (SUDs) in the 
world. An estimated 95,000 people die of alcohol-related causes in the United States each year 
(Esser-2020). AUD is responsible for a myriad of medical, psychological, social, economic and 
personal problems (Litten-2012). Tragically, more than 2.5 million individuals including 80,000 
Americans die each year from alcohol-related events. The total economic cost to society is a 
staggering $229 billion each year in the United States (US) (NIAAA-2019). Mintz (2021) 
reported that overall 5.8% of persons with AUD received treatment in the past year with 
breakdown by severity of 2.7% with mild AUD, 6.0% with moderate AUD, and 20.7% with 
severe AUD. 
Pharmacologic treatment of AUD has mostly focused on altering the reinforcing effects of 
alcohol use. Medication development has focused on several neurotransmitter systems that 
interact with the corticomesolimbic dopamine pathway, which can mediate reinforcement. Many 
available or promising compounds appear to act by modulating the function of opioids, 
glutamate (with or without gamma aminobutyric acid, GABA), and serotonin (5-HT) (Heilig and 
Egli-2006). 
During the past decade, advances have been made in medications development for AUD. 
Currently, there are four medications approved by the US Food and Drug Administration (FDA) 
to treat alcohol dependence: disulfiram, oral naltrexone, long-acting injectable (depot) 
naltrexone, and acamprosate. As these medications do not work for everyone or in all situations, 
additional research is vital to develop more efficacious and safe medications to treat AUD. 
4.1.1. 
Oxytocin  
Oxytocin is a nine amino acid peptide synthesized in the magnocellular neurons of the 
paraventricular (PVN), supraoptic (SON), and accessory magnocellular nuclei of the 
hypothalamus and is released into the bloodstream from axon terminals of these neurons that are 
located in the posterior pituitary.  
Oxytocin is also centrally released into the brain by various mechanisms. There is dendritic 
release from the PVN and SON in the hypothalamus, with subsequent passive diffusion to 
oxytocin receptors that are located throughout the brain. Parvocellular neurons of the PVN also 
produce oxytocin and these neurons project centrally to diverse regions including the olfactory 
bulb, tubercule, medial and central amygdala, lateral septum, hippocampus, brainstem, and 
spinal cord (Lee and Weerts-2016). Oxytocin is also widely distributed into peripheral tissues 
(Gimpl and Farenholz-2001). 
4.1.2. 
Rationale for Studying Oxytocin 
The neurochemical neurocircuits in drug rewards particularly those due to alcohol have been 
described (Koob-2013). The medial forebrain bundle represents ascending and descending 
projections between the ventral forebrain (nucleus accumbens, olfactory tubercle, and septal 
area) and ventral midbrain (ventral tegmental area). Alcohol activates GABA receptors or 

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enhances GABA release in the ventral tegmental area, nucleus accumbens, and amygdala. 
Alcohol is also hypothesized to facilitate the release of opioid peptides in the ventral tegmental 
area, nucleus accumbens, and central nucleus of the amygdala. Alcohol facilitates the release of 
dopamine in the nucleus accumbens via an action either in the ventral tegmental area or nucleus 
accumbens. The intersection of the central release of oxytocin with many of these structures 
gives anatomic support for the idea that oxytocin might influence the neurocircuits in drug 
rewards particularly those related to alcohol abuse (Lee and Weerts-2016). 
There have been two main threads of investigation of oxytocin on neuropsychology. One follows 
the initial discovery that this peptide influences forms of neuroadaptation, including learning and 
memory and drug addiction. The other thread is linked to the effects of oxytocin on maternal, 
social and other forms of affiliative behavior. These two pathways of investigation are 
summarized by Sarnyai and Kovács (2014). 
Oxytocin has gained significant interest for the treatment of AUD and other drug use disorders 
(reviewed recently by Lee and Weerts-2016, Lee-2016 and Pederson-2017). This is primarily 
related to research of oxytocin’s effects in emotional regulation, pain, and stress, and its 
purported ability to modulate response to rewarding behaviors promoted by food, sex, and drugs 
(Meyer-Lindenberg-2011; Onaka-2012). Lee and Weerts-2016 speculate that, “The 
comodulation of both stress and motivational processes is believed to be because of the 
important role of oxytocin to shift salience to social, affiliative processes, both by increasing the 
salience itself of rewarding stimuli and/or by reducing stress, allowing for attention to social 
bonding (Baskerville and Douglas-2010). This is obviously relevant to addiction, where salience 
of drug stimuli overshadows motivation for social affiliation and where stress may trigger drug 
seeking and relapse (Sinha-2008).” Lee and Weerts-2016 speculation is based on their following 
observations: “Heavy alcohol drinking is associated with dysregulation of HPA-axis activity, as 
shown by episodes of hypercortisolism between drinking bouts and a blunted corticosterone 
(CORT) response to stress during early abstinence (Kemper-1990; Wand and Dobs-1991; Errico-
1993; Vescovi-1997; Boschloo-2011). A blunted CORT response has been associated with 
increased anxiety and craving during acute abstinence and subsequent relapse to heavy drinking 
(Higley-2011; Sinha-2011; Walter- 2006).” 
4.1.3. 
Pharmacokinetics in the Natural State (non-drug treated) 
Most of the oxytocin in the body is stored in the posterior pituitary. In humans, the pituitary 
oxytocin content has been estimated at 14 U (28 µg). This gland lies outside the blood-brain 
barrier, so peptide released from this gland readily enters the blood. There is no barrier to the 
passage of peptides between the blood and interstitial fluid of the body, so the distribution 
volume for oxytocin is much larger than the plasma volume. 
Circulating concentrations (except in pregnancy) are 1–10 pg/mL, and the pharmacokinetics 
(PK) after intravenous injection fit a two-compartment model, with a distribution volume of 
33 L, a distribution half-life of 3.2 minutes, and an elimination half-life of 20 minutes. Oxytocin 
is stable in plasma (except in pregnancy, when oxytocinase is abundant) and is cleared from the 
blood via the kidneys and liver. Oxytocin is thought to be cleared from cerebral spinal fluid 
(CSF) by a combination of flow into the subarachnoid space and active transport into blood. 

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4.1.4. 
Pharmacokinetics after Intranasal Administration 
4.1.4.1. 
Non-clinical 
When 12 µg (mice) or 20 µg (rat) were administered to rodents, analysis of microdialysates 
showed that oxytocin levels in the amygdala and hippocampus increased by approximately 
100%, demonstrating evidence that nasally applied oxytocin indeed reaches behaviorally 
relevant brain areas, and this uptake is paralleled by changes in plasma oxytocin 
(Neumann-2013). Studies performed in rhesus macaques have also demonstrated that 
intranasally administered oxytocin resulted in increased concentrations in both CSF and plasma 
as compared with saline (Dal Monte-2014). When nasal spray delivered oxytocin was compared 
with nebulizer delivery, similar elevations of CSF oxytocin concentration were observed; 
however, elevations of plasma oxytocin were greater with the nasal spray administration.  
Lee (2018) showed that plasma and CSF concentrations were increased after intravenous and 
intranasal administration in Rhesus macaques and that this increase was due to the administered 
oxytocin and not to increases in endogenous levels. That oxytocin was detected in the CSF, 
supports that intranasal oxytocin penetrates through the blood-brain barrier. 
4.1.4.2. 
Clinical 
Measurement of oxytocin plasma levels following intranasal administration of 24 U of oxytocin 
showed elevations in both plasma and CSF oxytocin levels. Quantitative analysis demonstrated 
that plasma levels peaked 15 min post administration, whereas CSF levels did not peak until 75 
min after administration (Striepens-2013).  
In a recent review, Leng and Sabatier (2016) have suggested that two routes may exist for the 
passage of oxytocin from nose to brain. The first route is internalization of peptide into olfactory 
or trigeminal neurons, followed by axonal transport and exocytosis. The second is passage 
through intercellular clefts into the subarachnoid space. If vast amounts of peptide accumulate in 
the subarachnoid space, the concentration difference across the blood-brain barrier might support 
nonspecific passage. It is further suggested that peptides may cross the blood–brain barrier in 
small amounts either by extracellular active transport or by transcellular diffusion. 
4.1.5. 
Nonclinical Efficacy  
4.1.5.1. 
Mouse Models 
King (2017) reported that oxytocin in a dose dependent manner reduces ethanol self-
administration in C57BL/6 mouse model of binge-like drinking.  In this report, male C57BL/6J 
mice were assessed for reduction in binge-like drinking after administration of oxytocin (0, 0.3, 
1, 3, or 10 mg/kg) given access to ethanol (20% v/v) using a model of binge-like drinking 
(“drinking in the dark”) that included the use of lickometer circuits to evaluate the temporal 
pattern of intake as well as 2-bottle choice drinking in the home cage. They concluded that the 
effects of oxytocin on reduction of ethanol drinking were not due to a sedative effect and that 
oxytocin receptors had a role in mediating the effects. In a subsequent C57BL/6 mouse study, 
King (2019) evaluated alcohol relapse-like behavior using lever responses in operant 
conditioning chambers for alcohol in daily self-administration sessions. Once lever responding 
and alcohol intake stabilized mice were tested under extinction conditions for 14 days before 

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reinstatement testing. Oxytocin at doses of 0.1, 0.5, 1 mg/kg, attenuated alcohol-seeking 
behavior in a dose-related manner in male and female mice in response to acute challenge with a 
predator odor. Additionally, oxytocin administration of 1 mg/kg produced a similar decrease in 
alcohol relapse-like behavior triggered by the pharmacological stressor yohimbine in both sexes. 
Mice develop tolerance to the hypothermic effect of ethanol by the second day of alcohol 
administration and mice do not become as hypothermic as on Day 1. One injection of oxytocin 
(1 U per animal) prior to the first injection of ethanol did not change temperature sensitivity in 
response to alcohol, but daily treatment with oxytocin did block the development of tolerance 
(Szabo-1987). In addition, Szabo (1987) showed that picrotoxin-induced seizures in alcohol 
dependent mice were ameliorated by oxytocin. Mice were made physically dependent on 
ethanol, and the severity of withdrawal symptoms was assessed by picrotoxin administration. 
Oxytocin-treated mice displayed milder withdrawal symptoms in response to increasing doses 
(0.2-2.0 U). Earlier studies confirmed that oxytocin attenuated tolerance to ethanol-induced 
hypothermia, and also attenuated tolerance to ethanol-induced myorelaxation and akinesia 
(Jodogne-1991).  
In another study (Bahi-2015), ethanol-induced conditioned place preference (EtOH-CPP) in mice 
was established by rewarding the choice of one chamber with an injection of alcohol. The effects 
of oxytocin receptor pharmacological modulation, using the oxytocin analog Carbetocin, and 
genetic overexpression in the nucleus accumbens, using lentiviral-mediated gene transfer 
technology, was investigated. In the first experiment, results showed that Carbetocin 
administration and nucleus accumbens oxytocin receptor-overexpression reduced EtOH-CPP 
establishment. In the second experiment, systemic Carbetocin treatment and oxytocin receptor 
overexpression resulted in decreased time spent in the ethanol paired compartment following 
completion of a 7-day extinction protocol. Finally, the third experiment showed that Carbetocin 
and oxytocin receptor-overexpression suppressed primed reinstatement of EtOH-CPP. The 
authors concluded that pharmacological and genetic modulation of the oxytocin receptor can 
modulate the acquisition, extinction, and reinstatement of conditioned reinforcing effects of 
ethanol (Bahi-2015). 
4.1.5.2. 
Rat Models 
Studies were conducted in animals to better understand how oxytocin affected consumption of a 
sweet alcohol-containing beverage that is popular with young Australian humans (Raspberry 
Vodka Cruiser, 5% ethanol v/v; McGregor and Bowen-2012). Alcohol-preferring rats were given 
a choice between this beverage and a non-alcoholic sweet solution (3% sucrose) in daily sessions 
in a “lickometer” apparatus. A single administration of oxytocin (1 mg/kg) resulted in a long 
lasting decline (at least 6 weeks) in the preference for the alcoholic beverage relative to sucrose. 
When rats were given a choice between 0.05% saccharine and 10% ethanol in 0.05% saccharine, 
there was a decrease in total ethanol intake of about 40% on days when oxytocin (0.05, 0.1, 0.3, 
and 0.5 mg/kg was administered intraperitoneally (MacFadyen-2016). 
Tunstall (2017) used an established rat model of alcohol dependence to investigate oxytocin’s 
effects on dependence-induced alcohol drinking, enhanced motivation for alcohol, and altered 
GABAergic transmission in the central nucleus of the amygdala (CeA). In this model, when 
oxytocin was administered intraperitoneally, intranasally, or into the brain, it blocked enhanced 
alcohol drinking at doses that did not alter non–alcohol-related behaviors or alcohol drinking in 

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nondependent rats. These data suggest that the effect was specific to alcohol drinking in alcohol 
dependence. They also examined ex vivo electrophysiological recordings from CeA neurons that 
indicated that oxytocin decreases evoked GABA transmission in nondependent but not in 
dependent rats, but oxytocin decreased the amplitude of spontaneous GABAergic responses in 
both groups. They concluded that “Oxytocin blocked the facilitatory effects of acute alcohol on 
GABA release in the CeA of dependent but not nondependent rats. Together, these results 
provide converging evidence that oxytocin specifically and selectively blocks the enhanced 
motivation for alcohol drinking that develops in alcohol dependence likely via a central 
mechanism that may result from altered oxytocin effects on CeA GABA transmission in alcohol 
dependence.” 
4.1.5.3. 
Prairie Vole Models 
Prairie voles are an interesting species to study the effects of medications to treat AUD, as this 
species both consumes high amounts of alcohol and forms oxytocin dependent social bonds in a 
manner similar to humans. Oxytocin treatment (1.0, 3.0, and 10.0 mg/kg, i.p.) reduced alcohol 
consumption in male and female prairie voles in animals that had access to 15% ethanol vs water 
every other day for 12 alcohol drinking sessions (Stevenson-2017). In an open field locomotor 
test, oxytocin (1.0, 3.0, and 10.0 mg/kg, i.p.) did not affect overall locomotor activity. 
4.1.5.4. 
Conclusions from Animal Models 
Overall, in animal models there is evidence that oxytocin, administered systemically or centrally, 
reduces self-administration of alcohol and reinstatement of responding induced by exposure to 
drug cues and stress. The mechanisms seem to involve the midbrain dopaminergic as well as 
medial prefrontal glutamatergic pathways (Lee and Weerts-2016, Pederson-2017, Tunstall-
2017).  
4.1.6. 
Clinical Efficacy in Alcohol Use Disorder 
Ryabinin and Fulenwider (2021) have recently reviewed the extensive literature on rodent and 
human studies evaluating the effects of oxytocin on alcohol’s effects and alcohol-related 
behaviors. They present studies reporting both positive and no effects. They concluded that most 
studies support that oxytocin reduces alcohol consumption in both males and females, but that 
more studies are needed to examine oxytocin’s effects on alcohol-related tolerance, withdrawal, 
craving, anxiety and social affiliations in subjects of both sexes. 
The following summarizes studies relevant to the design of this trial with respect to dose 
selection and regimen, safety and efficacy on intranasal oxytocin. 
Pederson’s group completed 3 small randomized-controlled trials of intranasal oxytocin in 
patients with AUD (Pederson-2013, Pederson-2017) suggesting that intranasal oxytocin may 
attenuate alcohol withdrawal symptoms, reduce very heavy drinking, reduce anxiety scores, and 
can be safety administered at doses of 80 IU/day for 12 weeks. 
Pederson (2013) reported the results of a small pilot study of very heavy drinking subjects with 
alcohol dependence. This study was a randomized, placebo-controlled, double-blind pilot study 
of 3 days of BID intranasal oxytocin (24 IU /dose) versus placebo in 11 alcohol-dependent 
inpatient subjects undergoing inpatient detoxification with symptom-triggered lorazepam for 
withdrawal symptoms. Outcome measures included the amount of lorazepam received, Alcohol 

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Craving Visual Analog Scale, Alcohol Withdrawal Symptom Checklist (AWSC), Clinical 
Institute Withdrawal Assessment for Alcohol scale (CIWA), Penn Alcohol Craving Scale 
(PACS), and Profile of Mood States (POMS). For the 7 oxytocin treated patients versus the 4 
placebo patients, lorazepam use was less (3.4 mg ± 4.7 mg (SD) vs 16.5mg ±4.4; P=0.0015), 
CIWA scores were less on Days 1 and 2, AWCS scores were less on Day 1, and POMS 
tension/anxiety subscale was significantly lower in the oxytocin group (P=0.007). The authors 
concluded that the results are the first evidence that oxytocin may block alcohol withdrawal 
symptoms in humans. In another study of the effects of intranasal oxytocin on the need for 
oxazepam for alcohol detoxification, a 3-day course of a lower dose 24 IU BID, did not show 
statistically significant differences in oxazepam use, although there was a trend for a lower 
amount (Melby-2019). There were no SAEs or oxytocin-related AEs in participants with alcohol 
dependence. 
The Pederson (2013) study was replicated in a substantially different cohort of patients with low 
socioeconomic status heavy drinking (Pederson-2017). Intranasal test treatments (24 IU oxytocin 
or placebo three times daily – total daily dose 72 IU) were initiated within the first 36h of their 
inpatient stay in individuals who had not received more than a total of 6mg of lorazepam to 
control withdrawal symptoms since admission. CIWA ratings were obtained every 4h in patients 
admitted for alcohol detoxification. During the 48h after initiation of randomly assigned 
intranasal test treatments, mean CIWA scores declined in oxytocin recipients (N=4) but 
increased in placebo recipients (N=4) (P=0.025). The sum of lorazepam doses (each 2 mg) given 
for elevated CIWA scores during the 48-h period trended toward being lower in oxytocin 
recipients (P=0.076). 
In a 12-week randomized-controlled trial comparing twice daily intranasal oxytocin to intranasal 
placebo (40 IU of oxytocin/dose or placebo three times daily for the first 2 days and then twice 
daily for the remainder of the 12-week treatment period), Pederson (2017) evaluated treatment 
effects in patients with AUD who were very heavy drinkers (≥35 standard drinks/week for men, 
≥28 standard drinks/week for women). Twelve patients received intranasal oxytocin and 10 
patients received placebo of which 13 were males and 9 were females. Statistical analyses 
revealed that the oxytocin compared to the placebo treatment group had significantly fewer 
heavy drinking days (P=0.047; about 15 fewer heavy drinking days during the 12-week trial, 
d=0.97) and drank very significantly fewer drinks/drinking day (P=0.0008; about 2.6 fewer 
drinks/drinking day during the trial, d=1.83). No significant oxytocin effect on abstinent days 
was noted. Spielberger state anxiety self-ratings trended weakly toward being lower in the 
oxytocin compared to the placebo group (P=0.098), corresponding to an on-average 3.5-point 
difference. There were no group differences in alcohol craving scores. No severe adverse events 
occurred. Also, vital signs remained stable and laboratory measures remained within normal 
limits in all subjects except for transient, asymptomatic, and mild hyponatremia in three oxytocin 
subjects. 
In a human laboratory double-blind, crossover study of 32 non-treatment seeking alcohol 
abusing (defined as per Diagnostic and Statistical Manual of Mental Disorders, 4th Edition 
criteria), the effects of single dose intranasal oxytocin (40 IU) were evaluated on measures social 
perceptual ability, cue-induced craving, and approach bias for alcohol and appetitive imagery 
(Mitchell-2016). Oxytocin significantly improved recognition of easier items on a social 
perception task. Although there was no main effect of oxytocin on cue-induced craving for 
alcohol, a subsequent analysis revealed that oxytocin’s effect on craving was moderated by 

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attachment anxiety, such that oxytocin reduced craving in more anxiously attached individuals 
and increased craving in less anxiously attached individuals. Subjects did not display an 
approach bias to alcohol images on the placebo day, preventing meaningful analysis of the 
effects of oxytocin on this measure. However, subjects did display an approach bias to appetitive 
images on the placebo day, which was significantly reduced by oxytocin administration. No 
adverse reactions were reported. 
4.1.7. 
Clinical Efficacy and/or Safety of Intranasal Oxytocin in Other Substance Abuse 
and Mental Health Disorders 
In a double-blind placebo-controlled study of 16 cannabis-dependent subjects, pretreatment with 
oxytocin (40 IU) reduced marijuana craving and stress scores after a human laboratory session 
but did not alter anxiety scores (McRae-Clark-2013).  
In a double-blind, placebo-controlled study of 31-cocaine dependent subjects, Flanagan (2015) 
examined the effect of oxytocin on neuroendocrine reactivity to a laboratory social stress 
paradigm. Participants were randomized to receive a single dose of oxytocin (40 IU) or placebo 
before the Trier Social Stress Test (TSST). Administration of intranasal oxytocin induced a 
significant decrease in both cortisol and DHEA levels (Cortisol: Δ= -0.29±0.13, p=0.035 and 
DHEA: Δ=−0.40±0.13, p=0.004) prior to administration of the TSST. These changes were not 
significant for subjects who received placebo (Cortisol: Δ = -0.12±0.13, p=0.348 and DHEA: Δ= 
-0.11±0.12, p=0.368). There was no effect of the administration of intranasal oxytocin on cortisol 
or DHEA response levels immediately following the TSST (Cortisol: Δ=0.20±0.15, p=0.166 and 
DHEA: Δ=0.10±0.13, p=0.419). 
Feifel (2010) conducted a randomized, double blind cross over study in 19 schizophrenia patients 
with residual symptoms despite being on a stable dose of at least one antipsychotic drug. 
Intranasal oxytocin was dosed at 20 IU (5 sprays) twice a day for the first week and 40 U (10 
sprays) twice a day for the following 2 weeks. Analysis of the 15 subjects who completed all the 
study visits revealed that oxytocin significantly reduced scores on the Positive and Negative 
Symptom Scale and Clinical Global Impression-Improvement Scale (p < .001) compared with 
placebo at the 3-week end point. Oxytocin was well tolerated and produced no adverse effects 
based upon patient reports or laboratory analyses. 
A double-blind, placebo-controlled study of 12 obsessive-compulsive patients examined the 
effect of 18 IU of oxytocin intranasally daily for 6 weeks on obsessive compulsive behaviors 
(Den Boer-1992). No reductions in the number of compulsive behaviors were observed in either 
treatment group. Two additional patients were treated with 54 IU of oxytocin intranasally of 
which only one patient had a slight reduction in obsessive-compulsive behavior. Side effects 
were mild and transient. In the placebo group, 1 patient complained of headache. In the oxytocin 
group, 4 patients had mild dizziness and 2 patients reported dry mouth and mild headache.  
Epperson (1996) also conducted a placebo-controlled of intranasal oxytocin in 7 patients with 
obsessive compulsive disorder administered higher doses of oxytocin (320 IU oxytocin 
intranasally per day for 7 days). No cardiac or serum osmolarity AEs were reported; and as 
reported by Den Boer (1992), there was no clinical benefit.  
In a double-blind, placebo-controlled multicenter study, 59 women with chronic constipation 
were administered placebo (30 subjects) or intranasal oxytocin (29 subjects) twice daily (five 

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nasal inhalations in each nostril) for a total daily dose of 80 IU per day for 13 weeks (Ohlsson-
2005). There was no significant advantage on constipation. In addition, no effects on blood 
pressure or electrolyte concentrations were seen in either the treated or placebo group. Eleven 
subjects in the oxytocin group (48%) and 12 subjects in the control group (47%) reported side 
effects including headache (11), nausea (6), abdominal pain (6), weight gain (4) and local 
irritation in the nasal mucosa (8). The distribution of side effects was equal in the two groups.  
4.1.8. 
Safety of Single Dose and Multiple Dose Intranasal Oxytocin 
Macdonald (2011) published a systematic review of 38 randomized controlled trials conducted 
between 1990 and 2010 that investigated the central effects of intranasal oxytocin. In the 
1529 subjects included in this review, 79% of subjects were male and 8% were participants with 
developmental or mental health difficulties. Single dosages ranged from 18 U to 40 U. Most 
were single doses except for the reports of Epperson-1996 (320 U oxytocin intranasally per day 
for 7 days) and Ohlsson-2005 (80 U per day in divided doses of 40 U twice daily for 13 weeks). 
The data from this review are summarized in Table 1. Side effects were not different between 
oxytocin and placebo. Participants were unable to accurately report on whether they had received 
oxytocin or placebo.  
Table 1:  
Summary of Reported Adverse Events 
Symptom 
Total Number of Times Reported 
  
Total 
Placebo 
Oxytocin 
Light headedness/vertigo 
21 
10 
11 
Drowsiness/sleepy 
38 
22 
16 
Dry throat/mouth 
12 
6 
6 
Nasal irritation 
14 
8 
6 
Runny nose 
13 
6 
7 
Abdominal/stomach pain 
8 
3 
5 
Anxious/worried/uncomfortable 
18 
11 
7 
Euphoric/energized/uplifted 
14 
5 
9 
Calm/relaxed/comfortable 
59 
27 
32 
Headache 
29 
14 
15 
Three SAEs related to hyponatremia were cited among 3 patients receiving oxytocin. One was in 
an obsessive-compulsive patient who was treated with ~12 U oxytocin intranasally daily for 4 
weeks and who had a marked decrease in plasma sodium (126 mmol/L) and osmolarity (252 
mosm/kg which was down from 290 mosm/kg prior to therapy), in addition to an SAE involving 
psychotic symptoms (Ansseau-1987). Two reports involved long-term use of intranasal oxytocin 
plus excessive water intake to facilitate lactation (Ansseau-1987). Hyponatremia in response to 
oxytocin may be due to the chemical similarity between oxytocin and the other pituitary 
hormone, argentine vasopressin (anti-diuretic hormone).  

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4.1.9. 
Safety of Multiple-Dose Intranasal Oxytocin 
Studies of 1-4 Weeks Duration: Four studies provided safety information for oxytocin twice 
daily (BID) dose regimens of 1-4 weeks duration, with dose regimens ranging from 20 IU 
(Feifel-2010) to 72 IU (Finger-2015). In the 3 studies which listed specific AEs (Feifel-2010, 
Finger-2015, Parker-2017), those AEs that were reported in more than 1 patient included: 
inappropriate sexual behavior/ hypersexuality; sleep impairment; headache; dyspepsia /nausea; 
dizziness/lightheadedness; nasal irritation; and nasal congestion. There appeared to be no dose 
relationship with respect to any of these AEs. Nasal AEs (nasal irritation or nasal congestion) 
were the only AEs that were reported in more than 1 study (Feifel-2010, Parker-2017), and nasal 
discomfort from the intranasal spray was also a reason for 1 subject withdrawal (Feifel-2010). In 
one study in patients with dementia (Finger-2015), inappropriate sexual behaviour/ 
hypersexuality was reported in 5 (31%) of the 15 patients receiving oxytocin, compared with 1 
(14%) of the 7 placebo patients (p = 0.4). However, there was no clear dose-response 
relationship, as this behaviour was seen only at the 2 lower doses of oxytocin (24 or 48 IU BID) 
and not at the highest dose (72 IU BID). Information on vital signs effects was available from 3 
studies, with 2 of the 3 studies showing no oxytocin effect on vital signs (Finger-2015, 
Pedersen-2011), and the third study (Parker-2017) suggesting that systolic standing blood 
pressure increased in subjects treated with oxytocin 24 IU BID for 4 weeks. Oxytocin 24 IU - 40 
IU BID for 2 weeks was not associated with changes in blood chemistry or urine parameters in 
two studies (Pedersen-2011, Feifel-2010). 
Studies of 5-8 Weeks Duration: Eight studies provided safety information for oxytocin BID or 
three-times-per-day (QID) dose regimens of 5-8 weeks duration. Dosing regimens varied widely 
in these studies, with 3 of the studies investigating an oxytocin regimen of 24 IU BID 
(Anagnostou-2012, Watanabe-2015, Cacciotti-Saija-2014) and 2 studies employing doses up to 
40 IU BID (Einfeld-2014, Modabbernia-2013). The highest daily dose of oxytocin (24 IU QID) 
and the highest cumulative exposure (96 IU/day x 56 days for a total of 5376 IU) was an 8-week 
study of oxytocin use against binge eating disorder (Agabio-2016). Only one of the 8 studies 
reported SAEs associated with oxytocin treatment. That was the study by Yatawara (2016), 
where 2 (13.3%) of 15 autistic patients treated with oxytocin 12 IU BID developed hyperactivity 
and aggression. Although many different types of AEs were reported in these studies, it was 
difficult to appreciate any major trends. AEs that occurred in more than 1 subject in more than 1 
study included constipation, thirst, increased urination, nausea, palpitations, and dizziness. 
Among these, the most frequently reported was constipation, which occurred in more than 1 
subject in 3 different studies (Yatawara-2016, Cacciotti-Saija-2014, Modabbernia-2013).  
Studies of 12-13 Weeks Duration: Three studies provided safety information for oxytocin BID 
dose regimens of 12-13 weeks duration. In 2 of the 3 studies, oxytocin was administered at a 
dose of 40 IU BID (Pederson-2017, Ohlsson-2005), while in the third study, oxytocin daily 
dosing was titrated to as high as 72 IU BID (Feifel-2013). No SAEs were reported in any of 
these studies. Furthermore, the study by Pederson (2017) reported no AEs of any type in the 
oxytocin treatment group. In the 2 studies that did report AEs (Feifel-2013, Ohlsson-2005), the 3 
AEs that occurred in more than 1 subject in both studies were headache, nausea, and weight gain. 
Two studies (Feifel-2013, Ohlsson-2005) found that oxytocin had no adverse effects on blood 
chemistry/electrolytes, while a third study found that oxytocin did not affect urine (Feifel-2013). 
Only one study (Ohlsson-2005) addressed changes in vital signs, concluding that oxytocin did 
not affect blood pressure. 

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Most Frequently Reported AEs: For all of the multiple-dose studies described above, AEs that 
were reported in more than 1 subject in more than 1 study of 1-13 weeks duration included: 
nausea (5 studies), headache (5 studies), dizziness (3 studies), constipation (3 studies), nasal 
irritation (3 studies), thirst (2 studies), increased urination (2 studies), palpitations (2 studies), 
increased appetite (2 studies), weight gain (2 studies), dry mouth/throat (2 studies), and 
somnolence/drowsiness (2 studies).  Table 2 presents these AEs grouped by increasing 
cumulative dose of oxytocin. In the majority of cases, there was no clear evidence of dose-
dependent relationship. The one possible exception was the AE of “palpitations”, which was 
reported in 11.1% of subjects at a cumulative oxytocin dose of 2016 IU in one study and in 25% 
of subjects at a higher 5376 IU cumulative dose in a second study.  However, because data for 
this AE is available from only 2 studies, the ability to identify a true trend is very limited. 

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Table 2: 
Adverse Events Reported in More than One Subject in More than One 
Oxytocin Study of 1-13 Weeks Duration: Percentages of Adverse Events 
Reported at Selected Cumulative Doses of Intranasal Oxytocin 
Adverse 
Events 
No. AEs/ No. Subjects ( Percentage) at Cumulative Dose of Oxytocin 
739 IU 
768 IU 
1400 IU 
2016 IU 
4200 IU 
5376 IU 
7280 IU 
Cumulative 
Dose Not 
Calculable 
Nausea 
 
 
4/15 
(26.7%) 
3/27 
(11.1%) 
4/20 
(20%) 
 
3/23 
(13.0%) 
2/13 
(15.4%) 
Headache 
 
 
4/15 
(26.7%) 
7/27 
(25.9%) 
4/20 
(20%) 
 
6/23 
(26.1%) 
2/13 
(15.4%) 
Dizziness 
4/6 
(66.7%) 
 
4/15 
(26.7%) 
 
3/20 
(15%) 
 
 
 
Constipation 
 
10/15 
(66.7%) 
 
2/27 
(7.4%) 
2/20 
(10%) 
 
 
 
Nasal 
irritation 
 
 
4/15 
(26.7%) 
2/10 
(10%) 
 
 
4/23 
(17.4%) 
 
Thirst 
 
10/15 
(66.7%) 
 
8/27 
(29.6%) 
 
 
 
 
Increased 
urination 
 
10/15 
(66.7%) 
 
5/27 
(18.5%) 
daytime 
4/27 
(14.8%) 
night time 
 
 
 
 
Palpitations 
 
 
 
3/27 
(11.1%) 
 
2/8 
(25.0%) 
 
 
Increased 
appetite 
 
 
 
 
5/25 
(25.0%) 
 
 
3/13 
(23.1%) 
Weight gain 
 
 
 
 
 
 
2/23 
(8.7%) 
2/13 
(15.4%) 
Dry 
mouth/throat 
 
 
 
 
2/20 
(10.0%) 
 
 
2/13 
(15.4%) 
Somnolence/ 
drowsiness 
 
 
 
 
6/20 
(30.0%) 
 
 
2/13 
(15.4%) 
 
Given that the cumulative dose of oxytocin administered in the current protocol is 5320 IU over 
12 weeks, AEs reported at cumulative doses of 4200 IU – 7280 IU in Table 2 are especially 
relevant. These include nausea, headache, dizziness, constipation, nasal irritation, palpitations, 
increased appetite, weight gain, dry mouth/throat, and somnolence/drowsiness. Based on the AEs 
percentages shown in Table 2 at increasing cumulative doses of oxytocin, there was no 
suggestion of a dose-response for any of these AEs. In addition, 4 of the AEs (drowsiness, dry 
throat/mouth, nasal irritation, and headache) were also seen in the systematic review of single-
dose studies (Table 1) but occurred at comparable or lower frequencies than in Placebo subjects.  
In conclusion, oxytocin appears safe at a variety of doses and in a range of clinical populations as 
reported in the literature. However, because oxytocin can modify heart rate and the anti-diuretic 

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effect might lead to seizures, Macdonald (2011) recommended screening potential recipients of 
intranasal oxytocin for allergies, significant cardiovascular disease, and neurological disorders. 
4.1.10. 
Rationale for Selection of Doses for this Study 
As presented above, intranasal oxytocin has been studied in small clinical trials of patients with 
mental health disorders at doses ranging from 18 IU to 320 IU given as single doses or in divided 
doses given BID or QID for as long as 13 weeks. The 3 small randomized controlled trials 
examining the effects of intranasal oxytocin in patients with AUD reported by Pederson 
(Pederson-2013, Pederson-2017) suggested that intranasal oxytocin may attenuate alcohol 
withdrawal symptoms, reduce very heavy drinking, reduce anxiety scores, and can be safely 
administered at doses of 80 IU/day for 12 weeks. This Phase 2 trial proposes to study a dose of 
70 IU/day in a larger group of patients, with a run-in period of 2-weeks of once-daily intranasal 
oxytocin at 35 IU, followed by 10-weeks of twice daily oxytocin at 35 IU for a total daily dose of 
70 IU that is similar to the dose shown to be safe and effective in reducing drinking, craving, 
anxiety, and withdrawal by Pederson (2017). 
4.2. 
Study Design 
This study is a double-blind, randomized, placebo-controlled, parallel group, multi-site clinical 
trial designed to assess the efficacy of oxytocin compared with placebo to reduce drinking in 100 
subjects (50 in each group) who report 4 or more Diagnostic and Statistical Manual of Mental 
Disorders – Fifth Edition (DSM-5™) symptoms of AUD. This study will be conducted at 4 
clinical sites. If eligible for the study, subjects will be randomized using a stratified permuted 
block randomization procedure with “clinical site” as a stratification variable in an approximate 
1:1 ratio (targeting 50 subjects per group) to receive either intranasal oxytocin or placebo for 12 
weeks. 
If eligible for the study, subjects will receive blinded intranasal oxytocin at 35 IU once-per-day 
or intranasal placebo (same volume once-per-day) for 2 weeks (initial tolerability assessment 
period), then for the next 10 weeks (maintenance period) subjects will receive oxytocin at 35 IU/ 
BID, (total daily dose 70 IU) or intranasal placebo (same volume BID). 
Subjects will be seen in the clinic at screening visit(s), at randomization (Week 1), and at Weeks 
2, 3, 4, 6, 8, 10 and 13. During the alternate weeks when the subjects will not be coming into the 
clinic they will be contacted once during that week by telephone to encourage study drug 
compliance and to assess withdrawal, adverse events (AEs), and concomitant medications. A 
final follow-up telephone interview will occur during Week 14/15 (1-to-2 weeks after the end of 
dosing). 
The overall study schema is provided in Figure 1. The study schedule of visits and assessments is 
shown in Table 3. 
Enrollment will be halted if 2 or more at least possibly related SAEs as judged by the 
investigator or medical monitor occur. If this occurs, a DSMB will be convened and a decision in 
conjunction with the study Sponsor will be made regarding stopping the study.   
 

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Figure 1:  
Overview of Study Design 
 
 

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Table 3. 
Schedule of Assessments  
 
Screen 
 
Maintenance 
EOSa 
Safety 
Follow-up 
Study Week 
-2 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14/15 
Clinic Visit # 
1 
2 
3 
4 
5 
 
6 
 
7 
 
8 
 
 
9 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Alcohol Breathalyzer 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
Urine Drug Screenb 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
Locator Form  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/Surgical History 
X 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
Xd 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
MINI V 7.0.2 (AUD module at EOS) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
C-SSRS 
 
X 
X 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
Clinical Chemistrye 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
Vital Signs 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
ECG (12-lead) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Prior and Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CIWA-AR 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
Eligibility Checklist  
X 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drug Compliance – Diary review 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
Drug Accountability (vial weight) 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
Pregnancy Test/Female Birth Control Methods 
X 
X 
Xf 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
Weight 
X 
 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
Drinking Goal 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AEs/SAEs 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Other Services Used for Alcohol Use 
Problemsg 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
RANDOMIZATION 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brief Telephone Interviewh 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
X 
 
 
Take Control 
 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
 
 
Exit Interview 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Treatment Referral 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Follow-Up Telephone Interview 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Final Subject Disposition 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 

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Screen 
 
Maintenance 
EOSa 
Safety 
Follow-up 
Study Week 
-2 to -1 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14/15 
Clinic Visit # 
1 
2 
3 
4 
5 
 
6 
 
7 
 
8 
 
 
9 
 
Subject Reported Outcomes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hyperkatefia Scale 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Barrett Impulsivity Scale 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Spielberger Trait Anxiety Inventory 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
BPAQ - SFi 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
Simplified Nutritional Appetite Questionnaire  
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
Cigarette and other nicotine use 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
ECR-RSj 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
IDS-30k 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
POMS 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
PROMIS – alcohol negative consequences 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
PROMIS – sleep disturbances 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
PROMIS – pain interference 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
UPSITl 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
X 
 
Urge to drink questionnaire 
 
X 
 
 
 
 
X 
 
X 
 
X 
 
 
X 
 
Timeline followback (TLFB) 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
 
 
X 
 
Brief Drinking Questionnairem 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
a EOS=end of study. These assessments are to be done at Week 13 or if the subject discontinues early and agrees to a final clinic visit. 
b Test for opioids, cocaine, amphetamines, methamphetamine, THC, buprenorphine, methadone, benzodiazepines, oxycodone, 3,4-methylenedioxy-
methamphetamine (MDMA), and barbiturates. 
c Updated prior to randomization. 
d Complete physical exam at screening including examination of the nares, plus examination of the nares at all other visits as indicated. 
e AST, ALT, total bilirubin, creatinine, sodium, and potassium. 
f Only birth control methods are collected at this visit. 
g At baseline asks about lifetime treatment use and at EOS asks “since beginning this study 
h AEs, concomitant medications, and drug compliance reminder. 
i Buss Perry Aggression Questionnaire – Short Form  
j Experiences in Close Relationships—Relationship Structures Questionnaire (ECR-RS) (attachment related anxiety) 
k Inventory of Drinking Situations 
l University of Pennsylvania Smell Identification Test  
m Only asked to subjects who request to withdraw from the study and are not willing to provide TLFB drinking data. This questionnaire will be asked at whatever 
constitutes the EOS visit.

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4.3. 
Benefit/Risk Assessment 
Intranasal oxytocin is remarkably well tolerated and 80 IU per day has been administered for up 
to 13 weeks in two studies (Ohlsson-2005, Pederson-2017). Infrequent hyponatremia, probably 
secondary to an anti-diuretic effect, and infrequent nasal irritation have resulted in cessation of 
treatment. To minimize this risk, patients with significant gastrointestinal, cardiac, neurological, 
and renal disorders as well as pregnant or lactating women will be excluded. Sodium levels in 
addition to other liver enzyme and creatinine levels will be monitored over the course of 
treatment. A physical examination of the nares and throat will also be performed for signs of 
irritation; and sense of smell will be regularly evaluated. Dose reductions are permitted in the 
event of intolerance. The benefit of participating in this study is that all subjects will be asked to 
view the “Take Control” behavioral platform. The intervention is derived from a self-help 
approach developed by NIAAA that provides evidence-based, field tested information for 
individuals with alcohol problems, and suggestions for making changes in their drinking. In 
addition, it is possible that subject randomized to receive Oxytocin nasal spray may reduce their 
alcohol drinking which can have positive overall health benefits. 
 

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5. 
Study Objectives 
5.1. 
Primary Objective 
The primary objective of the study is to compare the efficacy of oxytocin in reducing the weekly 
percentage of heavy drinking days over 10 weeks of maintenance treatment among subjects with 
moderate to severe AUD. A “heavy drinking day” is 4 or more drinks per drinking day for 
women and 5 or more drinks per drinking day for men. 
5.2. 
Secondary Objective 
Secondary objectives include assessment of other measures of the effects of oxytocin compared 
with placebo on reduction of alcohol use as well as effects on alcohol craving, alcohol-related 
consequences, cigarette smoking and other nicotine use, psychological assessments, retention in 
the study, and safety and tolerability throughout the study. 

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6. 
Study Interventions 
6.1. 
Investigational Products: Oxytocin and Placebo 
Investigational products will be manufactured under contract with University of Iowa and will be 
packaged and distributed in drug kits by Catalent, Inc. Oxytocin and Placebo liquid formulations 
will be packaged in 20 mL vials with a fill volume of 18 mL with a Nemera P270 pump spray 
actuator device crimped to the vial. Oxytocin is supplied at a concentration of 70 IU/mL. The 
pump spray actuator delivers 100 μL in a single spray (equivalent to 7 IU of oxytocin).  
Oxytocin and placebo will be administered once daily (morning) for 2 weeks (Weeks 1 and 2) 
and then twice daily (morning and evening) for 10 weeks (Weeks 3 through 12). One dose is 
defined as the intranasal administration of 100 μL per each nostril for a total of 5 insufflations 
alternating between nostrils with a 30 second wait between insufflations for a total dose of 
500 μL equivalent to 35 IU. Thus, subjects will receive oxytocin 35 IU per day for 2 weeks, then 
35 IU twice per day for 10 weeks for a total daily dose of oxytocin 70 IU.  
6.2. 
Investigational Product Packaging, Labeling, and Distribution of Drug Kits 
Investigational products will be provided in drug kits containing 6 bottles of either oxytocin or 
placebo in each kit with each bottle containing 18 mL of oxytocin or placebo. Kits will be 
shipped periodically to sites during the study depending on enrollment. 
The study number and the words “oxytocin or placebo study” will be preprinted on each vial 
label. The label will also have a unique kit number, the volume contained in the bottle, storage 
conditions, and the words “Caution: New Drug – Limited by Federal (or United States) Law to 
Investigational Use” and “Keep Out of Reach of Children”. A separate label will be supplied to 
affix to the vial each time a bottle is dispensed. This label will contain the clinical site name, 
clinical site phone number and 24/7 emergency phone number, and places to record the subject 
number and the date dispensed. 
6.3. 
Investigational Product Storage 
Kits should be stored under refrigeration (within the range of 36°F to 46°F; 2°C to 8°C) in a 
secured area at the clinical site. After dispensing subjects will be instructed to store the vials 
under refrigerated conditions; however, stability at room temperature (68°F to 77°F; 20°C to 
25°C) has been demonstrated for one month, so excursions to room temperature for 30 days or 
less should not impact the product. 
6.4. 
Investigational Product Dispensing 
Prior to dispensing the study drug vials, each vial will be weighed on an analytical balance that 
measures to the 0.01g or lower level and the weight will be recorded. The person dispensing the 
drug will prime the pump by depressing the actuator 5 times and will weigh the vial again. This 
will be done each time a new vial is dispensed. Repriming of the pump between uses is not 
necessary. 
The subject will be instructed to return study vials at each clinic visit. Upon return of the used 
study drug vial, the vial will be weighed a second time to estimate the amount of drug insufflated 

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during the dosing period. Bottle weights will be collected at each visit when the subject returns 
the vial.  
Dispensing will be in accordance with the plan in Table 4, unless the subject does not return 
within the scheduled windows around visits, then other arrangements can be made. Vials contain 
sufficient volume of investigational product in one vial for 16 to 17 days of dosing at 2 doses per 
day. As the first two weeks are one per day dosing, then vial #1 will have enough for the first 
two weeks, plus approximately another 7 days at twice daily dosing. Vial #1 can serve as a back-
up if needed. When vials are dispensed, the subject will be provided with a card that shows 
which numbered vial to use over the date range covered by the amount in the vial. 
Table 4: 
Investigational Product Dispensing Plan 
Study Weeka 
Vial # Dispensed 
Vial #s Returned 
1 
1 
NA 
2 
1 
1 (weighed and redispensed) 
3 
2 
1 (weighed)  
4 
2 + 3 
2 (weighed and redispensed) 
6 
4 
2 + 3 (weighed) 
8 
5 
4  (weighed) 
10 
6 
5  (weighed) 
13 
NA 
6 (weighed) 
a Only weeks where clinic visits are scheduled are shown. 
6.5. 
Investigational Product Accountability and Compliance 
The site principal investigator (PI) or designated study personnel will maintain a log of the 
receipt of all investigational products and record of dispensing of all investigational products to 
the subject. Investigational product for each subject will be inventoried and accounted for 
throughout the trial. The site PI or his/her staff will count the drug kits/individual vials remaining 
at the end of the study and record the vial count on the appropriate drug accountability form. 
Subjects will be asked to return any used and/or unused vials of investigation product at each 
clinic visit for accountability. Subjects will be provided with a Diary Card (Appendix A) to 
complete each time they self-administer a dose and will be asked to bring the card back at each 
clinic visit for site staff to review and confirm dosing compliance. 
6.6. 
Used/Unused Investigational Product Supplies 
Unused investigational products will be retained at the clinical sites until the end of the study, at 
which time they will be shipped back to Catalent for destruction.  
6.7. 
Investigational Product Administration 
To control dosing and absorption of investigational product, subjects will be instructed to 
administer the nasal spray with their head in an upright position closing one nostril with one 
finger while administering the spray in the other nostril and sniffing during administration. At 
the first administration on Study Day 1, subjects will be provided with instruction on how to self-

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administer their first dose, will be observed while administering the first dose, and will be given 
an instruction sheet to take home. At subsequent visits, subjects will be asked to return the nasal 
spray devices.  
Missed Doses: Subjects will be instructed if the dose is not taken at the recommended time, to 
skip this dose, and the next dose should be taken at the time of next scheduled dose; doses should 
never be doubled up.  
Dose Reductions and Discontinuation. If the subject is not tolerating the investigational 
product, the dose can be reduced by 14 IU or 200 μL increments per dose (2 less sprays) to 
determine if the subject can tolerate a lower dose. For example, one spray in each nostril can be 
omitted for each reduction. Then the subject should try to continue to give one dose in the 
morning and one dose in the evening if during the maintenance period. If the dose is reduced 
during the initial 2-week tolerability period, then subjects will not escalate to the maintenance 
dose and will stay at the tolerated dose. If the subject develops a medical condition requiring 
discontinuation of the investigational product, he/she can simply discontinue immediately. In the 
event that a female subject becomes pregnant, she will be instructed to discontinue taking the 
investigational product immediately.  
6.8. 
Take Control Behavioral Platform 
The behavioral platform “Take Control” consists of a series of 7 computerized modules. Subjects 
will view each module of “Take Control” at clinic visit starting at Week 1 after randomization. 
Thereafter, it will be as shown in Table 3. If a visit is missed, missed modules will be reviewed 
at the next visit. The paper versions of the modules are not to be given to the subject to take 
home and must remain at the clinical site. The intervention is derived from a self-help approach 
developed by NIAAA that provides evidence-based, field tested information for individuals with 
alcohol problems, and suggestions for making changes in their drinking. The NIAAA material is 
publicly available in a NIAAA booklet entitled “Rethinking Drinking” and on a NIAAA website 
http://rethinkingdrinking.niaaa.nih.gov. Delivering these materials in a computerized method in 
this trial has the advantage of standardizing the amount of educational material received by the 
subject.  
6.9. 
 Concomitant Medications 
For study inclusion, subjects cannot be taking oxytocin for any reason and must agree to not take 
non-study oxytocin during the study. In addition, subjects cannot have taken any anti-
convulsants, hypnotics, barbiturates, antipsychotics, psychomotor stimulants (such as 
methylphenidate), or benzodiazepines within 5-half-lives prior to the date of randomization. In 
addition, if a subject is taking a medication for depression or anxiety, he or she must have been 
taking a stable dose in the 2-months prior to randomization and plan to continue during the 
study. This includes drugs such as the following: 
• selective serotonin reuptake inhibitors (SSRIs)  
• dual uptake inhibitors  
• serotonin-norepinephrine reuptake inhibitors (SNRIs)  
• tricyclic antidepressants  

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• monoamine oxidase inhibitors (MAOIs) 
• bupropion 
Pharmaceutical treatments approved for treatment of alcoholism or treatments known to be used 
off-label or experimentally for treatment of alcoholism are prohibited during the study. The 
following drugs are thus prohibited: 
• Oral naltrexone (Revia, Depade) 
• Depot naltrexone (Vivitrol) 
• Disulfiram (Antabuse) 
• Acamprosate (Campral) 
• Nalmefene (Selincro) 
• Baclofen  
• Varenicline 
Also, if a subject reports using a drug or having been prescribed a drug to treat alcoholism during 
the trial, they will be asked to discontinue its use. 
The use of nicotine nasal sprays will be prohibited during the study. The use of other intranasal 
vasoconstricting products is allowed; however, subjects will be instructed to not use these within 
2 hours before or 1 hour after intranasal investigational products are self-administered. Examples 
are decongestant nasal sprays containing oxymetazoline, epinephrine or phenylephrine. 
Subjects will be instructed to check with study staff before taking any new medications or 
stopping current medications. Subjects will be informed that starting any new medication 
without consulting study staff could pose health risks and/or result in their discontinuation for the 
study drug. 
Management of investigational products and concomitant medications during the study is at the 
discretion of the PI or designated medical doctor. The PI or designee may consult with the 
medical monitor if there are questions. 
When oxytocin has been given intravenously to induce labor, severe hypertension has been 
reported when oxytocin was given three to four hours following prophylactic administration of a 
vasoconstrictor in conjunction with caudal block anesthesia. Cyclopropane anesthesia may 
modify oxytocin's cardiovascular effects, so as to produce unexpected results such as 
hypotension. Maternal sinus bradycardia with abnormal atrioventricular rhythms has also been 
noted when oxytocin was used concomitantly with cyclopropane anesthesia. Therefore, subjects 
should be cautioned if undergoing elective surgery or emergency surgery to discuss the use of 
anesthetics with the prescribing physician and possible drug-drug interactions with oxytocin.  

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7. 
Study Procedures 
7.1. 
Recruitment of Subjects 
Subject recruitment methods at each site will be based on their local population; however, 
standard tactics will be used (i.e., flyers, newspaper advertisements, radio advertisements, and 
television advertisements). Advarra Investigational Review Board (IRB) and NIAAA will 
approve all advertising materials used for subject recruitment. Interested candidates responding 
to recruitment materials by telephone will be asked to complete a standardized telephone 
interview that includes questions about their drinking behavior, health status, interest in 
participation, and availability for the entire 13 weeks of the trial post randomization. Study staff 
will ask these questions without revealing the entry criteria for the study. Candidates who report 
drinking and other information consistent with the entry criteria and appear to be available and 
interested in the study will meet with the investigator or designated investigational staff ideally 
within 14 days after the initial inquiry to start the informed consent and assessment process. 
7.2. 
Informed Consent 
At the first screening visit, candidates will meet with either the site PI or his/her designee and 
receive an explanation of the study purpose and requirements. If still interested after receiving an 
explanation of the study, the candidate will be given an opportunity to review, inquire about, and 
sign the study informed consent form approved by the IRB. Subjects must have blood alcohol 
content (BAC) of 0.000 measured by breathalyzer when signing the informed consent document 
(tested shortly before or just after providing consent). Repeat measurements of BAC are 
permitted at the discretion of the investigator. Subjects will be given a copy of the signed 
informed consent form. All subjects who sign informed consent must be registered in the 
electronic data management system (EDMS) as enrolled in the study. The EDMS will assign the 
subject a unique subject ID number that will be used on all of the data collection forms and 
electronic system entries. 
7.3. 
Selection and Withdrawal of Subjects 
7.3.1. 
Inclusion Criteria 
Subjects must meet each one of the following inclusion criteria in order to be eligible for 
participation in the study: 
1. Be at least 21 years of age. 
2. Have a current (past 12 months) DSM-5 diagnosis of AUD (4 or more symptoms) 
assessed using the MINI neuropsychiatric interview version 7.0.2 (at least moderate 
severity, ICD-10-CM Code F10.20 alcohol dependence, uncomplicated). 
3. If male, report drinking an average of at least 28 drinks per week or if female report 
drinking an average of at least 21 drinks per week and at least one heavy drinking day per 
week for the 28-day period prior to consent and at least one heavy drinking day in the 
7- day period prior to randomization.  

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4. Have a BAC by breathalyzer equal to 0.000 when s/he signed the informed consent 
document (either just prior to or immediately after signing consent). 
5. Be seeking treatment for problems with alcohol and express a goal of abstinence or a 
reduction in drinking. 
6. Be able to verbalize an understanding of the consent form, able to provide written 
informed consent, verbalize willingness to complete study procedures, able to understand 
written and oral instructions in English and able to complete the questionnaires required 
by the protocol. 
7. Agree (if the subject is female and of childbearing potential) to use at least one of the 
following methods of birth control, unless she is surgically sterile, partner is surgically 
sterile or she is postmenopausal: 
• oral contraceptives, 
• contraceptive sponge, 
• patch, 
• double barrier (diaphragm/spermicidal or condom/spermicidal), 
• intrauterine contraceptive system, 
• etonogestrel implant, 
• medroxyprogesterone acetate contraceptive injection, 
• complete abstinence from sexual intercourse, and/or 
• hormonal vaginal contraceptive ring.  
8. Be able to take intranasal investigational products and be willing to adhere to the 
investigational product regimen.  
9. Complete all assessments required at screening and baseline.  
10. Have a place to live in the 2 weeks prior to randomization and not be at risk that s/he will 
lose his/her housing by Study Week 15.  
11. Not anticipate any significant problems with transportation arrangements or available 
time to travel to the study site by Study Week 15. 
12. Not have any plans to move within Study Week 15 to a location which would make 
continued participation in the study impractical. 
13. Not have any unresolved legal problems that could jeopardize continuation or completion 
of the study. 
14. Provide contact information of someone, such as a family member, spouse, or significant 
other, who may be able to contact the subject in case of a missed clinic appointment. 
15. Be someone who in the opinion of the investigator would be expected to complete the 
study protocol. 
16. Agree to the schedule of visits, verbally acknowledge that s/he will be able to attend each 
scheduled visit, participate in phone visits and that s/he does not have any already 
scheduled events or a job that may substantially interfere with study participation. 

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17. If taking a medication for depression or anxiety, must have been taking a stable dose in 
the 2-months prior to randomization and plan to continue during the study. This includes 
drugs such as the following: 
• SSRIs 
• Dual uptake inhibitors  
• SNRIs 
• Tricyclic antidepressants  
• MAOIs 
• Bupropion 
18. Not currently taking oxytocin and agree not to take non-study oxytocin for the duration of 
the study. 
19. Agree to not use nicotine nasal spray for the duration of the study. Note; other forms of 
nicotine replacement therapy (gum, patch, etc., are permitted). 
7.3.2. 
Exclusion Criteria 
Subjects will not be eligible to participate in this study if any one of the following exclusion 
criteria is met: 
1. Have current substance use disorder for any psychoactive substance (including sedatives 
and hypnotics) other than alcohol, nicotine or mild marijuana use disorder as defined by 
DSM-5 criteria. 
2. Have a urine toxicology screen positive during screening or baseline for any of the 
following substances:  
• benzodiazepines,  
• cocaine, 
• opioids,  
• amphetamines,  
• buprenorphine, 
• methadone,  
• methamphetamines 
• oxycodone,  
• MDMA, and/or 
• barbiturates. 
Note: Testing for tetrahydrocannabinol (THC) will be included in the urine drug test; 
however, subjects who test positive for THC are still eligible to participate in the study 
unless they endorse moderate or severe substance use disorder for marijuana as indicated 
by DSM-5 criteria. The results for THC will be recorded for information only. If positive 
for opioids but recent opiate use for acute pain is reported by the subject, then the subject 
can be re-screened. 

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3. Have been hospitalized for alcohol intoxication delirium, alcohol withdrawal delirium, 
alcohol-induced persisting dementia or amnestic disorder, or have had an alcohol 
withdrawal seizure, alcohol-induced psychotic disorder with a primary diagnosis of 
alcohol use disorder or a history of any seizure disorder. 
4. Have participated (received treatment) in any behavioral and/or pharmacological 
intervention research study for the treatment of alcohol problems in the past 7 years. 
5. Be mandated by the court to obtain treatment for problems with alcohol. 
6. Be anyone who in the opinion of the investigator could not be safely withdrawn from 
alcohol without medical detoxification. 
7. Be currently undergoing psychotherapy by a licensed therapist or psychiatrist for alcohol 
problems  
NOTE: Current psychotherapy should be considered on a case-by-case basis. Psychotherapy 
for a disorder that may be related to the subject’s use of alcohol should be exclusionary. 
However, shorter term focused behavioral therapy for defined, non-alcohol related problems 
may be acceptable. 
8. Have undergone medical detoxification (e.g., reports using a benzodiazepine) during the 
screening phase (prior to randomization). 
9. Have known allergy to oxytocin. 
10. Have significant medical conditions (e.g., chronic rhinitis during the past year) that may 
preclude successful insufflations of the intranasal investigational products or other 
medical conditions (e.g., nasal lesions) that could be affected by repeated intranasal 
administrations. 
11. Have been treated with a pharmacotherapy for alcohol problems within 6 months prior to 
randomization. 
12. Have taken any anti-convulsants, hypnotics, barbiturates, antipsychotics, psychomotor 
stimulants (such as methylphenidate), or benzodiazepines within 5-half lives days prior to 
the date of randomization. 
13. Have any of the following, based on DSM-5 criteria as assessed using the MINI: 
• Current or lifetime diagnosis of psychotic disorders 
• Current bipolar disorder 
Note: Subjects diagnosed with psychiatric disorders not specifically excluded above may 
be excluded at the discretion of the PI if the comorbid psychiatric condition compromises 
the study integrity by virtue of its type, duration, or intensity. 
14. Have any of the following: 
• attempted suicide past year,  
• current (past year) suicide behavior disorder in accordance with DSM-5 criteria as 
assessed using the MINI (see note below about assessment of subjects diagnosed at 
low risk), or 

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• current (since screening MINI) suicidality risk as indicated during the conduct of the 
C-SSRS with concurrence after a study physician’s evaluation if the response to 
C-SSRS questions 1 or 2 is “yes”). 
Note: The MINI suicidality module rates scores of 1 to 8 as a diagnosis of low risk of 
suicidality. As the MINI questions that could result in a low risk score are considered 
inadequate to fully determine the potential suicidal risk of an individual (e.g., “Feel 
hopeless” and “Think that you would be better off dead or wish you were dead?” 
responses of “yes” dictates a score of 1 for each question), any subject who scores in the 
low risk category should be evaluated further by a study physician or psychologist who 
should document whether the subject is appropriate for study inclusion based on his/her 
clinical judgment of the potential suicide risk of the subject. Likewise, if the subject 
responds “yes” to either of the first two questions on the screening C-SSRS performed on 
the day of randomization as a final eligibility check, the subject should also evaluated by 
a study physician for current suicidality risk, who should document the subject’s 
suitability for study inclusion. 
15. Have moderate or serious dementia as assessed by clinical exam. 
16. Be pregnant or breast-feeding or have plans to become pregnant at any time during the 
study. 
17. Have clinically significant abnormal liver enzyme levels defined as AST or ALT 5-fold 
above the upper limit of normal (ULN), or bilirubin greater than 2 times the ULN. 
Note: If the subject has values of liver enzyme that are 3.0-to-4.9 fold above the ULN and 
bilirubin that is 1.5-to-1.9 fold above the ULN of normal, these assessments should be 
repeated at least a week apart and if still in this range or higher, the subject should be 
excluded from the study and referred to their physician for further follow-up.  
18. Have sodium < 132 mmol/L or > 150 mmol/L or potassium < 3.2 mmol/L or > 
5.5 mmol/L or abnormal calculated creatinine clearance (<60 mL/min), as calculated by 
Cockcroft and Gault formula.  
19. Have a serious or unstable medical illness or any potentially life-threatening or 
progressive medical condition other than addiction that may compromise subject safety 
or study conduct. 
20. Have clinically significant gastrointestinal, neurological, renal, or cardiovascular disease 
such cardiac arrhythmia, uncontrolled hypertension, congestive heart failure, or any other 
ECG abnormality considered clinically significant by the PI. 
21. Have data suggesting cirrhosis of the liver. 
22. Have taken oxytocin during the 6-month period prior to randomization for treatment of 
any disorder or if ever treated with oxytocin for AUD. 
23. Have UPSIT score ≤ 30 in men and ≤31 in women at screening.  

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7.4. 
Eligibility Screening 
After the subject undergoes alcohol breathalyzer testing and signs informed consent, screening 
may begin. During the first screening visit (additional visits are permitted if needed), subjects 
will undergo the following assessments: 
• Demographics and locator form 
• Urine drug screen 
• Medical history 
• Physical examination and body weight 
• MINI  
• Clinical chemistry 
• Pregnancy test for females of childbearing potential and birth control methods, if 
female 
• Vital signs 
• ECG 
• TLFB for the previous 28 days 
• Prior medication use 
• CIWA-AR 
• Drinking goal 
• UPSIT 
Subjects will be instructed that if they are taking a medication for depression or anxiety that they 
should continue to do so throughout the study. They will also be instructed that they should 
report any new medications they are taking at each visit or telephone contract.  
The above assessments can be performed in any order except that it is recommended to perform 
physical examinations including vital signs prior to blood draws. If any of these assessments 
reveal that the subject is not eligible for the study, screening can be immediately terminated and 
no further data be collected. Clinical chemistry tests may be repeated at the discretion of the 
investigator if the first assessment yields values outside normal laboratory limits. The eligibility 
checklist will be reviewed, and if the subject is still eligible after the assessments are completed 
at the first screening visit (or additional screening visits), the subject will be scheduled for the 
final eligibility check and baseline visit. It is recommended that hypertensive subjects be referred 
to their primary care physician for additional assessment and possible treatment, and then be 
further evaluated for study inclusion.  
7.5. 
Baseline and Final Eligibility Assessments 
If the subject is eligible after performing all the initial screening assessments, s/he will be 
scheduled to start the study and will come to the clinic for a final eligibility check including the 
following assessments: 

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• Alcohol breathalyzer 
• Urine drug screen 
• Update medical history 
• Update physical exam – new symptoms directed exam 
• Vital signs 
• CIWA-AR 
• C-SSRS* 
• Pregnancy test for females of childbearing potential (must be completed within 2 days 
prior to the subject being randomized and dispensed investigational product) 
• Birth control methods, if female 
• Prior medications update 
• TLFB since screening visit 
*Note that the MINI will be used to rule out subjects who attempted suicide in the past year and 
current (past year) suicidal ideation at initial screening, with the C-SSRS providing an update on 
current suicidal ideation since screening. 
An eligibility checklist will be completed and reviewed by a study investigator and, if the subject 
is still eligible, he/she will complete the following baseline assessments: 
• Other Services for Alcohol Use Problems 
The subject will complete the following questionnaires electronically:  
• Hyperkatifeia Scale 
• Barrett Impulsivity Scale 
• Cigarette Smoking Quantity-Frequency and Other Nicotine Use  
• Buss-Perry Aggression Questionnaire – Short Form 
• Experiences in Close Relationships-Relationship Structures 
• PROMIS – Alcohol Negative Consequences 
• PROMIS – Sleep Disturbances 
• PROMIS – Pain Interference 
• POMS 
• IDS-30 
• Spielberger Trait Anxiety Scale 
• Urge to Drink Questionnaire 
• SNAQ 

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The screening period will not be extended. If the investigator determines that the subject could 
be a viable participant who could not for extenuating circumstances complete the screening 
period in 14-days, the subject can be re-screened by completing all of the screening assessments 
again. In this case, the subject will be assigned a new subject number. 
7.6. 
Measures Taken to Minimize/Avoid Bias 
7.6.1. 
Randomization  
If eligible for the study, subjects will be randomized in an approximate 1:1 ratio to receive either 
oxytocin or placebo using a stratified permuted block randomization procedure with “clinical 
site” as the stratification variable. Clinical site was chosen because both local study populations, 
and the investigative staff influence on the subject’s drinking behaviors may differentially 
influence endpoints.  
Centralized randomization will be performed using an interactive web response system (IWRS). 
The IWRS is available for randomization of subjects 24 hours/day, 7 days/week from any 
computer using a web browser. 
If the subject is determined to be eligible, site personnel who are authorized to randomize 
subjects and who have completed training for the IWRS, will log onto the system and provide 
the EDMS pre-assigned unique subject number. The IWRS provides the randomized group kit 
number and assigns the subject to one of the two interventions. If the subject is randomized and 
is never dispensed study drug, then the subject will be considered a randomization failure and an 
additional subject will be randomized with the next randomization sequence at the time he/she is 
randomized at that site. Likewise, if the subject was randomized and then is determined to not be 
eligible for the study, and never received study drug, then another subject will be randomized 
such that the total numbers of subjects who were eligible, randomized, and dispensed study drug 
meet the enrollment goals. In the case of a subject who was eligible, randomized, and dispensed 
study drug but did not return for follow-up visits, this subject will not be replaced. Any subject 
who received study drug but was later determined to be ineligible will likewise not be replaced. 
The reason(s) that a subject was considered a randomization failure or screen failure will be 
documented in source documents and eCRFs. 
7.6.2. 
Blinding 
Oxytocin and placebo bottles will be identically matched in appearance and the bottle labels will 
not reveal the drug identity. The site investigator or designated approved study physician will 
make the decision to un-blind the identity of the investigational product in the event that the 
study blind needs to be broken to make medical decisions regarding subject treatment. If it is 
determined that unblinding is necessary to assess AEs or SAEs for expedited reporting, NIAAA 
may decide to request unblinding of a subject. Site staff or Sponsor’s designee approved to 
un-blind the study drug will log into the IWRS to obtain the name of the investigational product 
to which the subject was randomized. The IWRS will automatically notify the un-blinded staff 
member at the Data Coordinating Center who will notify the Medical Monitor. NIAAA will be 
notified that an unblinding has occurred if unblinding has been performed by the investigator or 
medical monitor. Prior experience with oxytocin nasal spray compared with placebo nasal spray 
has not indicated that any differences would be noticed between formulations. 

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7.7. 
Interventions on Day 1 
At study Day 1, after the subject is randomized, he/she will receive the first vial of intranasal 
investigational product, and an instruction sheet. The vial(s) being dispensed will be weighed 
prior to providing it to the subject. Site staff will explain the dosing plan to the subject and how 
to complete a Diary Card to track when doses are taken. The subject will administer the first dose 
while in the clinic on Day 1 under observation by site staff to make sure that the subject is using 
the nasal spray appropriately. The subject will watch the first module of Take Control, will be 
given the schedule of visits, and the Week 2 visit will be scheduled.  
Every study subject will be provided with a wallet card and instructed to carry this card that 
identifies the potential investigational products that s/he could be taking during the study. The 
card will provide the name and 24-hour phone number of the investigator (physician) at the site 
who can be contacted in the event of an emergency. The card will also instruct the non-study 
physician rendering emergency care to contact the study physician and inform him/her about the 
care. Prior to release from the clinic, the subject will be asked if they are experiencing any side 
effects from the first dose of investigational product. 
If possible, clinic visits should be scheduled on the same day of the week that the subject 
received the first dose of study drug, but a 3-day window is allowed for conducting visits within 
the scheduled study week. Visits may be scheduled and conducted on any day of the week. Visits 
can be conducted outside of the scheduled study week, but only based upon subject request (e.g., 
for reasons related to patient non-compliance with the study schedule). Each subject will receive 
a visit schedule to take home for future reference. 
7.8. 
Treatment Phase 
During Study Weeks 1 through 12 of the treatment phase of the study, subjects will be seen in 
person at the clinical site 7 times and assessed by telephone 5 times. There is a final clinic visit at 
Week 13 at the end of the 12-week treatment period.  
An alcohol breathalyzer will be administered at each visit, prior to any study assessments, to 
determine if the subject meets the BAC requirement of a BAC ≤ 0.020 before proceeding with 
assessments. A urine drug test will be performed at each visit. At each of the clinic visits, 
subjects will meet with one or more study staff members who will systematically assess AEs 
since the last visit, take vital signs, collect concomitant medication use, administer 
questionnaires (CIWA-AR and C-SSRS), inquire about other medication use and assess drinking 
by TLFB. The UPSIT sniff card test and clinical chemistry, pregnancy test for women of child-
bearing potential and birth control methods (if female) will be collected in accordance with the 
schedule in Table 3. An examination of the nasal mucosa will also be performed. In addition, 
subjects will electronically complete the questionnaires according to the schedule in Table 3. If 
the subject is returning a used study drug vial, the vial will be weighed and the diary card will be 
reviewed for compliance.  
Brief telephone assessments will occur at Weeks 5, 7, 9, 11, and 12. The final in-clinic 
assessment will occur during Week 13. This visit should be scheduled after the subject takes the 
last dose of study drug. 
Subjects will view a single module of Take Control at all clinic visits up to and including Week 
10 that is expected to have a run-time of 10-15 minutes at clinic visits. The subject will be 

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instructed to bring the nasal spray vials and drug with them to the next visit so the site staff can 
perform drug accountability. The subject will also be instructed to contact site staff if they are 
experiencing any intolerable AEs and are contemplating drug discontinuation. 
Additional in-clinic visits are permitted under the protocol, if needed, due to the following 
circumstances: (1) the subject has concerns either about the medication or their drinking and 
wishes to be seen at a time other than their next scheduled in-clinic visit, or, (2) the subject has 
missed a visit and wishes to resume regular participation before their next scheduled visit, (3) the 
subject has reported some change in health, functioning, or circumstances which necessitate a 
visit to conduct safety assessments and evaluate the risk of continued participation in the trial, or 
(4) clinical laboratory measurements need to be repeated.  
Subjects desiring additional counseling or professional therapy for non-crisis psychiatric matters 
(e.g., marital problems, work issues) should be encouraged if within reason to postpone such 
activity until their study participation is concluded. Attendance at self-help support groups (i.e., 
Alcoholics Anonymous) will neither be encouraged or discouraged. Any attendance at self-help 
support groups will be recorded at the randomization visit and at the end of study visit in the 
Other Services Used for Alcohol Use Problems electronic case report form (eCRF). 
7.9. 
Telephone Assessments 
The brief telephone interview (approximately 10 minutes) will occur in accordance with the 
schedule in Table 3 to assess AEs, concomitant medication use and to encourage the subject to 
continue taking investigational products, to verify that the subject is taking the prescribed dose, 
and to remind the subject of the next scheduled visit. A summary of the telephone script follows: 
1. AEs: An open-ended question will be asked as follows: “How have you been feeling 
since your last clinic visit or phone contact?” If the subject reports a new AE, the 
resolution of an AE, or a change in the severity of an AE, ask additional questions to 
determine the severity and dates of occurrence or resolution.  
2. Concomitant Medications: Ask the following question: “Have you taken any new 
medications since you were last seen in the clinic or since our last call? If the subject 
responds affirmatively, record the name of the medication, the daily dose, route of 
administration, and reason used. If the medication is contraindicated for the study, notify 
a study physician, nurse practitioner, or physician assistant for follow-up with the subject. 
3. Drug Compliance: Ask the subject is s/he has been taking the nasal spray and check on 
the number of actuations they report using and if they have had any issues with the 
device. Review procedures with the subject to ensure that the subject is taking the 
prescribed dose. 
4. Reminders: Remind the subject of their next scheduled clinic visit, and adjust the date 
within the visit week if they have a conflict.  
7.10. 
Final Clinic Visit 
The final clinic visit occurs during Week 13; at which time the subject has completed taking 
investigational product. In addition to the assessments previously stated, subjects will have an 
Exit Interview assessment. The subject will be asked about their impression of whether they 
were receiving active drug or placebo, if they felt that the medication helped drinking, how they 

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would describe their experience taking the medication, if they would recommend it to a friend, if 
they would take it again if they needed further treatment in the future. The subject will be 
provided with a referral to a treatment program for their alcohol dependence. If a subject 
withdraws from the study early for any reason, the subject should be asked to return to the clinic 
for the conduct of all of the final clinic visit assessments. 
7.11. 
Telephone Follow-up  
Subjects will be contacted by telephone for a follow-up interview 1 to 2 weeks after the final 
in-clinic visit. During the telephone follow-up interview, the subject will be asked about any 
ongoing AEs that they may have been experiencing at the last clinic visit and any newly emerged 
medical conditions/AEs since that visit. To prompt reporting of new AEs, the subject will also be 
asked about any ongoing or new medication use. 
7.12. 
Duration of Subject Participation 
The total time period that each individual subject will participate is 17 weeks including up to 
2 weeks for screening, 12 weeks of study interventions, the final safety and efficacy follow-up to 
one week after completing treatment (Week 13), and a final safety follow-up telephone contact 
1- to 2-weeks after completion of study drug dosing (Weeks 14/15). 
7.13. 
Safety Criteria for Stopping Doses 
The PI or sub-investigator will follow the protocol to identify and intervene with subjects 
experiencing clinical deterioration during study participation. Criteria to determine when a 
subject requires a higher level of care and discontinuation from the trial intervention are detailed 
below.  
7.14. 
Investigational Product Discontinuation 
If the investigator determines that any study subject should discontinue taking investigational 
products, the subject should be told to discontinue taking the investigational products 
immediately. No dose reduction is necessary in this case. Subjects should continue in the study, 
even if withdrawn from investigational products, and complete all assessments. Dose reductions 
for intolerance are permitted (see section 6.7). 
Pregnancy. Females who become pregnant during the course of the study will be instructed to 
discontinue use of the investigational product immediately. The investigator must report a 
pregnancy within 1 working day of the site being aware to the NIAAA Study Manager and the 
Medical Monitor.  
Physical Illness. Subjects will need to be removed from investigational products if they have a 
serious illness or a disabling condition that precludes them from taking the investigational 
product. 
Adverse Events. If the subject experiences any AEs that are considered study drug related and 
for which the investigator has determined that continuation of the study drug could be 
detrimental to the health of the subject, then drug will be immediately discontinued as described 
above. 

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UPSIT Score. If UPSIT score decreases to ≤ 26, study drug will be discontinued but the subject 
should continue in the study and be monitored using the UPSIT to determine if this AE is 
reversible. 
7.15. 
Subject Withdrawal or Discontinuation Procedures 
Each subject has the right to withdraw consent and withdraw from the study at any time. In 
addition, the investigator may find it necessary to discontinue a subject although it is 
recommended to continue to perform all study assessments, if possible.  
In the event that a subject withdraws or is discontinued from the study, the reason(s) for the 
discontinuation from the study will be recorded and the final end of study assessments shown in 
Table 3 will be completed.  
7.16. 
Situations Requiring Discontinuation from the Study as well as from 
Investigational Product 
It is possible that there will be some subjects who cannot be safely managed in the clinical study 
even though investigational products have been discontinued. Examples are given below. 
1. Increased Drinking. Subjects whose alcohol problem worsens, and, in the opinion of the site 
medical staff, require a more intense level of care than provided in the study may have 
investigational product suspended, and referred to more appropriate care.  
2. Psychiatric Crises. Examples of psychiatric crises include but are not limited to the 
following: 
a. Acute psychosis (hallucinations, impaired reality testing, paranoid ideation, etc.) 
requiring medication and/or hospitalization or intensive outpatient intervention;  
b. Suicidal or homicidal ideation that results in a credible threat of violence directed at 
oneself or others; 
c. Hospitalization for psychiatric symptoms  
Subjects requiring more intensive treatment resulting from acute psychosis or 
suicidal/homicidal behavior will be referred to local treatment centers, emergency 
departments, or hospitalization as appropriate, but will not be provided with medication or 
psychotherapy by study staff.  
3. Absence from the Protocol due to Confinement in a Controlled Environment. If a 
subject is confined to a controlled environment (such a hospital or jail where access to 
alcohol is presumably restricted) for less than 2 weeks, they can resume full participation in 
the trial if in the judgment of the investigator, the subject is still a good candidate for the 
study and continues to meet eligibility requirements. Before resuming investigational 
products the subject should be assessed by the study physician for appropriateness to resume 
the trial (e.g., any new medications or symptoms, pregnancy test, etc.). The decision to restart 
study drug at the full dose will be made in the judgment of the investigator based on the 
subject’s time off study drug and past experience with side effects with the study drug. 
If a subject is in a controlled environment (such a hospital or jail where access to alcohol is 
presumably restricted) for 2 weeks or more, the subject will be discontinued from the study. 

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7.17. 
Study Suspension and/or Termination Criteria 
Enrollment will be halted if more than 2 treatment-related SAEs occur.  In the event that this 
occurs, a DSMB will be convened and a decision in conjunction with the study Sponsor will be 
made regarding stopping the study.   
NIAAA may terminate this study prematurely, either in its entirety or at any site, for reasonable 
cause provided that written notice is submitted in advance of the intended termination. The 
investigator may also terminate the study at his/her site for reasonable cause, after providing 
written notice to NIAAA in advance of the intended termination. Advance notice is not required 
by either party if the study is stopped due to safety concerns. If NIAAA terminates the study for 
safety reasons, NIAAA will immediately notify the investigators by telephone and subsequently 
provide written instructions for study termination. The FDA may stop the study at any time as 
well. If the FDA notifies NIAAA to stop the study, then NIAAA will notify the sites of this 
action. 

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8. 
Study Endpoints 
8.1. 
Efficacy Endpoints 
8.1.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the weekly percentage of heavy drinking days during the 
10- week treatment period. A “heavy drinking day” is 4 or more drinks per drinking day for 
women and 5 or more drinks per drinking day for men.  
8.1.2. 
Secondary Efficacy Endpoints 
Secondary endpoints will be analyzed over the 12 weeks of treatment including:  
1. Percentage of subjects with no heavy drinking days during treatment 
2. Percentage of subjects abstinent from alcohol during treatment 
3. Percentage of subjects with a WHO drinking risk category decrease during treatment of: 
a.  1-level  
b.  2-levels  
4. Endpoints analyzed monthly and with 1- and 2-month grace periods: 
a. Percentage of subjects with no heavy drinking days during the period 
b. Percentage of subjects abstinent from alcohol during the period 
c. Percentage of subjects with WHO drinking risk category decrease during the period 
of: 
− at least 1 level 
− at least 2 levels 
5. Percentage of days abstinent per week 
6. Weekly mean number of drinks per week 
7. Weekly mean drinks per drinking day 
8. MINI AUD Score at end of study  
9. Cigarettes smoked per week among smokers 
10. Abstinence from cigarette smoking 
11. Other nicotine product use per week among other nicotine product users 
12. Experiences in Close Relationships—Relationship Structures Questionnaire (ECR-RS) 
(attachment related anxiety) 
13. PROMIS – alcohol-related negative consequences 
14. PROMIS – sleep disturbances 
15. PROMIS – pain interference 
16. Profile of Moods States (POMS) scores (including subscale scores) 

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17. Urge to Drink Scores 
8.2. 
Exploratory Endpoint 
Hyperkatifeia Scale score at EOS 
8.3. 
Safety Endpoints 
Safety endpoints will be analyzed over the entire treatment and follow-up period. 
1. Vital signs 
2. Physical examination of the nasal mucosa 
3. Smell testing with the UPSIT 
4. Blood chemistries  
5. Urine drug screen results 
6. Blood alcohol concentration (BAC) by breathalyzer  
7. AEs/SAEs 
8. Electrocardiogram (ECG)  
9. Clinical Institute of Withdrawal - Alcohol Revised (CIWA-AR) scores 
10. Frequency of subjects with suicidal ideation at any time during the treatment period -
Columbia-Suicide Severity Rating Scale (C-SSRS) 
11. Change in appetite - Simplified Nutritional Appetite Questionnaire (SNAQ) scores and 
percentage of subjects with scores ≤14. 
12. Buss-Perry Aggression score 
8.4. 
Compliance 
Compliance will be assessed using the Subject Diary and by weighing used study drug vials prior 
to and after use to calculate the amount dispensed. 

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9. 
Safety Monitoring Plan 
Safety monitoring will be conducted throughout the study; therefore safety concerns will be 
identified by continuous review of the data by the PI, clinic staff, clinical monitor, medical 
monitor, and NIAAA.  
Study Safety Management: The IRB, Medical Monitor, PI, clinical monitors, and NIAAA will 
review any safety concerns throughout the trial. In addition, a data and safety monitoring board 
(DSMB) will participate in this study. The roles of these individuals/committee are described 
below. 
Medical Monitor: A Medical Monitor and Alternate Medical Monitor have been appointed by 
NIAAA for the study. The Medical Monitor will be available for making recommendations to 
the investigator and NIAAA on the severity of any SAEs, and the relatedness to the study 
interventions. The Medical Monitor will also be responsible for tracking and assessing trends in 
the AEs reported.  
Clinical Monitors: All investigators will allow representatives of the Data Coordinating Center 
(Fast-Track Drugs and Biologics, LLC) staff to periodically monitor, at mutually convenient 
times during and after the study, all study data. These monitoring visits provide the Data 
Coordinating Center and NIAAA with the opportunity to evaluate the progress of the study and 
to obtain information about potential problems. The monitors will assure that submitted data are 
accurate and in agreement with any paper source documentation used; verify that investigational 
products are properly stored and accounted for, verify that subjects’ consent for study 
participation has been properly obtained and documented, confirm that research subjects entered 
into the study meet inclusion and exclusion criteria, and assure that all essential documentation 
required by Good Clinical Practices (GCP) guidelines are appropriately filed. 
Monitors will conduct a site initiation visit prior to the start of the study. At this visit, they will 
assure that proper study-related documentation exists, assist in training investigators and other 
site personnel in study procedures and GCP guidelines, confirm receipt of study supplies, and 
assure that acceptable facilities are available to conduct the study. 
Routine monitoring visits by the Data Coordinating Center and NIAAA’s representatives will be 
scheduled at appropriate intervals but more frequently at the beginning of the study. A 
monitoring visit soon after the first two subjects have been randomized is planned. At these 
visits, the monitors will verify that study procedures are being conducted according to the 
protocol guidelines, monitor eCRFs against source documents, review AEs and SAEs, and 
perform drug accountability. At the end of the study, they will confirm that the site has the 
appropriate essential documents on file, advise on storage of study records, and inspect the return 
and destruction records for unused investigational products.  
Sponsor Site Visits: All investigators will allow NIAAA full access to study records during 
periodic site visits by NIAAA. Visits by NIAAA will be made at a mutually convenient time and 
will be scheduled in advance. 
DSMB: An independent DSMB of external advisors will meet prior to the start of the study, 
quarterly during enrollment and follow-up and at trial end to review safety data. The Board will 
be blinded to subjects’ actual randomized group assignments but may request at any time that the 

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blind be broken by the data center, if concerns arise from the blinded data. Ad hoc meetings will 
be convened if SAEs occur that are considered at least possibly related to the investigational 
product. 
 

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10. 
Assessment Methods 
All study assessments will be performed at the visits and time points outlined in the Schedule of 
Assessments (Table 3); the following sections outline the details and procedures associated with 
the assessments. All assessments will be recorded on a source document with the exception of 
staff or subject completed questionnaires that will be completed electronically within the EDMS. 
If the EDMS is not accessible, then subject questionnaires can be completed using paper forms 
provided by the Data Management Center and transcribed into eCRFs. 
10.1. 
Alcohol Breathalyzer 
An alcohol breathalyzer will be administered at consent, at screening, and at every in-clinic visit 
as a safety measure. Acceptable BAC level at consent is equal to 0.000 and ≤ 0.020 for all other 
in-clinic visits prior to performing other assessments. 
10.2. 
Adverse Events and Serious Adverse Events 
The investigator and study site staff are responsible for the detection, documentation, 
classification, reporting, and follow-up of events meeting the definition of an AE or SAE.  
10.2.1. 
Adverse Event Definition 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and may not necessarily have a causal relationship with 
the administered treatment. An AE can therefore be any unfavorable and unintended sign 
(including a clinically significant laboratory abnormality), symptom, or disease temporally 
associated with the use of an investigational product, whether or not related to the investigational 
product. Pre-existing conditions, diseases, or disorders are not considered AEs unless there is a 
change in severity or frequency. 
10.2.2. 
Serious Adverse Events and Serious Unexpected Adverse Events Definition 
An SAE is any untoward medical occurrence that meets one of the following: 
• Results in death 
• Is life-threatening (at the time of the event) 
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly/birth defect 
A serious and unexpected AE is an SAE that is not identified in nature, intensity, or frequency in 
the risk information included in the Product Label for the drug. 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the study subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in the definition.  

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10.2.3. 
Methods/Timing for Assessing, Recording, and Analyzing Safety Endpoints 
AEs will be assessed at study visits starting after the first administration of investigational 
product until the final follow-up visit. However, SAEs will be collected from the time of 
informed consent onward. General symptoms will be collected via an open-ended question: 
“How have you been feeling since your last visit or the last time we spoke?”  
AEs will be documented in the source records and recorded on the eCRFs using accepted 
medical terms and/or the diagnoses that accurately characterize the event. When a diagnosis is 
known, the AE term recorded on the eCRF will be the diagnosis rather than a constellation of 
symptoms. The investigator will assess all AEs for seriousness, relationship to investigational 
product, and severity. When an event has not resolved by study closure, it will be documented on 
the AE eCRF as “ongoing”. 
If a woman has a positive pregnancy test after enrollment, the NIAAA Medical Monitor will be 
contacted and the pregnancy will be recorded as an AE. The site will contact the subject at least 
monthly and document the subject’s status until the pregnancy has been terminated or completed. 
The outcome of the pregnancy will be reported to the NIAAA Medical Monitor without delay 
within 24 hours of knowledge of the event if the outcome is a SAE (e.g., death, abortion, 
congenital anomaly, or other disabling or life-threatening complication to the mother or 
newborn).  
All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless 
of severity, will be followed by study physicians until satisfactory resolution (the event either 
resolved or stabilized and is not expected to resolve in the near term). AEs must be reported up 
to 2 weeks following completion of, or termination from investigational product administration. 
At the follow-up telephone contact, AEs will be recorded and followed to resolution only if they 
are serious, or if the study physician assesses them to be clinically significant. 
10.2.4. 
Clinical Laboratory Abnormalities and Other Abnormal Assessments 
Abnormal clinical laboratory findings (e.g., clinical chemistry) will be reported as an AE unless 
the value was outside normal laboratory limits at baseline and did not increase by a severity 
grade level at the follow-up assessment. Grade 2 or greater hypokalemia and Grade 3 or greater 
results for any other laboratory test will be considered clinically significant. Likewise if blood 
pressure was elevated at baseline [pre-hypertension (systolic BP 120 - 139 mmHg or diastolic BP 
80 - 89 mmHg)] and increased to a level indicative of an increase in the severity grade, 
hypertension will be reported as an AE.  
10.2.5. 
Classification of Adverse Event Intensity and Relationship to Investigational 
Product 
The severity of AEs or SAEs will be in accordance with the National Cancer Institute Common 
Terminology Criteria for Adverse Events (CTCAE version 5.0). A physician-investigator must 
make an assessment of severity. For those not listed in the CTCAE, the following criteria will be 
used: 

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Mild: 
An event that is usually transient, requiring no special treatment, and does 
not generally interfere with the subject’s daily activities. 
Moderate: 
An event that interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the 
subject. The event is usually ameliorated with additional specific 
therapeutic intervention.  
Severe: 
 
An event that interrupts usual activities of daily living or significantly 
affects clinical status. The event poses a significant risk of harm to the 
subject and hospitalization may be required, and typically requires 
intensive therapeutic intervention. 
The investigator must make an assessment of relationship to the investigational product based on 
the following criteria: 
Unrelated: 
The subject did not receive the investigational product, the temporal sequence 
of the AE/SAE onset relative to administration of the investigational product 
is not reasonable, or there is another obvious cause of the AE/SAE. 
Unlikely: 
There is evidence of exposure to the investigational product but there is 
another more likely cause of the AE/SAE. 
Possible: 
There is evidence of exposure to the investigational product, the temporal 
sequence of the AE/SAE onset relative to administration of the investigational 
product is reasonable, but the AE/SAE could have been due to another equally 
likely cause. 
Probable: 
There is evidence of exposure to the investigational product, the temporal 
sequence of the AE/SAE onset relative to administration of the investigational 
product is reasonable, and the AE/SAE is more likely explained by the 
investigational product than by any other cause. 
Definite 
There is evidence of exposure to the investigational product, the temporal 
sequence of the AE/SAE onset relative to administration of the investigational 
product is reasonable, the AE/SAE is more likely explained by the 
investigational product than by any other cause, and the AE/SAE shows a 
pattern consistent with previous knowledge of the investigational product or 
investigational product class. 
10.2.6. 
Outcomes and Actions Taken 
All unresolved AEs will be followed for a minimum of 7 days (unless the AE is an ongoing 
pregnancy which must be followed to conclusion) after the subject’s final study visit, unless the 
investigator’s judgment dictates otherwise, the event has resolved or stabilized prior to the 7-day 
period, or the subject is lost to follow-up.  
Investigators are not obligated to actively seek AEs or SAEs in former study subjects that occur 
following the follow-up period.  
For each recorded AE or SAE, the investigator must make an assessment of outcome at the time 
of last observation, as follows: 

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Fatal: 
The subject died. 
Resolved without Sequelae: 
The AE or SAE has ended. 
Resolved with Sequelae: 
The AE or SAE has ended but changes are noted from 
baseline. 
Unresolved – Ongoing: 
The AE has not ended and is ongoing at the end of the 
reporting period (i.e., 7 days after the final Follow-up visit) and 
the investigator deems that further follow up is not medically 
required 
Unknown – Lost to Follow-up: 
Lost to follow-up after repeated unsuccessful attempts to 
contact the subject. 
Actions taken with respect to investigational agents (discontinuation or not) will also be 
recorded. In addition, if the AE was treated (medications or other physical measures), this will 
also be recorded. 
10.2.7. 
Reporting Serious Adverse Events 
10.2.7.1. 24 hour Reporting Requirements (Initial Report) 
Any SAE, including death due to any cause, which occurs to any subject from the time of 
signing consent through the final follow-up visit whether or not related to the investigational 
product, must be reported within 24 hours of knowledge of the event by completing the AE/SAE 
eCRF. This will trigger an automatic notification of the SAE via an email communication to 
NIAAA and Fast-Track. Fast-Track will notify the Medical Monitors upon receipt of the 
notification and coordinate communications with the Medical Monitors.  
10.2.7.2. 3-Day Supporting Documentation Requirements (Follow-up Report) 
Written documentation for all SAEs must be received by the NIAAA Medical Monitor/Alternate 
within 3 days of reporting the event. Required eCRF that must be completed include the 
following: 
• AE/SAE eCRF (revised if additional information is available) 
• Concomitant Medication eCRF 
In addition, paper copies of the following may be requested 
• Copies of source documents pertinent to the event (laboratory reports, ECG tracings, 
medical chart notes, etc.). These should be identified only by Subject number and not 
include any subject identification information prohibited by Health Insurance 
Portability Accountability Act (HIPAA). 
• Any other relevant information necessary to support the investigator’s judgment 
regarding the SAE’s relatedness severity to the investigational product OR by request 
of the Medical Monitor/Alternate. 
These paper documents may be submitted by facsimile, as email attachments, or by attaching 
them to the subject’s eCRF casebook. 

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10.2.7.3. Reporting to Advarra IRB 
Reporting requirements for Advarra IRB include: 
Immediately Reportable: 
• Findings detected in the monitoring process when those findings could affect the 
safety of participants or their willingness to continue participation, influence the 
conduct of the study, or alter Advarra’s approval to continue the study. 
• Changes in research that were initiated without IRB review and approval to eliminate 
apparent immediate hazards to the human subjects to ensure the continued safety and 
welfare of subjects.  
• Modifications to previously approved documents. 
• Safety information that may help to provide additional protections for subject’s safety 
and well-being, throughout the course of the study and after study completion. 
• Communication of results from a research study to subjects when those results 
directly affect their safety or medical care. 
• DSMB Reports  
Report within 10 calendar days of discovery: 
• Revisions to the Investigator's Brochure, as applicable.  
• Revisions to the report of prior investigations, as applicable.  
• Non-compliance – Failure by an investigator and/or sponsor to follow Advarra’s 
requirements, applicable regulations or to protect human research subjects, including 
but not limited to the principles of the Belmont Report ‘Serious non-compliance 
issues – non-compliance as defined as above and as determined to be serious in a way 
that adversely affects the rights and welfare of human subjects following the 
investigation and review by the IRB Continuing non-compliance issues – A pattern of 
repeated non-compliance or serious non-compliance as determined by the IRB. 
• Significant deviations – Significant deviations are those that deviate from the 
approved protocol, informed consent process and affect or potentially affect the safety 
of subjects. Advarra does not consider protocol deviations to be different from 
protocol violations. 
• Unanticipated adverse device effects.  
• Unanticipated problems should be reported regardless of whether they occur during 
the study, after the study completion, or after participant withdrawal or completion. 
Any unanticipated problems involving risks to human subjects or others that are (1) 
unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the IRB-
approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied; (2) related or possibly related 
to participation in the research (possibly related means there is a reasonable 
possibility that the incident, experience, or outcome may have been caused by the 

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procedures in the research); and (3) suggests that the research places subjects or 
others at a greater risk of harm (including physical, psychological, economic, or 
social harm) than was previously known or recognized. Examples of problems or 
events that may meet the definition of unanticipated problems involving risk to 
subjects or others may include, but are not limited to the following:  
− Imminent threat of a reportable event that has not yet occurred  
− Information indicating a change to the risk/benefit ratio of the research  
− Death 
− Breach of confidentiality, including lost or stolen study documents/data  
10.3. 
Barrett Impulsiveness Scale 
The Barratt Impulsiveness Scale (BIS-11; Patton-1995) is a questionnaire designed to assess the 
personality/behavioral construct of impulsiveness. It is a 30-item scale with items scored on a 
4-point scale (1=rarely/never; 2= occasionally; 3=often; 4=almost always/always). Items 1, 7, 8, 
9, 10, 12, 13, 15, 20, 29, and 30 are reverse scored. The total score is the sum of the individual 
items. This questionnaire will be completed by the subject electronically and will be both the 
source and eCRF. 
10.4. 
Buss Perry Aggression Questionnaire – Short Form (BPAQ-SF) 
The BPAQ-SF is a 12-item self-report measure that includes four subscales: physical aggression 
(4 items), verbal aggression (3 items), anger (2 items), and hostility (3 items) validated by 
Diamond and Magaletta (2006) that was developed from the 29-item scale developed by Buss 
and Perry (1992). There is no time frame specified, and items are rated using a five-point scale 
from 1 “very unlike me” to 5 “very like me” with the score as the sum of the scores obtained by 
a respondent for the individual factors. This questionnaire will be completed by the subject 
electronically and will be both the source and eCRF. 
10.5. 
Cigarette Smoking Quantity-Frequency and Other Nicotine Use  
A smoking quantity frequency and nicotine use interview will include 3 questions to assess 
nicotine use via cigarette smoking or via other products during the study: 1) Over the past week, 
on how many days did you smoke cigarettes?; 2) On the days you smoked during the past week, 
how many cigarettes did you smoke on average?; and 3) Over the past week, on how many days 
did you use other nicotine products (ex. chew, cigars, cigarellos, e-cigarettes, vape, gum, patch, 
etc...)? This questionnaire will be completed by the subject electronically and will be both the 
source and eCRF. 
10.6. 
Clinical Institute Withdrawal Assessment for Alcohol-revised (CIWA-AR) 
The CIWA-AR modified telephone version is an adaptation for telephone administration of the 
CIWA-AR a brief 10-item measure used to provide a quantitative index of the severity of the 
alcohol withdrawal syndrome (Sullivan-1989). The CIWA-AR has been used both in clinical and 
research applications and has demonstrated both reliability and validity (Sellers-1992, 
Stuppaeck-1994). This questionnaire will be administered by a clinical staff member and subject 
responses will be recorded electronically and will be both the source and eCRF. 

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10.7. 
Clinical Chemistry 
Clinical laboratory tests will be performed at the clinical site’s local clinical laboratory. 
Laboratories performing these assessments should be directly regulated by the College of 
American Pathologists (CAP) or Clinical Laboratory Improvement Act (CLIA) guidelines. The 
laboratory will need to provide a copy of current certification. Additional laboratory samples 
may be taken at the discretion of the investigator if the results of any tests fall outside reference 
ranges or clinical symptoms necessitate testing to ensure safety. Clinical chemistry tests are 
listed below. 
• Creatinine 
• Total bilirubin 
• Alanine aminotransferase (ALT) 
• Aspartate aminotransferase (AST) 
• Sodium 
• Potassium 
Serum creatinine levels will be used to calculate creatinine clearance (CrCl) according to the 
Cockroft-Gault (1976) formula as follows:  
Males 
CrCl (mL/min) = 
(140 – age in years) x body weight in kg 
72 x serum creatinine mg/dL 
 
Females 
CrCl (mL/min) = 
0.85 x (140 – age in years) x body weight in kg 
72 x serum creatinine mg/dL 
For any laboratory test value outside the reference range that the investigator considers clinically 
significant: 
• The investigator will repeat the test to verify the out-of-range value 
• The investigator will follow the out-of-range value to a satisfactory clinical resolution 
• A laboratory test value will be reported as an AE with the severity score assigned in 
accordance with the CTCAE version 5.0 
10.8. 
Columbia Suicide Severity Rating Scale (C-SSRS) 
The C-SSRS is a 4-page form asking questions about suicidal ideation, intensity of ideation, and 
suicidal behavior developed by Posner and collaborators at the New York State Psychiatric 
Institute (Oquendo-2003). This scale is intended for use by trained administrators. The questions 
contained in the C-SSRS are suggested probes. Ultimately, the determination of the presence of 
suicidality depends on clinical judgment. Training is required before administering the C-SSRS 
through a 30-minute interactive slide presentation followed by a question-answer session through 
the Columbia University Medical Center. Those completing the training are certified to 
administer the C-SSRS, and will receive a training certificate. As the MINI will be used to 
establish subject initial eligibility with respect to suicidality, the “Since Last Visit” version of the 
C-SSRS will be used at each clinic visit starting at Week 1. At Week 1, this scale will be used to 
assess current suicidal ideation since the MINI interview. This questionnaire will be 

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administered by a clinical staff member and subject responses will be recorded electronically and 
will be both the source and eCRF. 
10.9. 
Demographics 
Demographics data include the subject’s age, gender, race/ethnicity, marital status, education, 
employment pattern, occupation, and income level. These data will be collected by site staff on a 
source document and entered into an eCRF. 
10.10. 
Device Issues/Failures 
The subject will be asked to report any issues using the nasal spray and record the issue on their 
Drug Diary. If a nasal spray pump failure occurs (e.g., no spray is coming out), then the subject 
will be asked to call the number on the wallet card to make arrangements to obtain a replacement 
nasal spray vial. The site will notify Fast-Track of any device problems within 24-hours after 
learning of the problem. A eCRF will be provided for reporting problems. 
10.11. 
Drinking Goal  
A subject’s drinking goal will be assessed to determine the desire and motivation to completely 
abstain from drinking alcohol or reduce drinking without abstinence. 
The Drinking Goal Questionnaire includes 4-items that will be administered by a member of the 
study staff. The questions include: 
1. What goal have you chosen for yourself about drinking by the end of the study? 
a. To stop drinking 
b. Reduce drinking but not stop 
2. Subjects who respond to question 1 with “Reduce drinking but not stop” will be asked to 
estimate, having achieved their drinking goal, the number of drinks they might consume 
on each day of a typical week. 
All subjects will be asked questions capturing: 
3. The level of motivation to reach this goal. Responses are a 1 to 10 scale with 1=not 
motivated and 10 = extremely motivated. 
4. The level of confidence to reach this goal. Responses are a 1 to 10 scale with 1=not 
confident and 10 = extremely confident. 
10.12. 
Brief Drinking Questionnaire 
If a subject is withdrawn from the study early and is no longer participating in clinic visits or 
providing TLFB drinking data but is willing to be contacted by phone at the week most proximal 
to dropout, then they will be administered the Brief Drinking Questionnaire. The questions are 
taken from the list recommended by the NIAAA Task Force on Recommended Alcohol 
Questions (Oct 15-16, 2003) and ascertain: if there was any drinking during the target period; if 
so, how many a day on average; the largest number of drinks consumed on any one day; and, the 
number of times reaching the heavy drinking limit (4 or more for women and 5 or more for 
men). This data will be recorded on a source document and eCRF. This does not apply to 
subjects who are willing to supply daily drinking data by the TLFB method. 

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10.13. 
ECG 
A 12-lead resting ECG will be obtained. Any abnormalities will be noted and an assessment of 
clinical significance will be done by a study physician.  
10.14. 
Exit Interview 
At the final in-clinic visit (or by phone if the subject withdraws early), the subject will complete 
a questionnaire for his/her impression of whether he/she was receiving active drug or placebo, if 
they felt that the medication helped drinking, how they would describe their experience taking 
the medication, if they would recommend it to a friend, if they would take it again if they needed 
further treatment in the future, and a question about desire to please people. This questionnaire 
will be completed by the subject electronically and will be both the source and eCRF. 
10.15. 
Experiences in Close Relationships—Relationship Structures Questionnaire 
(ECR-RS)  
The Experiences in Close Relationships-Relationship Structures scale (ECR-RS; Fraleyl-2011) 
is a questionnaire assessing two-dimensional relationship-specific attachment structures in adults 
beyond the traditional focus on romantic relationships. This is a 36-item questionnaire of which 
the first 18-item attachment-related anxiety scale will be assessed and evaluated. The 
presentation of the items will be randomized on the form for subject completion. Each item is 
rated on a 7-point scale where 1 = strongly disagree and 7 = strongly agree. The attachment-
related anxiety is determined by averaging the scores of these 18 items. The ECR-RS 
questionnaire is completed by the subject electronically and will be both the source and eCRF 
10.16. 
Family History of Alcohol Problems 
Information on family history of alcohol problems will also be collected using the Family 
History of Alcohol Problems. The questionnaire provides subjects with a consistent set of cues 
for identifying blood relatives with alcohol problems by using a family tree listing for relatives 
(Mann-1985). This questionnaire will be restricted to subject’s parents’ alcohol history. The 
questionnaire will be completed by the subject electronically and will be both the source and 
eCRF. 
10.17. 
Hyperkatifeia Questionnaire 
Hyperkatifeia is referred to as an exacerbated negative emotional state during drug and alcohol 
withdrawal characterized as emotional distress and pain. Hyperkatifeia falls within the negative 
affect stage of the addiction cycle where individuals experiencing hyperkatifeia are vulnerable to 
relapse to alcohol or drug use motivated by alleviation of such negative affective symptoms 
(Koob-1997; Koob-2019). Negative reinforcement becomes the source of motivation to a person 
to prevent hyperkatifeia of alcohol and drug withdrawal (Koob-2021). Koob (2021) postulates: 
“Although all drugs of abuse have positive reinforcing properties, the termination of drug taking 
inevitably leads to negative emotional states of acute and protracted withdrawal in the 
withdrawal/negative affect stage, which generates a second motivational drive from negative 
reinforcement. Negative reinforcement can be defined as an increase in the probability of a 
response that is produced by the removal of an aversive event. Here, negative reinforcement 
becomes the source of motivation for drug seeking as the individual works to reduce, terminate, 
or prevent the negative emotional state or hyperkatifeia of drug withdrawal.”  

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Negative emotionality has been shown to be particularly important in predicting alcohol 
treatment outcomes (Votaw-2020). Individuals with comorbid diagnoses of depression or anxiety 
tend to have higher AUD severity entering treatment and greater drinking and functional 
impairment following treatment (Burns-2005). Furthermore, changes in negative affect have 
been shown to play a mediating role in alcohol treatment outcomes (Wilcox-2018). 
NIAAA has developed a 24-item self-report Hyperkatifeia Scale to capture negative emotionality 
after stopping alcohol drinking that will be assessed for the first time in this study of heavy 
drinkers with a diagnosis of moderate to severe AUD. The items address four measures 
associated with negative emotional state including stress/anxiety, depression, stress, irritable and 
pain and is provided in Appendix C. It takes less than two minutes to complete. 
One major distinction between the Hyperkatifeia Scale and other negative emotional state scales 
is the Hyperkatifeia Scale directly links negative emotional state to the absence of alcohol.  
Another key difference between this scale and other negative emotional state scales is questions 
directly related to pain. Pain may be particularly important in AUD and hyperkatifeia as there is 
a positive association between pain severity and a higher risk for AUD (Lawton- 2009; Edlund-
2013). Also, physical pain appears to be a significant predictor of alcohol use and heavy alcohol 
use and relapse to drinking after a period of abstinence (Larson-2007; Caldeiro-2008; 
Witkiewitz-2015). 
This questionnaire will be completed by the subject electronically and will be both the source 
and eCRF. 
10.18. 
Inventory of Drinking Situations (IDS-30) 
The IDS-30 is a 30-item patient completed questionnaire of reward and relief drinking that asks 
subjects to rate the frequency (0= never, 3 = almost always) of heavy drinking in various 
situations over the past year. Fifteen items measure reward drinking tendencies and 15 items 
measure relief drinking tendencies (Mann-2017). This questionnaire will be completed by the 
subject electronically and will be both the source and eCRF.  
10.19. 
Locator Form 
After signing informed consent, subjects will be asked to provide names, addresses, and phone 
numbers of several friends and/or family members who can be contacted if the subject cannot be 
located (Locator Form). This locator form will be used to assist in contacting subjects between 
visits and at follow-up. This form asks subjects his/her name, address, and phone number and to 
provide names, addresses, and phone numbers of several friends and family members who can be 
contacted if the subject cannot be located. This information is essential and will be collected 
during screening and will be updated throughout the study as necessary. This information will 
remain exclusively at the site.  
10.20. 
Medical/Surgical History 
A medical history will be taken for all potential study subjects to assure medical fitness during 
screening. Current and past year chronic rhinitis will be specifically queried as this is 
exclusionary. Chronic rhinitis is defined as symptoms of rhinitis lasting longer than 6 weeks. 
Signs and symptoms of rhinitis may include stuffy or runny nose, sneezing, phlegm in the throat 
(postnasal drip) and cough. The age at which the subject started drinking alcohol regularly at 

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least 3 times per month (age of onset) will also be collected as part of the medical history. Dates 
of prior surgeries will be recorded. 
The medical/surgical history will be updated on the day planned for randomization by asking the 
subject if anything has changed since the initial screening interview.  
10.21. 
MINI 
The MINI (paper version 7.0.2) is a short structured diagnostic interview, developed jointly by 
psychiatrists and clinicians in the United States and Europe, for DSM-5 and ICD-10 psychiatric 
disorders (Sheehan-1998). With an administration time of approximately 15 minutes, it was 
designed to meet the need for a short but accurate structured psychiatric interview for multicenter 
clinical trials and epidemiology studies and to be used as a first step in outcome tracking in non-
research clinical settings. Diagnoses recorded on the MINI will be recorded on the interview 
form and entered into an eCRF. The individual items of the Alcohol Use Disorders Module will 
be also collected on an eCRF in addition to all other diagnoses. At the last study visit, the 
Alcohol Use Disorders Module will be assessed again, but the initial drinking question will not 
be asked and the time period for which the questions apply has been revised to “the past month” 
instead of the past 12 months. 
10.22. 
Other Services Used for Alcohol Use Problems 
Prior (lifetime) treatment for alcohol problems and drinking will be collected at baseline. The 
answers to the following questions will be collected: 
1. Number of lifetime inpatient hospitalizations (i.e. at least one overnight stay) to get help 
with reducing or quitting drinking. 
2. Number of lifetime inpatient hospitalizations (i.e. at least one overnight stay) for 
illnesses, injuries, or accidents due to drinking. 
3. Number of times in lifetime underwent alcohol detoxification using medication.  
4. Number of lifetime outpatient visits (i.e. no overnight stay) with a health professional to 
get help with reducing or quitting drinking. 
5. In the past year, how many alcoholics anonymous (AA), 12 Step, Save Ourselves, or 
similar group meetings attended for alcohol problems or drinking. 
At the end of the study, the subject will be interviewed about attendance at group meetings [AA, 
12-step programs, secular organizations for sobriety (SOS), or similar group meetings] and visits 
with health professionals for assistance in reducing or stopping drinking during the 12-week 
treatment period. Use of additional counseling or professional therapy for non-crisis psychiatric 
matters or any additional pharmacologic or non-pharmacologic treatments received will be 
documented. This questionnaire will be administered by a clinical staff member and subject’s 
responses will be recorded electronically and will be both the source and eCRF. 

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10.23. 
Profile of Mood State (POMS) 
The POMS measures dimensions of affect or mood (McNair and Heuchert-2005). It consists of 
65 adjectives to which the subject responds according to a 5-point scale ranging from “not at all” 
to “extremely.” Six subscale scores will be computed for items grouped as follows: Tension-
Anxiety, Depression-Dejection, Anger-Hostility, Vigor-Activity, Fatigue-Inertia, and 
Confusion-Bewilderment. A total mood disturbance score will also be computed which consists 
of the sum of the 5 of the six subscale scores (the Vigor-Activity score is not included). This 
questionnaire will be completed by the subject electronically and will be both the source and 
eCRF. 
10.24. 
Pregnancy Test and Birth Control Record 
An FDA approved rapid result urine pregnancy test will be used (i.e., dipstick test). If applicable, 
subjects will be asked to sign a release of information form for study personnel to access medical 
records to obtain information regarding the outcome of a pregnancy that occurred during the 
study. 
The Birth Control Assessment is designed to determine a female subject’s compliance with the 
birth control specifications detailed in the inclusion criteria.  
10.25. 
Prior and Concomitant Medications 
All medications taken by the subject 2-months prior to the start of screening, during the 
screening period, and through the final follow-up contact will be recorded on a source document 
and eCRF.  
10.26. 
PROMIS Questionnaires 
PROMIS® (Patient-Reported Outcomes Measurement Information System) is a set of person-
centered measures that evaluates and monitors physical, mental, and social health in adults and 
children that were developed through the support of U. S. Department of Health and Human 
Services. See http://www.healthmeasures.net/explore-measurement-systems/promis for a 
description of the development of these assessments. Three of these assessments, described 
below, will be utilized in this study. 
10.26.1. 
Patient-Reported Outcomes Measurement Information System (PROMIS) – 
Alcohol Use Negative Consequences – Long Form 
For negative consequences for alcohol use, the long form of the PROMIS Alcohol Negative 
Consequences questionnaire will be used to assess outcomes of alcohol use over the past 30 
days. This 31-item questionnaire assesses drinking patterns (e.g., quantity and frequency of 
consumption, time spent drinking, episodes of heavy drinking), cue-based drinking (internal 
states and external contexts), cravings to drink (e.g., urgency, compulsivity), and efforts to 
control drinking (e.g., difficulty in limiting drinking) that indicate problematic drinking, 
particularly at the high end of the severity continuum. The PROMIS Alcohol Negative 
Consequences questionnaire is completed by the subject electronically and will be both the 
source and eCRF. 

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10.26.2. 
PROMIS – Sleep Disturbances – Short From 8b 
For assessment of subject’s sleep quality, the PROMIS Sleep Disturbance Short Form 8b will be 
used. The questionnaire consists of 8 questions regarding the quality of sleep over the past 7 
days. Each item on the measure is rated on a 5-point scale with a range of scores from 8 to 40 
with higher scores indicating greater severity of sleep disturbance. The American Psychiatric 
Association has established levels of severity (none to slight, mild, moderate or severe based on 
the T-score derived from a conversion table). The PROMIS Sleep Disturbance questionnaire 
completed by the subject electronically and will be both the source and eCRF. 
10.26.3. 
PROMIS – Pain Interference – Short Form 8a 
For the assessment of pain interference, the shortened 8a version of the PROMIS for pain 
interference will be used to measure the self-reported consequences of pain over the past 7 days. 
This 8-item questionnaire assesses how pain hinders daily activities. Each item on the measure is 
rated on a 5-point scale with a range of scores from 8 to 40. The PROMIS pain interference 
questionnaire completed by the subject electronically and will be both the source and eCRF. 
10.27. 
Physical Examination 
A physical examination of the oral cavity, head, eyes, ears, nose, and throat, cardiovascular 
system, lungs, abdomen, extremities, skin, neuropsychiatric mental status and sensory/motor 
status, musculoskeletal system and general appearance will be performed during screening. The 
nasal exam should specifically assess any nasal lesions that could be affected by repeated 
intranasal administrations, as this may be exclusionary. The physical exam will be updated on 
the day planned for randomization by querying the subject about any physical changes since the 
screening examination. An examination of the nasal mucosa will be performed again at Week 1 
and at all clinic visits after the initiation of investigational products to assess local application 
site reactions. In addition, a limited nasal and oral mucosal inspection and any symptom directed 
physical examination will be performed, as applicable, at other visits if the subject reports any 
problems. Weight (pounds) will be collected per the schedule in Table 3. Abnormal findings will 
be reported as AEs, if appropriate. 
10.28. 
Screen Failures Documentation 
To document the reason that a subject who consented to the study was not randomized, the 
Reasons the Subject Was Not Eligible eCRF will be completed for these subjects.  
10.29. 
Spielberger Trait Anxiety Inventory (STAI) 
The Spielberger State-Trait Anxiety Inventory (STAI) has been used extensively in research and 
clinical practice (Spielberger-1983). The fundamental qualities evaluated by the STAI are 
feelings of apprehension, tension, nervousness, and worry. The assessment includes separate 
self-report scales for measuring state and trait anxiety. Only the trait anxiety scale will be 
collected in this study. The T-Anxiety scale (STAI Form Y-2) named on the form as “Self 
Evaluation Spielberger Trait Scale” consists of 20 statements that assess how people generally 
feel. This is a subject completed questionnaire that takes approximately 6 to 10 minutes to 
complete. This questionnaire will be completed by the subject electronically and will be both the 
source and eCRF. 

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10.30. 
Simplified Nutritional Appetite Questionnaire (SNAQ) 
Oxytocin reduces appetite, body weight, reward and hunger driven eating. The 8-item Council on 
Nutrition appetite questionnaire scale and its 4-item derivative The Simplified Nutritional 
Appetite Questionnaire (SNAQ) were developed to assess appetite and predict weight loss. The 
changes in appetite during the study will be evaluated using the clinically simpler version of the 
two scales, the SNAQ (Wilson-2005). The 4 item SNAQ asks: 1) My appetite is; 2) When I eat; 
3: Food tastes; and 4) Normally I eat; with 5 possible responses that are scored numerically from 
1 to 5. The sum of the responses is the total scale score. A SNAQ score ≤14 indicates significant 
risk of at least 5% weight loss within six months. This questionnaire will be completed by the 
subject electronically and will be both the source and eCRF. 
10.31. 
Subject Disposition 
A subject disposition eCRF will be completed for all subjects who are randomized to the study 
and who are dispensed investigational product. This eCRF will be used to record the following 
data as applicable: 1) completion status of the subject at the end of their participation and if they 
were discontinued early, and reason for early discontinuation. 
Completion status is as follows: 
1. Subject completed full study (i.e., telephone contact was made at the Week 14/15 follow-
up). 
2. Subject completed the full intervention phase of the study (i.e., subject came to Week 13 
clinic visit – during Week 13). 
3. Subject was withdrawn prior to the Week 13 visit, but completed the end of study 
assessments scheduled at Week 13 (reasons for early withdrawal are to be specified). 
4. Subject was withdrawn prior to the Week 13 visit and did not complete the end of study 
assessments (reasons for early withdrawal are to be specified). 
5. Subject discontinued investigational products and the reason(s). 
Even if the subject had investigational product suspended for any reason but attended clinic 
visits, the above definitions still apply. 
In addition, if the subject was confined and/or incarcerated at any time during the study, the dates 
of confinement and/or incarceration will be collected. 
10.32. 
TLFB Interview 
Drinking behavior will be assessed using the TLFB methodology (Sobell & Sobell-1992). The 
TLFB is a semi-structured interview that provides estimates of the daily quantity of alcohol 
consumption during specified time periods. It uses a calendar prompt and a number of other 
memory aids (e.g., holidays, payday, and other personally relevant dates) to facilitate accurate 
recall of drinking or other drug use during the target period. The procedure has been widely used 
in clinical and research contexts. It has demonstrated adequate levels of reliability and validity 
when administered as an in-person interview, over the telephone, and when administered via 
computer (Carey-1997, Sobell-1988, Sobell-1996). After consent is signed, the TLFB interview 
will be performed for the 28-day period prior to signing consent. Thereafter, the interview will 

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be for the previous days between the last assessment and the day prior to the day of the 
assessment. It is estimated that a 28-day TLFB assessment will take 20 minutes to complete. In 
the event of missed visits, collection of missed drinking data at the following visit is required. 
If a subject requests to withdraw from the study but agrees to continued telephone contact to 
assess drinking, the TLFB will be performed over the phone for the duration of the study at a 
frequency acceptable to the study subject and site staff.  
An Excel spreadsheet customized for use in this study will be used for double data entry by 
clinical site staff to collect the TLFB drinking data. This spreadsheet contains a calculator to 
determine standard drink units (SDUs). This spreadsheet will be reviewed, compared with source 
documents and collected by study monitors for upload into the main study database. 
Drinking days are defined as the number of days in which the subject reported any alcohol 
consumption (i.e., > 0 standard drinking units [SDUs]). A standard drink contains approximately 
0.6 fluid ounces (oz) of pure alcohol. The data given by the subjects on amount and type of 
alcoholic beverage(s) consumed will be converted to SDUs. Standard drink unit definitions are 
provided in Table 5. 
 
Table 5: Standard Drink Unit Definitions 
For beer (~ 5% alcohol), the approximate number of SDUs in: 
• 12 oz = 1.0  
• 16 oz = 1.3 
• 24 oz = 2.0 
• 40 oz = 3.3 
For malt liquor (~ 7% alcohol), the approximate number of SDUs in: 
• 12 oz = 1.4 
• 16 oz = 1.9 
• 22 oz = 2.6 
• 40 oz = 4.7 
For table wine (~ 12% alcohol), the approximate number of SDUs in: 
• 750 mL bottle = 25oz = 5.0 
• 5 oz glass = 1.0 
• 10 oz glass = 2.0 
For 80 proof spirits (~ 40% alcohol), or hard liquor, the approximate number of 
SDUs in: 
• 1.5 oz (mixed drink) = 1.0 
• 12.7 oz (pint) = 8.5 
• 25 oz ( a fifth) = 17.0 
• 1.75 L (59 oz) = 39.0 
10.33. 
World Health Organization Drinking Risk Categorical Scale 
The WHO has developed a drinking risk categorical scale that can be used in a responder 
analysis approach to assess clinically relevant decreases in alcohol consumption (Aubin-2015). 
Two dichotomous endpoints will be analyzed: WHO 1-level and WHO 2-level decrease in 
alcohol consumption. The WHO 1- and 2-level decrease endpoints are the percentage of subjects 

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experiencing at least a 1- and 2-level decrease in WHO levels of alcohol consumption, 
respectively, from the level at baseline (the period including the 28 days before screening) to the 
level during the treatment phase (e.g., Study Weeks 9-12).  
The WHO levels of average alcohol consumption per day are as follows: 
             
 
 
Males              Females 
Low Risk        
1 to 40g            1 to 20g 
Medium Risk    
41 to 60g          21 to 40g 
High Risk       
61 to 100g        41 to 60g 
Very High Risk  101+g               61+g 
where 14g = 1 SDU (WHO-2000). In computing the WHO alcohol consumption level, average 
drinks per day will be used, computed as the sum of all drinks in the 28 day period divided by 
the number of days with non-missing drinking data in that period. Abstinent subjects will be 
included in a separate “Abstinent” category.  
10.34. 
University of Pennsylvania Smell Identification Test 
The UPSIT will be assessed at screening and at clinic visits shown in Table 3 to determine if 
intranasal investigational products cause any changes in sensory discrimination. It consists of 4 
booklets each containing 10 microencapsulated (scratch and sniff) odors. The UPSIT test has 
been studied in individuals with alcohol addiction and has shown that this population generally 
had generally lower UPSIT scores that non-drinking controls. Ditralgilia (1991) reported that: 
“Thirty-two percent of the alcoholics' UPSIT scores, in comparison to five percent of the 
controls' scores, fell into the clinically impaired range. Although current smoking patterns 
correlated significantly with UPSIT indices, comparisons limited to nonsmokers still indicated 
that the alcoholics were significantly impaired on this olfactory task”. Anosmia (loss of sense of 
smell) and microsmia (reduced ability to smell) will be reported as AEs when the following 
scores are reported: anosmia: score of 6 - 18, severe microsmia: score between 19 and 25, 
moderate microsmia: 26 - 30 in women and 26 - 29 in men, mild microsmia: 31 - 34 in women 
and 30 - 33 in men Normosmia (not an AE) is a score of more than 34 in women and 33 in men. 
If a subject presents with clinically impaired values at baseline, numeric decreases in the score 
will be reported as an AE when the score decreases to a more severe level of microsmia or 
anosmia.  
10.35. 
Urge-to-Drink Questionnaire 
The Urge to Drink Scale is a modified version of an assessment that was developed and validated 
by researchers at the University of Pennsylvania’s Center for Studies of Addiction 
(Flannery-1999). This measure has been shown to be a valid and reliable instrument for 
assessing an individual’s urge to drink alcohol. Total scores of 10 or higher during treatment 
have been reported to be associated with increased risk for relapse (Flannery-1999); 
Flannery-2003). This scale has 5 items with 7 different responses to each item scored as 0 to 7. 
The questions pertain to the past week. The total score is the sum of the point scores for the 
individual items. 

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10.36. 
Urine Drug Screen 
An FDA cleared, CLIA waived urine drug test card will be used to assess candidates for recent 
use of opiates (i.e., morphine test), cocaine, amphetamines, methamphetamine, THC, 
buprenorphine, methadone, benzodiazepines, oxycodone, barbiturates, 3,4-methylenedioxy-
methamphetamine (MDMA – also known as ecstasy). During screening subjects must be 
negative for all substances except THC and in special cases opioids. If positive for opioids but 
recent opioid use for acute pain is reported by the subject, then the subject can be re-screened. If 
positive for these drugs at other times during the study, the subject will not be removed from the 
study but should be asked about medication use and possibly have re-evaluation of their medical 
history for substance abuse. 
10.37. 
Vital Signs  
Vital signs to be assessed include sitting blood pressure and pulse rate (after sitting for at least 3 
minutes).  

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11. 
Statistical Methods and Determination of Sample Size 
11.1. 
Statistical and Analytical Plans 
Complete details of the statistical analyses to be performed will be documented in a SAP, which 
will be completed prior to locking and unblinding the study data. This document will include 
more detail of planned statistical analyses and additional exploratory analyses. Any changes to 
the final SAP will be outlined in the final study report. 
11.2. 
Statistical Hypotheses 
Primary Efficacy Endpoint: It is hypothesized that oxytocin, as compared to placebo will 
reduce the weekly percentage of heavy drinking days over the 10-week maintenance treatment 
period. This hypothesis will be tested using other time periods during treatment. 
Secondary Efficacy Drinking and Smoking Endpoints: 
Over the 10-week maintenance treatment period, it is hypothesized that the oxytocin group, as 
compared to the placebo group, will: 
1. Increase the percentage of subjects with no heavy drinking days 
2. Increase the percentage of subjects abstinent from alcohol  
3. Increase the percentage of subjects with a WHO drinking risk category decrease of at 
least: 
a.  1-level 
b.  2-levels  
4. Increase the percentage of days abstinent per week 
5. Decease the weekly mean number of drinks per week  
6. Decrease the weekly mean drinks per drinking day 
7. Decrease the cigarettes smoked per week among smokers 
8. Increase the smoking abstinence rate among smokers 
9. Decrease the weekly number of days of nicotine use among nicotine users 
10. Decrease in attachment related anxiety scores of the ECR-RS  
11. Decrease in PROMIS sleep disturbance, alcohol negative consequences, and pain 
interference scores 
12. Decrease in POMS subscale tension-anxiety and depression scores 
13. Decrease in the Urge to Drink scale scores 
11.3. 
Analysis Populations 
The study analysis populations will consist of the following: 

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Full Analysis Set: The full set is defined as subjects randomized to participate in the study who 
took at least one dose of investigational product. The full analysis set will be used to evaluate all 
efficacy and safety endpoints. 
11.4. 
Description of Statistical Methods 
11.4.1. 
General Approach 
For descriptive purposes, dichotomous and categorical variables will be presented as number of 
observations and percentages; continuous variables will be given as means, standard deviations 
(SD), median, minimum (min) and maximum (max). Statistical tests will be two-tailed at a 0.05 
Type I error rate. P-values for the primary and secondary endpoints of < 0.05 will be considered 
statistically significant. The SAP will define the covariate selection process. Endpoint data will 
also be screened for outliers and skewness. Appropriate non-parametric tests will be used to 
compare treatment groups on continuous baseline characteristics that are not normally 
distributed. Continuous endpoint data that are not normally distributed will be transformed. 
Cohen’s d will be used to calculate the effect size for means and Cohen’s h will be used to 
calculate the effect size for proportions. Odds ratios will be provided for all dichotomous 
outcomes and least squares means will be provided for all continuous endpoints. Descriptive 
statistics – mean, SD, median, min and max – of all endpoint data will be provided for each 
assessment point or summarized at each week for drinking endpoints. All data will be presented 
in listings. 
11.4.2. 
Analysis Addressing the Primary Efficacy Endpoint 
The analysis of the primary endpoint will be a mixed-effect model for repeated measures. 
Treatment group, study week, treatment group by study week interaction, clinical site and 
baseline percentage of heavy drinking days will be covariates in the mixed effects model. 
Additional covariates may be selected as specified in the SAP. The primary endpoint will be 
performed on available data in the Full Analysis Set with no imputation for missing data. A 
sensitivity analysis will be performed using multiple imputation for missing drinking data 
(Jakobsen-2017). Multiple imputation replaces each missing value with a set of “m” plausible 
values that represent the uncertainty about the right value to impute. The imputation model will 
include a limited set of variables likely to be associated with missingness on the primary 
endpoint, excluding treatment assignment. The variables may include but are not limited to site, 
time and baseline alcohol use. Specification of the variables used in the multiple imputation 
models will be provided in the SAP. 
11.4.3. 
Secondary Efficacy Endpoints Analysis 
Analysis of the continuous secondary endpoints (weekly mean drinks per week, weekly mean 
drinks per drinking day, percentage of days abstinent, number of cigarettes smoked per week, 
number of days of other nicotine product use per week, POMS scores, ECR-RS scores, PROMIS 
scores, and Urge to Drink scores will be analyzed in a similar fashion to that of the primary 
outcome (except substituting baseline equivalent of the outcome). Analysis of the dichotomous 
secondary outcomes (percentage of subjects with no heavy drinking days, percentage subjects 
abstinent from alcohol, percentage of subjects with 1- and 2-level decreases in WHO drinking 
categories, and percentage of smokers abstinent from smoking) will be conducted via logistic 

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regression of the endpoint measured across the entire treatment period (monthly and with grace 
periods, as specified). Secondary analyses to satisfy statistical hypotheses will be performed on 
data collected during the 10-week maintenance period; however, as appropriate descriptive 
statistics will be used to present these data during the initial 2-week period as well. Covariate 
selection beyond treatment group, clinical site, and baseline equivalent of the endpoint will be 
specified in the SAP. These analyses will be performed using the Full Analysis Set subjects with 
no imputation for missing data. 
11.4.4. 
Safety Analyses 
AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA) and will be grouped by system organ class (SOC) and preferred term (PT) 
designation. The severity, frequency, and relationship of AEs to investigational product will be 
presented by SOC and PT groupings. Listings of each individual AE including start date, stop 
date, severity, relationship, outcome, and duration will be provided. Each AE (based on PT) will 
be counted once only for a given study subject. If the same AE occurred on multiple occasions, 
the highest severity will be assumed. Thus, study subjects are not counted multiple times in a 
given numerator in the calculation of frequencies for a specific AE. C-SSRS reports of 
suicidality or suicidal ideation will be reported as AEs and analyzed as AEs if the investigator 
determines after an interview with the subject that the responses are consistent with suicidal 
ideation or attempt.  
Clinical chemistry, urine drug screen results, pregnancy test results, BAC results, and SNAQ 
scores will be reported as summary statistics for each assessment time point. The percentages of 
subjects in each group with a SNAQ score ≤14 at each visit will be presented. Vital signs will be 
presented as summary statistics and change from baseline. The proportions of ECG results 
considered clinically significant will also be provided. In addition, change from baseline (shift 
tables) will also be presented for clinical chemistry data. The numbers and percentages of 
subjects who had urine tests positive for THC at each time point for all subjects, for subjects who 
were positive at baseline, and who were negative at baseline (representing new use) will be 
summarized. The numbers and proportion of subjects who reported CIWA-AR scores ≥ 10 at 
any time after the start of dosing will be presented. Buss-Perry Aggression scores, SNAQ scores 
and body weight changes will be presented for each visit and will be compared between groups 
using repeated measures ANOVA. The numbers and proportions of subjects mild, moderate, 
severe microsomia or any smell loss (anosmia) compared with screening assessment using the 
UPSIT will also be presented.  
11.4.5. 
Compliance and Retention Analyses 
Medication compliance, defined as the amount of investigational product taken as a proportion of 
the total amount prescribed per protocol, will be evaluated for the oxytocin and placebo groups 
based on the Subject Diary. Average amounts of investigational product taken (volume 
determined from weighing the vials prior to and after dispensing and subtracting the difference) 
overall and weekly will be reported for the oxytocin and placebo groups. The research 
participation rate, defined as percentage of subjects with complete drinking data, will be 
compared between treatment groups. In addition, the percentage of subjects discontinuing 
medication or early withdrawal from the study and a listing of these reasons for discontinuation 
will be provided. 

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11.4.6. 
Baseline Descriptive Statistics 
Summaries of the characteristics of the subjects in each of the study groups at baseline will be 
prepared. Baseline characteristics will be compared between the oxytocin and placebo groups 
using appropriate statistical methods. A summary will be prepared to show dropouts/retention 
over time in each group, along with the reason for early termination. The number of missing 
observations will be presented between groups. 
11.4.7. 
Exploratory Analyses 
A number of variables will be tested as potential moderators of the medication treatment effect 
on the PHDD primary endpoint. Weeks 3-12 will be the period of interest. Continuous moderator 
variables will be dichotomized. The potential moderator variables that will be examined include 
measures of anxiety and depression (ECR-RS subscales of attachment and anxiety, POMS 
subscales of depression and anxiety, STAI, and BIS), those suggestive of alcohol withdrawal 
(i.e., withdrawal question on the MINI for alcohol use disorder), and alcohol-related treatment 
goal.  
There is interest in exploring the use of a new Hyperkatifeia Scale as a predictor and moderator 
of drug response. Exploratory analyses utilizing Hyperkatifeia Scale scores will include: 
1) conducting moderator analyses using the total score; and 2) comparison of change from 
baseline between treatment groups for total score and subscales scores. 
11.4.8. 
Ad Hoc Analyses 
Ad hoc analyses may be performed on the Hyperkatifeia Scale as a planned part of exploring the 
utility of this scale including total scores, subscales, and individual items. Ad hoc analyses 
utilizing Hyperkatifeia Scale scores may include: 1) identification of baseline subsets and 
relationship to drinking outcomes; 2) conducting mediator analyses; 3) factor analysis to better 
understand the underlying dimensions of hyperkatifeia; and, 4) validity of the Hyperkatifeia 
Scale by comparing to other measures (e.g., POMS and PROMIS scales or subscale scores). The 
data from this study could be used for meta-analyses with results of other studies to expand data 
availability for the proposed ad hoc analyses. 
11.4.9. 
Adjustment for Covariates 
Covariates used in logistic regression and mixed effects models are described in section 11.4.2 
and 11.4.3. 
11.4.10. 
Interim Analyses and Data Monitoring 
No interim analyses are planned for this study. 
11.4.11. 
Multiple Comparison/Multiplicity 
No adjustments will be made in comparisons of multiple secondary endpoints as this is a pilot 
study designed to explore the potential of oxytocin for the treatment of AUD. 
11.4.12. 
Tabulation of Individual Response Data 
Individual subject data will be listed by measure and time point as appropriate. 

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11.5. 
Determination of Sample Size 
With an intake sample of 100 subjects (50 subjects per arm) and 12% attrition, it is projected that 
the sample size for primary endpoint analyses will be 88 (44 subjects per arm). The alpha level 
for the primary analyses will be 0.05, two-tailed. An estimate of the effect size (Cohen’s d) for 
the investigational products is 0.60. Equal variances in both groups are assumed. These 
assumptions lead to a projected power of 0.80.  

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12. 
Quality Control and Quality Assurance 
This study will be conducted under International Conference on Harmonization (ICH) Good 
Clinical Practice (GCP) guidelines and all applicable regulatory requirements.  
Actions to ensure the accuracy and reliability of data include the selection of qualified 
investigators and appropriate study centers; the review of protocol procedures with the 
investigator and study personnel prior to study start; the design of suitable source documents 
with appropriate instructions for use; the internal audit of source data according to GCP and 
internal procedures to ensure their accuracy, completeness, and verifiability; as well as the 
periodic site monitoring by the Sponsor’s representatives (clinical monitors of Fast-Track Drugs 
& Biologics, LLC). Written instructions will be provided for collection, preparation, and 
shipment of blood samples. Clinical monitors will review source documents and eCRFs for 
accuracy and completeness during on-site monitoring visits; any discrepancies will be resolved 
with the investigator, as appropriate.  
Significant and/or repeated noncompliance will be investigated and remedial action instituted 
when appropriate. Failure to comply with remedial actions may result in study site termination 
and regulatory authority notification. 
12.1. 
 Study Monitoring 
Study monitoring will be the responsibility of designated clinical monitors of Fast-Track. 
Monitors will assure compliance with the clinical protocol and ICH GCPs, human subject’s 
protection, drug accountability, maintenance of the site regulatory file, and conformance of 
eCRF data with source documents. Monitoring visits by clinical monitors will be scheduled to 
take place at the initiation of the study, during the study at appropriate intervals, and after the last 
subject has completed the study. A report of monitoring observations will be provided to the PI 
(for corrective actions) and the Sponsor. 
12.2. 
Audits and Inspections 
Authorized representatives of the Sponsor, the FDA, and the IRB may visit the site to perform 
audits or inspections, including source data verification. The purpose of the audit or inspection is 
to systematically and independently examine all study related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, GCP guidelines, and any applicable regulatory 
requirements. 
The PI should contact the Sponsor’s representative and Fast-Track if contacted by a regulatory 
agency about an inspection. 
 
 

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13. 
Ethics 
13.1. 
Central Institutional Review Board 
NIH has issued a policy requiring that NIH-funded, multi-site research use a single IRB of record 
for the ethical review of human subjects research protocols funded by the NIH that are carried 
out at more than one site in the United States. Advarra IRB will be the central IRB for this study. 
Advarra IRB will review the protocol, informed consent, advertisements and any other materials 
given to subject, as well as progress reports on a continuing basis in accordance with all 
applicable regulations, including Title 21, Code of Federal Regulations (CFR), Parts 50 and 56.  
13.2. 
Ethics Review 
The study will be conducted under a protocol reviewed by the central IRB; the study is to be 
conducted by scientifically and medically qualified persons; the benefits of the study are in 
proportion to the risks; the rights and welfare of the subjects will be respected; the physicians 
conducting the study will ensure that the hazards do not outweigh the potential benefits; the 
results to be reported will be accurate; subjects will give their informed consent and will be 
competent to do so and not under duress; and all study staff will comply with the ethical 
principles in 21 Code of Federal Regulations (CFR) Part 50 and the Belmont Principles. 
13.2.1. 
Review/Approval of Study Protocol 
The study may not begin until the IND has been submitted to the FDA and the 30-day waiting 
period has expired without notification by FDA to the Sponsor of any clinical hold issues. 
NIAAA will be the study Sponsor. The site must obtain written approval from the IRB to 
conduct the study before study initiation. NIAAA will issue a formal authorization letter for the 
study to be initiated at the site. Progress reports will be submitted to the IRB by the Investigator 
at the frequency requested by the IRB. 
13.2.2. 
Protocol Modifications 
All necessary protocol changes will be submitted in writing as protocol amendments to the IRB 
by Fast-Track for approval prior to implementation. NIAAA will submit all protocol 
amendments to the FDA. 
13.2.3. 
Protocol Deviation Reporting Procedures 
All subject-specific deviations from the protocol are to be documented. The PI or designee will 
be responsible for identifying and reporting all deviations, which are occurrences involving a 
procedure that did not follow the study protocol. Any protocol deviation that adversely affects 
the safety or rights of a subject or scientific integrity of the study is considered a major deviation 
and will be reported immediately to the NIAAA Project Manager and the IRB. 
13.3. 
Ethical Conduct of the Study 
This study will be conducted in accordance with all applicable Federal human research 
protections requirements and the Belmont Principles of respect for persons, beneficence, and 
justice.  

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The procedures set out in this study are designed to ensure that the sponsor’s representative and 
all study personnel abide by the principles of the ICH GCP Guideline and the Code of Federal 
Regulations (CFR). The PI confirms this by signing this study protocol and Form FDA 1572. 
13.3.1. 
Confidentiality 
13.3.1.1. Confidentiality of Data 
Particular attention is drawn to the regulations promulgated by the FDA under the Freedom of 
Information Act providing, in part, that proprietary information furnished to clinical investigators 
and IRB will be kept confidential by the FDA only if maintained in confidence by the clinical 
investigator and IRB. 
By signing this protocol the investigator affirms to NIAAA that information furnished to the 
investigator by NIAAA will be maintained in confidence and such information will be divulged 
to the IRB or similar or expert committee; affiliated institution; and employees only under an 
appropriate understanding of confidentiality with such board or committee, affiliated institution 
and employees. 
13.3.1.2. Confidentiality of Subject Records 
To maintain subject confidentiality, all laboratory specimens, eCRFs, reports and other records 
will be identified by a subject number only. Research and clinical records will be stored in a 
locked cabinet. Only research staff, NIAAA program officials, and Fast-Track Drugs & 
Biologics clinical monitors will have access to the records. Subject information will not be 
released without written permission, except as necessary for monitoring by representatives of 
NIAAA. Upon approval of the study by an IRB, an application will be filed with NIAAA for a 
Certificate of Confidentiality. 
By signing the protocol the investigator agrees that within local regulatory restrictions and 
ethical considerations, NIAAA or any regulatory agency may consult and/or copy study 
documents in order to verify eCRF data. 
13.3.2. 
Compensation for Participation 
Subjects will be compensated for travel expenses and for time contributed to this research study 
in the form of cash or vouchers. Compensation will be provided in increasing amounts with each 
subject visit and is detailed in the informed consent form.  
13.3.3. 
Written Informed Consent 
The informed consent process and document will be reviewed and approved by the IRB and 
sponsor’s representative prior to initiation of the study. The consent document contains a full 
explanation of the possible risks, advantages, and alternate treatment options, and availability of 
treatment in the case of injury, in accordance with 21 CFR Part 50. The consent document 
indicates that by signature, the subject, permits access to relevant medical records by the 
sponsor’s representative and by representatives of the FDA. The sponsor’s representative will 
submit a copy of the initial IRB- and sponsor’s representative-approved consent form to the FDA 
and will maintain copies of revised consent documents that have been reviewed and approved by 
the IRB. 

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A written informed consent document, in compliance with 21 CFR Part 50, 32 CFR Part 219, 
and the Belmont Principles, and HIPAA Authorization will be signed by the subject before any 
study-related procedures are initiated for each subject.  
All potential subjects for the study will be given a current copy of the Informed Consent Form to 
read. All aspects of the study and informed consent will be explained in lay language to the 
subject by either the investigator, or a medically trained designee. Any subject who is unable to 
demonstrate understanding of the information contained in the informed consent will be 
excluded from study participation. 
All study subjects will be given a copy of the signed informed consent. 
13.3.4. 
 Delegation of Responsibilities and Adequate Resources 
The PI should have adequate time to conduct the study properly and should have an adequate 
number of qualified staff to assist with the conduct of the study.  
The term “investigator” used throughout this protocol refers to the PI and/or qualified 
subinvestigators. The PI may delegate responsibilities to other study site personnel. The PI shall 
delegate tasks only to individuals qualified by education, training, and experience to perform the 
delegated tasks. The PI shall have direct oversight of all delegated activities and shall document 
delegation of responsibilities. The PI is responsible for ensuring all delegated staff has been 
properly trained on the protocol and their assigned study responsibilities. A delegation log 
identifying all delegated duties and the individual to whom they have been delegated will be 
maintained at the study site.  
13.3.5. 
Financial Disclosure 
Clinical investigators are required to provide financial disclosure information for the submission 
of certification or disclosure statements required under 21 CFR § 54. As defined in 21 CFR § 
54.2, a clinical investigator is a listed or identified investigator or subinvestigator who is directly 
involved in the treatment or evaluation of research subjects. The term also includes the spouse 
and each dependent child of the investigator. In addition, investigators must promptly update 
financial disclosure information if any relevant changes occur during the course of the 
investigation and for 1 year following completion of the study. 
 

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14. 
Data Handling and Record Keeping 
Source documents include but are not limited to original documents, data and records such as 
hospital/medical records (including electronic health records), clinic charts, laboratory results, 
data recorded in automated instruments, and pharmacy records, etc. This study will use an 
electronic data management system (EDMS) (IBM Clinical Development) and eCRFs. Data will 
be transcribed from source documentation into web-based eCRFs. Only questionnaire data will 
be entered directly into eCRF (i.e., without prior written or electronic record of data). Paper 
copies of the eCRFs will be provided in the event that the site cannot access the EDMS at the 
time the questionnaire is being completed. The transcribed data will be consistent with the source 
documents or the discrepancies will be explained.  
Clinical monitors will review all source records and compare them to the data entered into the 
eCRF. All entries, corrections, and alterations will be made by the investigator or other 
authorized study personnel. Any errors identified during monitoring will have a query posted by 
monitor for site staff to address. The EDMS system maintains a full audit trail of data entry, data 
corrections, and data queries. 
14.1. 
Subject Identification and Confidentiality 
Subjects will be identified on eCRFs by a unique subject number. No personal identifier will be 
used in any publication or communication used to support this research study. The subject 
number will be used if it becomes necessary to identify data specific to a single subject. The 
Sponsor’s representative and designated clinical monitors of Fast-Track, the IRB, and the FDA 
are eligible to review medical and research records related to this study as a part of their 
responsibility to protect human subjects in clinical research. Personal identifiers will be removed 
from photocopied or electronic medical and research records. 
14.2. 
Inspection of Records 
The sponsor’s representative or designee will be allowed to visit the investigation facilities for 
the purpose of monitoring any aspect of the study. The investigator agrees to allow the monitor 
to inspect the drug storage area, investigational product stocks, drug accountability records, 
subject charts, study source documents, and other records relative to study conduct. 
Subjects’ health information is used to report results of research to the sponsor’s representative 
and Federal regulators and may be reviewed during study audits for compliance with study plans, 
regulations, and research policies. The consent document indicates that by signature, the subject 
permits access to relevant medical records by the sponsor’s representative and by representatives 
of the FDA. 
Upon a subject’s termination from the trial, completed eCRFs will be ready and available for on-
site review by the sponsor’s representative at scheduled monitoring visits. 
14.3. 
Retention of Records 
The investigator is responsible for creating and/or maintaining all study documentation required 
by Title 21 Code of Federal Regulations (21CFR) Parts 50, 54, 56, and 312, ICH E6 section 8, as 
well as any other documentation defined in the protocol. The investigator must provide key 

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documents to the Sponsor prior to start of the study. A complete list of required regulatory 
documents will be provided in the study Manual of Procedures. 
Federal and local regulations require that the investigator retain a copy of all regulatory 
documents and records that support the data for this study for whichever of the following is the 
longest period of time: 
• A period of 2 years following the final date of approval by the FDA or other regulatory 
agency of the study drug for the purposes that were the subject of the investigation; or 
• A period of 5 years following the date on which the results of the investigation were 
submitted to the FDA or other regulatory agency in support of, or as part of, an 
application for a research or marketing permit for the study drug for the purposes that 
were the subject of the investigation. 
The Sponsor will notify investigators once one of the above 2 timeframes has been satisfied. 
If the investigation does not result in the submission of the data in support of, or as part of, an 
application for a research or marketing permit, records must be retained for a period of 2 years 
following notification by the Sponsor that the entire clinical investigation (not merely the 
investigator’s portion) is completed, terminated, or discontinued or 2 years following withdrawal 
of the Investigational New Drug application/Clinical Trial Authorization or request for 
marketing approval (New Drug Application/Marketing Authorization Application).  
If the investigator retires, relocates, or for other reasons withdraws from the responsibility of 
keeping the study records, custody must be transferred to a person who will accept the 
responsibility. The Sponsor must be notified in writing of the name and address of the new 
custodian. Study records should not be destroyed without consultation with the Sponsor. 
14.4. 
Trial Registration 
As the IND holder and Sponsor, NIAAA will register the trial on the National Library of 
Medicine’s Clinical Trials Registry on the world wide web at http://www.clinicaltrials.gov.  

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15. 
Publication Policy 
Review of manuscripts resulting from this study or from data generated during this study must 
occur according to the NIAAA Publications Policy prior to submission for publication. 
Authorship shall be consistent with NIAAA policies. 

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16. 
Protocol Signature Page  
 
NIAAA REPRESENTATIVES 
Typed Name  
 
 
 
Signature  
 
 
 
 
 
Date 
 
Raye Z. Litten, Ph.D. 
  
 
  
  
 
 
Daniel E. Falk, Ph.D. 
  
 
  
  
 
 
Jenica Patterson, Ph.D. 
  
 
  
  
 
 
Megan Ryan, MBA, CCRP 
  
 
  
  
 
 
INVESTIGATORS 
I agree to conduct this clinical study in accordance with the design and specific provisions of this 
protocol; deviations from the protocol are acceptable only with a mutually agreed upon protocol 
amendment with the IRB approval. I also agree to report all information or data in accordance 
with the protocol, and in particular I agree to report any serious adverse experiences as defined in 
section 10.2.7 of this protocol. 
 
Typed Name  
 
    Signature  
 
 
 
 
 
Date 
 
________________  
_________________________     __________________ 
 
 
________________  
_________________________     __________________ 
 

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18. 
Appendices 
Appendix A. 
Example Drug Diary Card 
 
 
Subject ID Number: _________________________     Bottle # 1 
 
Administer one dose (5 sprays in alternating nostrils) each morning. 
Days 
Date 
# sprays morning 
1 
 
 
2 
 
 
3 
 
 
4 
 
 
5 
 
 
6 
 
 
7 
 
 
8 
 
 
9 
 
 
10 
 
 
11 
 
 
12 
 
 
13 
 
 
14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Subject ID Number: _________________________     Bottle # 2 - 6 
 
Administer one dose (5 sprays in alternating nostrils) each morning and each evening. 
 
Bottle # 
Days 
Date 
# sprays morning 
# sprays evening 
 
15 
 
 
 
 
16 
 
 
 
 
17 
 
 
 
 
18 
 
 
 
 
19 
 
 
 
 
20 
 
 
 
 
21 
 
 
 
 
22 
 
 
 
 
23 
 
 
 
 
24 
 
 
 
 
25 
 
 
 
 
26 
 
 
 
 
27 
 
 
 
 
28 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix B. 
Common Terminology Criteria for Adverse Events for Clinical 
Laboratory Adverse Events and Elevated Blood Pressure 
The following are the toxicity grades for which grading criteria are provided by the CTCAE 
(Version 4.03) for chemistry tests performed in this study and for elevated blood pressure 
(hypertension). 
Table 6: 
CTCAE Criteria for Clinical Laboratory Adverse Events and Blood Pressure 
Elevations 
Adverse Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
 
 
 
 
 
ALT elevated 
>ULN – 3.0 x ULN 
>3.0 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
AST elevated 
>ULN – 3.0 x ULN 
>3.0 – 5.0 x ULN 
>5.0 – 20.0 x ULN 
>20.0 x ULN 
Total bilirubin 
elevated 
(bilirubinemia) 
>ULN – 1.5 x ULN 
>1.5 – 3.0 x ULN 
>3.0 – 10.0 x ULN 
>10.0 x ULN 
Hypernatremia 
(elevated sodium) 
>ULN - 150 mmol/L 
>150 - 155 mmol/L 
>155 - 160 mmol/L; 
hospitalization 
indicated 
>160 mmol/L; life-
threatening 
consequences 
Hyponatremia 
(low sodium) 
<LLN - 130 mmol/L 
- 
<130 - 120 mmol/L 
<120 mmol/L; life-
threatening 
consequences 
Hyperkalemia 
(elevated potassium) 
>ULN - 5.5 mmol/L 
>5.5 - 6.0 mmol/L 
>6.0 - 7.0 mmol/L; 
hospitalization 
indicated 
>7.0 mmol/L; life-
threatening 
consequences 
Hypokalemia 
(low potassium) 
<LLN - 3.0 mmol/L 
<LLN - 3.0 
mmol/L; 
symptomatic; 
intervention 
indicated 
<3.0 - 2.5 mmol/L; 
hospitalization 
indicated 
<2.5 mmol/L; life-
threatening 
consequences 
Creatinine elevated 
>ULN - 1.5 x ULN 
>1.5 - 3.0 x ULN 
>3.0 - 6.0 x ULN 
>6.0 x ULN 
Hypertension 
Pre-hypertension 
(systolic BP 120 - 139 
mmHg or diastolic BP 80 
- 89 mmHg) 
Stage 1 hypertension 
(systolic BP 140 - 
159 mmHg or 
diastolic BP 90 - 99 
mmHg); medical 
intervention 
indicated; recurrent 
or persistent (24 hrs); 
symptomatic increase 
by >20 mmHg 
(diastolic) or to 
>140/90 mmHg if 
previously WNL; 
monotherapy 
indicated  
Stage 2 hypertension 
(systolic BP≥160 
mmHg or diastolic BP 
≥100 mmHg); medical 
intervention indicated; 
more than one drug or 
more intensive therapy 
than previously used 
indicated  
Life-threatening 
consequences (e.g., 
malignant 
hypertension, 
transient or 
permanent neurologic 
deficit, hypertensive 
crisis); urgent 
intervention indicated  

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Appendix C. 
Hyperkatifia Scale 
 
People sometimes experience uncomfortable feelings or sensations when they don’t drink 
alcohol for some time. These feelings or sensations could happen when waking up after 
overnight sleep, after a long day at work, or not drinking for several days or weeks.  
 
At baseline: Take a few minutes to think back to before you decided to enter this study and 
change your drinking. Think about how you felt during the time(s) you couldn’t have a drink. 
Please read each phrase and circle a number 0, 1, 2, 3, or 4 that indicates how intensely you 
felt these feelings and sensations when you were not drinking alcohol. 
 
At end of study:  During this study, think about how you felt during the time(s) you didn’t 
drink. Please read each phrase and circle a number 0, 1, 2, 3, or 4 that indicates how intensely 
you felt these feelings and sensations when you were not drinking alcohol.    
 
The rating scale is as follows: 
0  Not at all 
1  A little 
2  Moderately 
3  Quite a lot 
4  Extremely  
1 
Unhappy 
0 1 2 3 4 
2 
Low energy 
0 1 2 3 4 
3 
Distressed 
0 1 2 3 4 
4 
Grouchy 
0 1 2 3 4 
5 
Uneasy 
0 1 2 3 4 
6 
Unable to concentrate 
0 1 2 3 4 
7 
Fatigued 
0 1 2 3 4 
8 
Anxious  
0 1 2 3 4 
9 
Depressed 
0 1 2 3 4 
10 
Uncomfortable 
0 1 2 3 4 
11 
Nervous 
0 1 2 3 4 
12 
Restless 
0 1 2 3 4 
13 
Irritable 
0 1 2 3 4 
14 
Discontented 
0 1 2 3 4 
15 
On edge 
0 1 2 3 4 
16 
Annoyed 
0 1 2 3 4 
17 
Bad tempered 
0 1 2 3 4 
18 
Tense 
0 1 2 3 4 
19 
Revved up 
0 1 2 3 4 
20 
Light touches are painful 
0 1 2 3 4 
21 
Unable to sleep 
0 1 2 3 4 
22 
Angry 
0 1 2 3 4 

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23 
Fearful 
0 1 2 3 4 
24 
More sensitive to pain 
0 1 2 3 4 
 
When completing this checklist, I was thinking about a time when I didn’t drink alcohol for:  
• A few hours 
• Overnight or sleeping hours 
• 1-2 days 
• 3-5 days 
• 6-7 days 
• More than a week 
 
 
Scale and subscale scoring: 
 
The total score is the sum of the individual items. 
 
Subscale scores are the sum of the individual items for each subscale as follows: 
 
Stress/Anxiety = items 3 + 5 + 6 + 8 + 11 + 15 + 18 + 19 + 21 + 23 
 
Depression = items 1 + 2 + 7 + 9 
 
Irritable = items 4 + 12 + 13 + 14 + 16 + 17 + 22 
 
Pain = items 10 + 20 + 24