Conditions: Alcohol Use Disorder Alcohol Misuse
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 100
Healthy volunteers: no

Brief summary:
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.

Detailed description:

Arms:
arm 1: Oxytocin, 35 IU per dose, intranasally twice-daily. 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. The total daily dose of oxytocin will be 70 IU/mL. arm 2: Identically matched placebo administered intranasally twice-daily. 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.

Interventions: intervention 1: Instranasal Oxytocin
Intervention descriptions: intervention 1: Intranasal Oxytocin - concentrated formulation - 35 IU per dose

Protocol document:
ICF_002.pdf: 
National Institute on Alcohol Abuse and Alcoholism (NIAAA) / Protocol Number NCIG-007R 
Page 1 of 17   
 
«PiFullName» 
Advarra IRB Approved Version 10 Mar 2022 
Revised «PIApprovalDate» 
 
INFORMED CONSENT FORM 
AND  
AUTHORIZATION TO USE AND DISCLOSE PROTECTED HEALTH INFORMATION 
 
Sponsor / Study Title: 
  
National Institute on Alcohol Abuse and Alcoholism (NIAAA)/ 
“Randomized, Double-Blind, Placebo-Controlled Trial of the 
Efficacy and Safety of Intranasal Oxytocin for the Treatment of 
Alcohol Use Disorder” 
 
Protocol Number: 
 
NCIG-007R 
 
Principal Investigator: 
(Study Doctor) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Address: 
«PiLocations» 
 
KEY INFORMATION  
You are invited to take part in a research study. This research study is studying oxytocin nasal 
spray as a possible treatment for alcohol use disorder. The National Institute on Alcohol Abuse 
and Alcoholism (NIAAA) is sponsoring this research study. 
• Your participation in this study is completely voluntary.  
• Your participation will last about 17 weeks and will include about 9 visits to the study 
center. You will be paid for your participation. You will have to take the study drug 
home with you and bring it back to the clinic for each visit. 
• You will have your blood drawn about 5 times (25 mL; about 5 teaspoons), an 
electrocardiogram (ECG), physical exam (including the nose), review any medications 
you are taking, have a urine drug screen, take a smell test, you will be asked not to get 
pregnant/not to get your partner pregnant. 
• You will be asked about your drinking for the past 28 days and throughout the study. 
• You will be asked many questions about your mental health, drinking, drug use, and 
wellbeing. 
• You will be asked to think about how much you are drinking. 
• You will need to provide a contact person in case you are not able to be reached. 
• You will be asked about your occupation and income. 
• Participating in this study will not affect your ability to seek treatment for your alcohol 
use. 
 
Please read this form carefully. Take your time to ask the study doctor or study staff as many 
questions about the study as you would like. The study doctor or study staff can explain words 
or information that you do not understand. Reading this form and talking to the study doctor or 
study staff may help you decide whether to take part or not. If you decide to take part in this 
study, you must sign your name at the end of this form and date it.  


National Institute on Alcohol Abuse and Alcoholism (NIAAA) / Protocol Number NCIG-007R 
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«PiFullName» 
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BACKGROUND AND PURPOSE  
You are being considered for participation in this study because of the amount of alcohol you 
consume, and you have indicated the desire to stop or reduce your alcohol drinking. Oxytocin, 
the medication we are testing, is a human hormone that acts on the brain. It is approved by the 
United States Food and Drug Administration (US FDA) as an injectable to create contractions in 
pregnant women and control bleeding after childbirth, but it also is thought to affect social 
connections. Oxytocin is not approved by the FDA for the treatment of alcohol use disorder but 
is being studied because when someone stops drinking alcohol, their anxiety and craving for 
alcohol increases, and oxytocin is thought to help control this anxiety and craving. This may aid 
someone trying to reduce their alcohol drinking.  
 
The purpose of this research study is to:  
• Test the safety and effectiveness of the study drug, oxytocin nasal spray 
• See how your drinking changes during the study 
 
This is a research study to test a new investigational drug with a placebo. An investigational 
drug is one that is not approved by the US FDA.  The concentration of oxytocin being used in 
this study is 70 IU/mL in the nasal spray preparation, which is higher than the concentration in 
US FDA-approved products containing oxytocin.  
 
About 100 participants will participate in this study at 4 separate locations. Each location is 
expected to enroll about 25 participants.  
 
WHAT WILL HAPPEN DURING THE STUDY? 
Screening: 
Before any study-related tests and procedures are performed, you will be asked to read, sign, 
and date this consent document. There will be 2 screening visits. At the beginning of Screening 
Visit #1, your blood alcohol level will be measured using a breathalyzer and if it is greater than 
0.000% of alcohol, you will not be able to complete your visit as scheduled. Note: a 
breathalyzer test of 0.08% or greater blood alcohol is considered legally intoxicated.  
 
The following screening tests and procedures will then be performed to determine if you 
qualify to take part in this study:  
 
• Provide your age 
• Urine Drug Screen - provide a urine sample to test for drug use 
• Medical and Surgical History – provide study staff with any past/current medical issues 
and your past or upcoming surgeries 
• Physical Exam - undergo a Physical exam (including the nose) to assess your general 
health including your weight, vital signs, and an electrocardiogram (ECG) 
• Liver and Kidney Function tests - provide a blood sample to see how your liver and 
kidneys are working 


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• Urine Pregnancy test - provide a urine sample to test for pregnancy for females of 
childbearing potential 
• Birth Control - If you are female, you will be asked about your method of birth control 
• We will ask about your drinking habits and alcohol use for the previous 28 days 
• Past and Current Medications - provide the names of any prescription and “over the 
counter” medications you are currently taking or have taken in the past 2 months 
• Answer questions about your mental health, and withdrawal symptoms from alcohol 
• Goals you have with drinking 
• Smell test – a scratch and sniff test of different odors  
 
You will be asked to provide background information such as your gender and your 
race/ethnicity.  
 
You will be asked to provide addresses and telephone numbers for yourself and other people, 
such as family members or friends who will know how to contact you if you fail to show up for 
clinic visits, or if study personnel have problems getting in touch with you. In doing so, you give 
study personnel permission to contact these people to find out how to contact you. Please be 
aware that telling others you are in this study could jeopardize your privacy.  
 
At the beginning of Screening Visit #2, your blood alcohol level will be measured using a 
breathalyzer and if it is greater than 0.02% blood alcohol level, you will not be able to complete 
your visit as scheduled. Note: a breathalyzer of 0.08% or greater blood alcohol is considered 
legally intoxicated. At the Screening Visit #2 the following screening tests and procedures will 
be performed to determine if you qualify to take part in this study:  
• Review of your medical and surgical history 
• Review any changes to your general physical health (including the nose) since the last 
visit and taking your vital signs  
• Current Medications - review any prescriptions or “over the counter” medications you 
are taking 
• Urine Drug Screen - provide urine samples for a urine drug screen  
• Urine Pregnancy Test - If you are female of childbearing potential provide a urine 
sample for a pregnancy test 
• Birth Control - if you are female, you will be asked about your method of birth control 
• Ask about your alcohol use since your last visit 
• Smell Test -a scratch and sniff test of different odors 
• You will be asked questions about your mental health and drinking 
• Answer questions about thoughts you may have about harming yourself 
• Answer questions about any visits with health professionals for assistance in reducing or 
stopping drinking 
 
 
 


National Institute on Alcohol Abuse and Alcoholism (NIAAA) / Protocol Number NCIG-007R 
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This study will use competitive enrollment. This means that when the target number of 100 
participants begin the study, all further enrollment will be closed. Therefore, it is possible that 
you could be in the screening phase, ready to begin the study, and be discontinued without 
your consent if the target number of participants has already begun the study. 
 
If you qualify to take part in this study and go on to receive the study treatment, then the 
following will happen:  
 
Study Treatment:  
 
You will be randomly assigned by chance (like the flip of a coin) to receive either oxytocin nasal 
spray (active substance) or placebo nasal spray (the same spray without oxytocin). You will have 
a 50% (1 in 2) chance of receiving oxytocin nasal spray and a 50% (1 in 2) chance of receiving 
placebo. This is a double-blind study, which means neither you nor the study doctor will know 
to which of these study drug groups you are assigned. In case of an emergency, however, the 
study doctor can get this information.  
 
You will receive your first bottle of study drug (either oxytocin nasal spray or placebo nasal 
spray) to take in the clinic and at home. You will be shown how to use the nasal spray the first 
time you receive study treatment. You will self-administer the spray 5 times switching between 
nostrils with each spray. You will need to wait for 30 seconds in between sprays. For the first 
two weeks, you will do this once per day in the morning. For the next two weeks, you will do 
this twice per day, in the morning and evening (10 sprays total per day). Please bring this bottle 
(and any empty bottles) along with your diary card to each clinic visit. 
 
During Study Weeks 1 through 12 of the treatment phase of the study, you 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 study treatment period. The following assessments and 
procedures will be performed at each clinic visit unless otherwise noted:  
 
• Alcohol breathalyzer 
• Urine Drug Screen - provide a urine sample for drug testing  
• Review how you have been feeling 
• Current Medications - Ask you about any medications you have taken 
• Have an exam of your nasal cavity  
• Smell Test - a scratch and sniff test of different odors that measures your ability to smell 
(Weeks 1, 3, 6, 8, 10, and 13) 
• Vital Signs and weight - vital signs will be taken (weight will be recorded at Week 6, 8, 
10, and 13) 
• ECG (Week 13 only) 
• Side Effects – answer questions if experiencing side effects  
• Review any alcohol withdrawal symptoms you may be experiencing. 
• Answer questions about thoughts you may have about harming yourself 


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• Fill out questionnaires or answer questions about your anxiety, impulsiveness, and 
drinking patterns at Week 1 only. 
• Fill out questionnaires or answer questions about your mood, sleep habits, pain, 
aggressive feelings, appetite, drinking urges, and smoking cigarettes (Weeks 1, 6, 8, and 
10). 
• Answer questions about negative emotions at Weeks 1 and 13. 
• Fill out questionnaire or answer questions about alcohol craving and consequences of 
alcohol use (Weeks 1, 3, 6, 8, 10, and 13).   
• Answer questions about your attendance at group meetings and visits with health 
professionals for assistance in reducing or stopping drinking (Week 13 only). 
• Provide your daily alcohol use since your last visit. 
• Liver and Kidney Function tests - provide a blood sample for clinical laboratory tests to 
monitor your health (Weeks 6, 8, and 10).  
• Review the study diary card with clinic staff. 
• Watch a video that provides educational information about alcohol and importance of 
taking your study medication. 
• Urine Pregnancy Test – provide a urine sample to check for pregnancy if you are female 
(Weeks 1, 6, 8, 10, and 13) 
• Answer questions about your birth control methods if you are female. 
 
All participants will participate in the online “Take Control” program which consists of a series 
of 7 computerized modules. The intervention is derived from a self-help approach developed by 
NIAAA and provides evidence-based information for individuals with alcohol problems, and 
suggestions for making changes in their drinking. 
 
During the telephone visits you will be asked how you have been feeling, about any new 
medications you are taking, reminded about how to use the study drug, the dose you should be 
taking, and reminded of any upcoming visits to the study clinic. 
 
After Study Treatment: 
Because this is a research study, the study drug will be given to you only during this study and 
not after the study is over. 
 
One to two weeks after the study is over a study staff member will contact you by phone to ask 
you questions about your alcohol use and any side effects that you have noticed since you 
stopped taking the study drug. If study staff has problems getting in touch with you, they may 
contact friends or family members you provided at screening to get your new contact 
information. Please be aware that telling others such as family and friends that you are in this 
study could risk your privacy. To maintain your confidentiality when attempting to contact you 
or a contact person by telephone, the research staff will not say that you are a participant in 
this research study. Once we have contacted you and/or the contacts you gave us, your 
participation in the study will end. 
 


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EXPECTATIONS  
If you participate in this study, you will be expected to:  
• Bring your used and unused study drug bottles, and diary card, with you every time you 
attend a clinic visit.  
• Provide truthful and honest information when answering any of the study related 
questions.  
 
RISKS, SIDE EFFECTS, AND/OR DISCOMFORTS  
Risks from Taking Oxytocin Nasal Spray: 
Some people may experience some side effects from the study drug while others may not 
experience any side effects. Side effects of oxytocin nasal spray are rare. Decreased sodium 
(salt) levels in the blood, mild dizziness, dry mouth, headache, and heart rate changes 
(increases and decreases) nausea, nasal irritation, increased thirst, increased urination, 
increased appetite, weight gain, and drowsiness have been reported. There is a risk of losing 
your sense of smell which may not be reversible. 
 
Warnings and Precautions when Taking Oxytocin Nasal Spray: 
Oxytocin can cause changes in blood pressure if taken with anesthesia. If you are planning 
elective surgery or are having emergency surgery let your doctor know of your possible use of 
oxytocin. 
 
Risks from Alcohol Withdrawal: 
Some people may experience symptoms of alcohol withdrawal if they stop drinking suddenly. 
At your screening visit, you will be given information to help you recognize the symptoms of 
withdrawal. You will be monitored carefully throughout the study in case you begin to have 
symptoms of alcohol withdrawal. If you experience any of these symptoms, you will be 
instructed to call the clinical site using the 24-hour phone number provided to you. When you 
contact the clinical site, a study staff member will ask you questions to determine if you are 
having serious withdrawal symptoms and will arrange for medical supervision to help you 
during withdrawal, if needed. During your in-person clinic visits and telephone interviews 
throughout the study, you will be assessed for withdrawal symptoms you might be 
experiencing. You will be asked about changes in your health and drinking status. If you 
experience significant withdrawal symptoms, you will be asked to come to the clinical site or 
report to your local emergency room for further evaluation. 
 
RISKS OF STUDY PROCEDURES 
• Blood samples: Possible side effects from blood drawing include faintness, inflammation 
of the vein, pain, bruising, or bleeding at the site of puncture. There is also a slight 
possibility of infection. 
• ECG: Skin irritation is rare but could occur during an ECG from the electrodes or gel that 
is used. Hair on your chest may need to be removed to obtain the best electrical contact 
between the adhesive electrodes and your skin. 
 
 


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«PiFullName» 
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• Some of the questions about your personal habits, lifestyle, emotional state and drug 
and alcohol use may embarrass you. If any question makes you feel uncomfortable you 
may discuss its importance and the need to answer it with the specially trained 
interviewer. You may refuse to answer a question if it is upsetting to you.  
• If you are having suicidal thoughts call the study doctor at the telephone number listed 
on the first page of this form. If you feel in crisis, you can call 911 and/or a Nationwide 
Suicide Hotline that is answered 24 hours a day with a skilled, trained counselor. One 
example is the National Suicide Prevention Lifeline at 1-800-273-TALK (8255). 
• You may become bored with answering questionnaires.  
 
If you receive placebo (the inactive substance) as part of this study, your desire to reduce your 
drinking, may not improve or may get worse.  
 
UNFORESEEN RISKS  
Since the use of the study drug is investigational, there may be other risks that are unknown. 
Additionally, there may be unknown risks to a pregnancy, embryo, or fetus if you or your 
female partner become pregnant. 
 
EMERGENCY CARE 
If you experience any medical problems or psychological symptoms at any time during your 
participation, please contact the study doctor at the number listed on page 1 of this form. 
 
You will be given and encouraged to carry a wallet card that identifies the research study by 
number, states that you are taking either oxytocin or placebo, and indicates that you are 
participating in a double-blind clinical trial; however, this card does not identify you as a 
participant in alcohol research. This card provides the name and phone number of the main 
study doctor who can provide information to other doctors in the event of an emergency. The 
card also instructs the emergency room, or other doctor treating you to provide information to 
the study doctor about your care. 
 
BIRTH CONTROL RESTRICTIONS  
Taking the study drug may involve risks to a pregnant woman, an embryo, fetus (unborn baby) 
or nursing infant. Therefore, if you are pregnant, planning to become pregnant, planning to 
father a child, or are breastfeeding a child, you cannot participate in this study. 
 
Females: 
To reduce the risk of pregnancy, you must use an effective method of birth control while you 
are participating in this study. Acceptable methods of birth control for use in this study are: 
• Oral contraceptives 
• Contraceptive sponge 
• Patch 
• Double barrier (diaphragm/spermicidal or condom/spermicidal) 
• Intrauterine contraceptive system 
• Etonogestrel implant 


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• Medroxyprogesterone acetate contraceptive injection 
• Complete abstinence from sexual intercourse 
• Hormonal vaginal contraceptive ring 
 
The study doctor or study staff will discuss this with you.  
 
If you become pregnant while you are participating in this study after you have stopped taking 
the study drug, tell your study doctor or study staff immediately. You may be asked to allow the 
study staff to collect information about the pregnancy, its outcome, and the health of the child 
after birth. 
 
ALTERNATIVES TO PARTICIPATION  
You do not have to be in this study to receive treatment for your alcohol use. There are several 
alternative treatments that may be effective for treating alcohol problems, including FDA 
approved medications such as Naltrexone, Acamprosate or Antabuse, counseling, and AA. 
These other treatments are not offered to you as part of this research study, but if you decide 
not to participate, or are not eligible, study personnel will give you contact information for 
existing treatment programs in your area. 
 
NEW FINDINGS  
Any new important information that is discovered during the study and which may influence 
your willingness to continue participation in the study will be provided to you. 
 
BENEFITS 
You may benefit because of your participation in this study. There is, however, no guarantee 
that you will benefit from your participation in this study. Information learned from the study 
may help other people in the future.  
 
COMPENSATION FOR PARTICIPATION  
«Compensation» 
You will be paid either in cash or vouchers up to a total of $XXX if you complete this study. You 
will be paid for the visits you complete according to the following schedule: (site to define their 
specific payment schedule) 
• XXXXXX 
 
If you do not complete the study, for any reason, you will be paid for each study visit you do 
complete.  
 
You will be paid after each visit. If you have any questions regarding your compensation for 
participation, please contact the study staff.   
 
 
 
 


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CONFIDENTIALITY   
Records of your participation in this study will be held confidential except when sharing the 
information is required by law or as described in this informed consent. The Investigator, the 
sponsor or persons working on behalf of the sponsor, and under certain circumstances, the US 
FDA and the Institutional Review Board (IRB) will be able to inspect and copy confidential study-
related records which identify you by name. This means that absolute confidentiality cannot be 
guaranteed. If the results of this study are published or presented at meetings, you will not be 
identified. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
 
To make sure that the health information collected in this study is accurate, it will need to be 
checked from time to time against your medical records. Some persons may need to see these 
records to monitor the research and verify the accuracy of the study data, including: 
• A limited number of representatives from the study sponsoring drug company (namely 
its monitors and auditors),  
• The research ethics review board – Advarra IRB (an independent ethics committee that 
reviewed the ethical aspects of this study to help protect the rights and welfare of study 
participants),  
• Government regulatory authorities including the US FDA and other foreign regulatory 
agencies. 
 
Your study records including confidential information about you collected during the study will 
be kept at a secure location. 
 
While every effort will be made to protect the privacy of your information, absolute 
confidentiality cannot be guaranteed. This does not limit the duty of the researchers and others 
to protect your privacy. 
 
By signing and dating this information and consent form, you consent to the collection, access, 
use and disclosure of your information as described above. 
 
CERTIFICATE OF CONFIDENTIALITY 
This research is covered by a Certificate of Confidentiality (CoC) from the National Institutes of 
Health. This means that the researchers cannot release or use information, documents, or 
samples that may identify you in any legal action unless you say it is okay. They also cannot 
provide them as evidence unless you have agreed.  This protection includes federal, state, or 
local civil, criminal, administrative, legislative, or other proceedings. An example would be a 
court subpoena. 
 
 
 


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There are some important things that you need to know. The Certificate DOES NOT stop 
reporting that federal, state or local laws require. Some examples are laws that require 
reporting of child or elder abuse, some communicable diseases, and threats to harm yourself or 
others.  The Certificate CANNOT BE USED to stop a sponsoring United States federal or state 
government agency from checking records or evaluating programs. The Certificate DOES NOT 
stop disclosures required by the federal FDA.  The Certificate also DOES NOT prevent your 
information from being used for other research if allowed by federal regulations. 
 
Researchers may release information about you when you say it is okay. For example, you may 
give them permission to release information to insurers, medical providers or any other 
persons not connected with the research. The CoC does not stop you from willingly releasing 
information about your involvement in this research. It also does not prevent you from having 
access to your own information. 
 
COMPENSATION FOR INJURY  
If you become ill or are injured while you are in the study, get the medical care that you need 
right away. You should inform the healthcare professional treating you that you are 
participating in this study. If you tell the study staff that you think you have been injured then 
they will help you get the care you need.  
 
No medical care, evaluations or financial compensation for research-related injuries or illness 
will be provided. The costs of such additional treatment will be paid by you or by your health 
insurance carrier. You also have the right to pursue legal remedy if you believe that your 
injuries justify such action. Compensation for injury/illness may be payable under the Federal 
Tort Claims Act. The availability of this compensation may vary depending upon the 
circumstances involved and there are certain limitations.  
 
Please be aware that some insurance plans may not pay for research-related injuries. You 
should contact your insurance company for more information 
 
By signing and dating this document, you will not lose any of your legal rights or release anyone 
involved in the research from responsibility for mistakes. 
 
COSTS  
There will be no charge to you for your participation in this study. The study drug, study-related 
procedures, and study visits will be provided at no charge to you or your insurance company. 
 
FUTURE RESEARCH STUDIES  
Identifiers will be removed from your identifiable private information and so that your study 
data could then be used for future research studies or distributed to another investigator for 
future research studies without additional informed consent. 
 
 
 


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If you agree, NIAAA may share your data without direct identifiers as part of the combined 
study database through controlled access without additional informed consent. This means the 
data are made available for other research only after the researcher has obtained approval 
from NIAAA to use the requested data for a particular project. The data will not include direct 
identifiers like your name, medical record number or date of birth. To use your data, 
researchers must promise not to try to re-identify you. You can tell us at the end of this form 
whether you will allow us to share your data in this way.  
 
RESEARCH RESULTS  
Researchers are required to publish the results of this study. These results will be based on 
outcomes for the entire group of participants and will not identify you as a participant. No 
individual information about you or your participation in this research will be made public 
without your express written permission. You will not be told the results of this research, 
however, after the end of the study, you may request and be provided with the name of the 
study drug that you received, oxytocin nasal spray or placebo nasal spray. 
 
WHOM TO CONTACT ABOUT THIS STUDY 
During the study, if you experience any medical problems, suffer a research-related injury, or 
have questions, concerns or complaints about the study such as: 
 
• Whom to contact in the case of a research-related injury or illness; 
• Payment or compensation for being in the study, if any; 
• Your responsibilities as a research participant; 
• Eligibility to participate in the study; 
• The study doctor’s or study site’s decision to exclude you from participation; 
• Results of tests and/or procedures; 
 
Please contact the study doctor at the telephone number listed on the first page of this 
consent document.  
 
If you seek emergency care, or hospitalization is required, alert the treating physician that you 
are participating in this research study.  
 
An institutional review board (IRB) is an independent committee established to help protect the 
rights of research participants. If you have any questions about your rights as a research 
participant, contact: 
 
• By mail: 
Study Subject Adviser 
Advarra IRB 
6100 Merriweather Dr., Suite 600 
Columbia, MD 21044 
• or call toll free:    877-992-4724 
• or by email:          adviser@advarra.com 


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Please reference the following number when contacting the Study Subject Adviser: 
Pro00061563. 
 
VOLUNTARY PARTICIPATION / WITHDRAWAL  
Your decision to participate in this study is voluntary. You may choose to not participate, or you 
may withdraw from the study for any reason without penalty or loss of benefits to which you 
are otherwise entitled and without any effect on your future medical care. However, please 
note that the FDA requires that any information collected up to the point of your withdrawal 
cannot be removed from the study. 
 
You should not stop taking the study drug without consulting the study doctor. If you decide to 
stop taking the study drug, you are encouraged to participate in the other study procedures. If 
you leave the study, you may also be eligible to receive other services at the clinic or referrals 
to other clinics, if appropriate. 
 
The study doctor or the sponsor can stop your participation at any time without your consent 
for the following reasons: 
 
• If it appears to be medically harmful to you; 
• If you fail to follow directions for participating in the study; 
• If the study is canceled;   
• For administrative reasons; or 
• The Sponsor stops the study for any reason. 
 
If you leave the study for any reason, the study doctor may ask you to have some end-of-study 
tests for your safety.  
 
 
 


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CONSENT  
I have read and understand the information in this informed consent document. I have had an 
opportunity to ask questions and all my questions have been answered to my satisfaction. I 
voluntarily agree to participate in this study until I decide otherwise. I do not give up any of my 
legal rights by signing and dating this consent document. I will receive a copy of this signed and 
dated consent document. 
 
 
________________________________________ 
 
 
Participant’s Printed Name  
 
 
________________________________________ 
 
___________  
Participant’s Signature 
 
 
 
 
Date 
 
 
________________________________________ 
 
 
Printed Name of the Person Conducting the  
 
 
Consent Discussion   
 
________________________________________ 
 
___________ 
Signature of the Person Conducting the  
 
 
Date 
 
Consent Discussion   
 
 
 
 
 
 
 
 
 
 
 
 
 


National Institute on Alcohol Abuse and Alcoholism (NIAAA) / Protocol Number NCIG-007R 
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«PiFullName» 
Advarra IRB Approved Version 10 Mar 2022 
Revised «PIApprovalDate» 
 
Attachment #1 
CONSENT FORM QUESTIONS 
Oxytocin Nasal Spray for Alcohol Use Disorder 
 
Check the appropriate response: 
TRUE 
FALSE 
1) If a study participant becomes pregnant while participating in this 
study, she will be taken off the study drug. 
 
 
2) Oxytocin nasal spray has already been approved by the Food and 
Drug Administration (FDA) as a treatment for alcohol use disorder. 
 
 
3) You are expected to give truthful answers about your alcohol use. 
 
 
4) You will be told whether you are receiving oxytocin nasal spray or 
placebo. 
 
 
5) You will have to give blood and urine samples during the study. 
 
 
6) The study staff may end your participation in this study if they feel 
that it is in your best interest. 
 
 
7) You will be compensated for your time and travel. 
 
 
8) You must bring your spray bottle to every visit. 
 
 
9) You will never be contacted by telephone during the study. 
 
 
10) You must inform the study staff of starting any new medications 
that you take during the study. 
 
 
11) The research data I provide in this study may be made available to 
the general research community but will be de-identified so that 
any personally identifiable data will be removed. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
The correct answers to the questions above have been discussed with me. 
 
 
 
Participant Signature 
 
 


National Institute on Alcohol Abuse and Alcoholism (NIAAA) / Protocol Number NCIG-007R 
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«PiFullName» 
Advarra IRB Approved Version 10 Mar 2022 
Revised «PIApprovalDate» 
 
AUTHORIZATION TO USE AND DISCLOSE PROTECTED HEALTH INFORMATION 
 
If you decide to be in this study, the study doctor and study staff will use and 
share health data about you to conduct the study. Health data may include: 
• Your name. 
• Address. 
• Phone number. 
• Date of birth. 
• Valid form of ID. 
• Information from brief psychiatric examination. 
• Emergency contact information 
• Initial telephone screening information 
• Allergies. 
• Information from Physical Exam 
• ECG results 
• Blood Alcohol Results 
• Urine Drug Screen Results 
• Pregnancy Test results if you are female 
• Clinical Laboratory test results 
• Healthcare, drinking, mood, sleep, and questionnaires/forms 
• Medical history. 
• Information from your study visits, including all test results.  
 
Health data may come from your study records or from existing records kept by 
your doctor or other health care workers.  
 
For this study, the study staff may share health data about you with authorized 
users. Authorized users may include: 
• Representatives of NIAAA. 
• Representatives of Fast-Track Drugs and Biologics, LLC. 
• Representatives of Advarra IRB (an Institutional Review Board that reviews 
this study). 
• The Food and Drug Administration (FDA) and other US federal and state 
agencies. 
• Government agencies to whom certain diseases (like HIV, hepatitis, and 
STDs) must be reported. 
• Governmental agencies of other countries. 


National Institute on Alcohol Abuse and Alcoholism (NIAAA) / Protocol Number NCIG-007R 
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«PiFullName» 
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Revised «PIApprovalDate» 
 
• Outside individuals and companies, such as laboratories and data storage 
companies, that work with the researchers and sponsor and need to access 
your information to conduct this study. 
• Other research doctors and medical centers participating in this study.  
• A data safety monitoring board which oversees this study. 
 
Once your health data has been shared with authorized users, it may no longer be 
protected by federal privacy law and could possibly be used or disclosed in ways 
other than those listed here.  
 
Your permission to use and share health data about you has no time limit.  
 
You may revoke (take back) your permission to use and share health data about 
you at any time by writing to the study doctor at the address listed on the first 
page of this form. If you do this, you will not be able to stay in this study. No new 
health data that identifies you will be gathered after your written request is 
received. However, health data about you that has already been gathered may 
still be used and given to others as described in this form.  
 
Your right to access your health data in the study records will be suspended 
during the study to keep from changing the study results. When the study is over, 
you can access your study health data. 
 
If you decide not to sign and date this form, you will not be able to take part in 
the study. 
 
 
 


National Institute on Alcohol Abuse and Alcoholism (NIAAA) / Protocol Number NCIG-007R 
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«PiFullName» 
Advarra IRB Approved Version 10 Mar 2022 
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STATEMENT OF AUTHORIZATION 
I have read this form and its contents were explained. My questions have been 
answered. I voluntarily agree to allow study staff to collect, use and share my 
health data as specified in this form. I will receive a signed and dated copy of this 
form for my records. I am not giving up any of my legal rights by signing and 
dating this form.  
 
__________________________________ 
Printed Name of Participant 
 
 
__________________________________ 
 
 
__________ 
Signature of Participant  
 
 
 
 
Date 
 
 
 

Prot_000.pdf: 
Oxytocin for Alcohol Use Disorder 
NCIG, NIAAA, NIH 
Protocol Number: NCIG-007R 
Version 4.0 (5Jul2022) 
1 
NIAAA Confidential 
 
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 
NCIG, NIAAA, NIH 
Protocol Number: NCIG-007R 
Version 4.0 (5Jul2022) 
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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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NCIG, NIAAA, NIH 
Protocol Number: NCIG-007R 
Version 4.0 (5Jul2022) 
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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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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 


Oxytocin for Alcohol Use Disorder 
NCIG, NIAAA, NIH 
Protocol Number: NCIG-007R 
Version 4.0 (5Jul2022) 
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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 
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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 
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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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17. 
References 
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Anagnostou E, Soorya L, Chaplin W et al. Intranasal oxytocin versus placebo in the treatment of 
adults with autism spectrum disorders: a randomized controlled trial. Mol Autism 2012;3:16. 
Ansseau M, Legrus JJ, Mormont C, Cerfontaine JL, Papart P, Geenen V, Adam F, Franck G. 
Intranasal oxytocin in obsessive-compulsive disorder. Psychoneuroendocrinology. 1987;12:231-
236. 
Aubin HJ, Reimer J, Nutt DJ, Bladstrom A, Torup L, Francois C, Chick J. Clinical relevance of 
as-needed treatment with nalmefene in alcohol dependent patients. Eur Addict Res. 2015;21:160-
68. 
Bahi A. The oxytocin receptor impairs ethanol reward in mice. Physiol Behav. 2015:139:321-7.  
Baskerville TA, Douglas AJ. Dopamine and oxytocin interactions underlying behaviors: 
potential contributions to behavioral disorders. CNS Neurosci Ther. 2010;16:e92–e123. 
Boschloo L, Vogelzangs N, Licht CM, Vreeburg SA, Smit JH, van den Brink W, et al. Heavy 
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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 

SAP_001.pdf: 
STATISTICAL ANALYSIS PLAN 
PROTOCOL NO: NCIG-007R 
Randomized, Double Blind, Placebo-Controlled Trial of the Efficacy of 
Intranasal Oxytocin for the Treatment of Alcohol Use Disorder 
Protocol Version No.: 4.0 Version Date: 5 July 2022 
Study Sponsor: 
National Institute on Alcohol Abuse and Alcoholism 
Plan Authors: 
Charles B. Scott, Ph.D.  
Director of Biostatistics 
Janet H. Ransom, Ph.D. 
President 
Fast-Track Drugs & Biologics, LLC 
20010 Fisher Ave, Suite G 
Poolesville, MD 20837 
Daniel E. Falk, Ph.D. 
Director of Biostatistics  
Medications Development Branch 
Division of Treatment Research 
National Institute on Alcohol Abuse and Alcoholism 
National Institutes of Health 
6700B Rockledge Dr., Rm 1324 
Bethesda MD 20892 
Version Number 1.0 
Date: 7 September 2023 


Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
2 
STATISTICAL ANALYSIS PLAN 
PROTOCOL NO: NCIG-007R 
Randomized, Double Blind, Placebo-Controlled Trial of the Efficacy of Intranasal 
Oxytocin for the Treatment of Alcohol Use Disorder 
Prepared by: ________________________________ 
Date: _______________ 
Charles Scott, Ph.D. 
Director of Biostatistics 
Fast-Track Drugs & Biologics, LLC 
Reviewed by: _______________________________ 
Date: _______________ 
Janet H. Ransom, Ph.D. 
President 
Fast-Track Drugs & Biologics, LLC 
Approved by:________________________________  
Date: _______________ 
Daniel Falk, Ph.D. 
Director of Biostatistics 
Division of Treatment Research 
National Institute on Alcohol Abuse and Alcoholism 


Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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2. 
INTRODUCTION ________________________________________________________ 6 
3. 
PROTOCOL SUMMARY __________________________________________________ 7 
3.1 
Study Objectives ___________________________________________________________ 7 
3.1.1 
Primary __________________________________________________________________________ 7 
3.1.2 
Secondary ________________________________________________________________________ 7 
3.2 
Study Design _______________________________________________________________ 7 
3.3 
Study Endpoints ___________________________________________________________ 11 
3.3.1 
Primary Efficacy Endpoint __________________________________________________________ 11 
3.3.2 
Secondary Efficacy Endpoints _______________________________________________________ 11 
3.3.3 
Exploratory Efficacy Endpoint _______________________________________________________ 12 
3.3.4 
Safety Endpoints __________________________________________________________________ 12 
3.3.5 
Compliance ______________________________________________________________________ 12 
4.0 
DEFINITION OF ANALYSIS SETS ______________________________________ 12 
5.0 
ASSESSMENT AND JUSTIFICATION OF STUDY ENDPOINTS _____________ 13 
5.1 
Alcohol Consumption Endpoints _____________________________________________ 13 
5.1.1 
Daily Quantity of Alcohol Consumption _______________________________________________ 13 
5.1.2 
Drinking Days ____________________________________________________________________ 13 
5.1.3 
Heavy Drinking Day _______________________________________________________________ 14 
5.1.4 
Days at Risk _____________________________________________________________________ 14 
5.1.5 
Weekly Percentage of Heavy Drinking Days and Weekly Percentage of Days Abstinent ________ 14 
5.1.6 
Percentage of Subjects with No Heavy Drinking Days and the Percentage of Subjects Abstinent from 
Alcohol 14 
5.1.7  
Weekly Mean Number of Drinks and Weekly Mean Number of Drinks per Drinking Day _______ 14 
5.1.8 
World Health Organization Drinking Risk Categorical Scale _______________________________ 15 
5.2 
Alcohol Use Disorder (MINI Version 7 – DSM5) ________________________________ 15 
5.3 
Barrett Impulsiveness Scale _________________________________________________ 15 
5.4 
Smoking and Cigarettes Smoked per Week ____________________________________ 16 
5.5 
Nicotine use and Days of Other Nicotine Use per Week __________________________ 16 
5.6 
Experiences in Close Relationships – Relationship Structures Questionnaire (ECR-RS) 16 
5.7 
Hyperkatifeia _____________________________________________________________ 16 
5.8 
Inventory of Drinking Situations (IDS-30) _____________________________________ 16 
5.9 
PROMIS Questionnaires ___________________________________________________ 17 
5.9.1 
PROMIS – Alcohol-related Negative Consequences _____________________________________ 17 
5.9.2 
PROMIS – Sleep Disturbances ______________________________________________________ 17 
5.9.3 
PROMIS – Pain Interference ________________________________________________________ 17 
5.10 
Profile of Mood States (POMS) ______________________________________________ 18 
5.11 
Urge to Drink Scale (UDS) __________________________________________________ 18 
6.0 
HYPOTHESES TO BE TESTED _________________________________________ 18 
6.1 
Primary Efficacy Endpoint __________________________________________________ 18 
6.2 
Secondary Efficacy Endpoints _______________________________________________ 18 


Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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7.0 
SAMPLE SIZE CONSIDERATIONS______________________________________ 19 
8.0 
DATA QUALITY ASSURANCE __________________________________________ 19 
9.0 
STATISTICAL CONSIDERATIONS ______________________________________ 20 
9.1 
General Considerations _____________________________________________________ 20 
9.2 
Participant Accountability and Protocol Deviations _____________________________ 20 
9.3 
Demographics and Other Baseline Characteristics ______________________________ 20 
9.4 
Efficacy Analysis __________________________________________________________ 21 
9.4.1 
Primary Analysis of Primary Efficacy Endpoint _________________________________________ 21 
9.4.2 
Analysis of Secondary Endpoints _____________________________________________________ 22 
9.4.2.1 
Secondary Drinking Endpoints ____________________________________________________ 23 
9.4.2.2 
Alcohol Use and Craving Endpoints ________________________________________________ 23 
9.4.2.3 
Psychosocial Endpoints __________________________________________________________ 23 
9.4.2.4 
Nicotine-Related Endpoints _______________________________________________________ 23 
9.4.3 
Covariate Adjustment for the Analysis of Endpoints _____________________________________ 24 
9.5 
Handling of Missing Data ___________________________________________________ 25 
9.5.1 
Missing Data for Continuous Endpoints _______________________________________________ 25 
9.6 
Safety Analysis ____________________________________________________________ 25 
9.6.1 
Adverse Events ___________________________________________________________________ 25 
9.6.2 
Clinical Laboratory and Point of Care Tests ____________________________________________ 26 
9.6.3 
Vital Signs, Weight, and ECG _______________________________________________________ 26 
9.6.5 
CIWA-AR Scores _________________________________________________________________ 26 
9.6.6 
Buss-Perry Aggression Questionnaire (BPAQ) __________________________________________ 27 
9.6.7 
Simplified Nutritional Appetite Questionnaire (SNAQ) ___________________________________ 27 
9.6.8 
University of Pennsylvania Smell Identification Test (UPSIT) _____________________________ 27 
9.7 
Drug Exposure and Retention _______________________________________________ 27 
9.8 
Analysis of Other Services Used ______________________________________________ 28 
9.9 
Concomitant Medications, Medical History, and Pregnancy Tests _________________ 28 
9.10 
Eligibility and Screen Failures _______________________________________________ 28 
9.11 
Exploratory Analyses ______________________________________________________ 28 
9.12 
Ad hoc Analyses ___________________________________________________________ 29 
10. 
VALIDATION OF PROGRAMMING CODE _______________________________ 29 
11.0 
REFERENCES _______________________________________________________ 29 
12.0 
TABLE, LISTING, AND FIGURE SHELLS ________________________________ 32 
 
 
 
 
 


Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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1. ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse event 
AICc 
Akaike Information Criterion corrected for finite samples 
AUC 
Area under the concentration time curve 
AUD 
Alcohol Use Disorder 
BAC 
Blood alcohol concentration 
BID 
Twice daily 
BIS 
Barratt Impulsiveness Scale 
BPAQ 
Buss-Perry Aggression Questionnaire 
CFR 
Code of Federal Regulations 
CI 
Confidence interval 
CIWA-AR 
Clinical Institute Withdrawal Assessment for Alcohol-revised 
CrCl 
Creatinine clearance 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CTCAE 
Common terminology criteria for adverse events 
dL 
Deciliter 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders – Fifth Edition 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDMS 
Electronic Data Management System 
EOS 
End of study 
F 
Fahrenheit 
FA 
Full Analysis 
FDA 
Food and Drug Administration 
g 
Gram 
GCP 
Good Clinical Practice 
GGT 
Gamma-glutamyl transferase 
hr 
Hour 
ICH 
International Conference on Harmonization 
IDS 
Inventory of Drinking Situations 
IRB 
Institutional Review Board 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
μg 
Microgram 
min 
Minutes 
MINI 
MINI Neuropsychiatric Interview 
mL 
Milliliter 
Mm 
Millimeter 
NHDD 
No heavy drinking days 


Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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Abbreviation 
Definition 
NIAAA 
National Institutes on Alcohol Abuse and Alcoholism 
Oz 
Ounce 
POMS 
Profile of Mood State 
PSNHDD 
Percentage of subjects with no heavy drinking days 
PT 
Preferred term 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
SDU 
Standard drinking unit 
SNAQ 
Simplified Nutritional Appetite Questionnaire  
SOC 
System Organ Class 
STAI 
Spielberger Trait Anxiety Inventory 
THC 
Tetrahydrocannabinol 
TLFB 
Timeline followback  
ULN 
Upper limit of normal 
WHO 
World Health Organization 
 
2. INTRODUCTION 
This statistical analysis plan (SAP) for Protocol No. NCIG-007R, “Randomized, Double Blind, 
Placebo-Controlled Trial of the Efficacy of Intranasal Oxytocin for the Treatment of Alcohol 
Use Disorder” describes and expands upon the analytical plan presented in the protocol.  
This document contains all planned analyses, reasons and justifications for these analyses for all 
study data. This plan also includes sample tables, figures, and listings that will be populated. The 
SAP will follow the International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) Guidelines as indicated in Topic E3 
(Structure and Content of Clinical Study Reports), Topic E8 (General Considerations for Clinical 
Trials) and Topic E9 (Statistical Principles for Clinical Trials). The structure and content of the 
SAP provides sufficient detail to meet the requirements identified by the Food and Drug 
Administration (FDA) and ICH. 
The following sources were used in preparation of this SAP: 
• Protocol # NCIG-007R, Protocol Version No.: 4.0; Version Date: 05Jul2022 
• ICH Guidance Topics E9, E3 and E8 


Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
7 
 
3. PROTOCOL SUMMARY 
3.1 
Study Objectives 
3.1.1 
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. 
 
3.1.2 
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 alcohol craving, alcohol-related 
consequences, cigarette smoking and other nicotine use, psychological assessments, retention in 
the study, and safety and tolerability throughout the study. 
3.2 
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/ 
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 at Weeks 2, 3, 4, 6, 
8, 10, and 13. During the alternate weeks when subjects will not be coming into the clinic 
(Weeks 5, 7, 9, 11, and 12), subjects will be contacted once during that week by telephone 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 2 or more at least possibly related SAEs as judged by the 
investigator or medical monitor occur. If this occurs, a DSMB meeting will be convened and a 
decision, in conjunction with the study Sponsor, will be made regarding stopping the study. 
 
The overall study schema is provided in Figure 1. The study schedule of visits and assessments is 
shown in Table 1. 


Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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Figure 1.  Overview of Study Design 
 
 
 
 


Oxytocin for Alcohol Use Disorder 
NCIG, NIAAA, NIH 
Protocol Number: NCIG-007R 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
9 
 
Table 1.  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 
Subject Reported Outcomes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Oxytocin for Alcohol Use Disorder 
NCIG, NIAAA, NIH 
Protocol Number: NCIG-007R 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
10 
 
 
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 
 
Hyperkatifeia 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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3.3 
Study Endpoints 
3.3.1 Primary Efficacy Endpoint 
 
The primary efficacy endpoint is the weekly percentage of heavy drinking days during the 10 
week maintenance period (study weeks 3-12). A “heavy drinking day” is 4 or more drinks per 
drinking day for women and 5 or more drinks per drinking day for men. 
3.3.2 Secondary Efficacy Endpoints 
Secondary endpoints that will be analyzed during the 10-week maintenance period (study weeks 
3-12)include:  
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.  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: 
− 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 symptoms at end of study  
9. Cigarettes smoked per week among smokers 
10. Abstinence from cigarette smoking  
11. Days used other nicotine products per week 
12. Abstinence from nicotine use 
13. Experiences in Close Relationships—Relationship Structures Questionnaire (ECR-RS) 
(attachment related anxiety) 
14. PROMIS – alcohol-related negative consequences 
15. PROMIS – sleep disturbances 
16. PROMIS – pain interference 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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17. Profile of Moods States (POMS) (including subscales) 
18. Urge to Drink Scale (UDS)  
3.3.3 Exploratory Efficacy Endpoint 
Hyperkatifeia Scale score at end of study 
3.3.4 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 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) results 
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 SNAQ scores ≤14. 
12. Buss-Perry Aggression scores (BPAQ) 
3.3.5 Compliance 
 
Compliance will be assessed using the Subject Diary and by weighing the used study drug vials 
prior to and after use to calculate the amount dispensed. 
4.0 
DEFINITION OF ANALYSIS SETS 
The study analysis populations will consist of the following: 
Full Analysis (FA) 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. 


 
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5.0 
ASSESSMENT AND JUSTIFICATION OF STUDY ENDPOINTS 
5.1 
Alcohol Consumption Endpoints 
5.1.1 Daily Quantity of Alcohol Consumption 
 
Drinking will be assessed using the TLFB methodology (Sobell et al., 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 et al., 1988; Sobell et al., 1996). 
 
After consent is signed, the TLFB interview will be performed for the 28-day period prior to 
signing consent. Thereafter, the interview will be for the previous days between the last 
assessment and the day prior to the day of the assessment. 
 
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. 
5.1.2 Drinking Days 
A drinking day is one calendar day 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. 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). Standard drink unit 
definitions are provided in Table 2. 
Table 2: 
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 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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• 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 
 
5.1.3 Heavy Drinking Day 
A heavy drinking day is defined as a day with 5 or more drinks (SDUs) for males and 4 or more 
drinks (SDUs) for females.  
5.1.4 Days at Risk 
If a subject is being treated at an inpatient facility, is incarcerated, or otherwise under 
confinement, each day spent in under these conditions is considered a reduction in the days at 
risk for drinking and is deducted from the denominator in calculations of rates of drinking days. 
5.1.5 Weekly Percentage of Heavy Drinking Days and Weekly Percentage of Days 
Abstinent 
Weekly percentage of heavy drinking days is the number of heavy drinking days in a 7-day 
period divided by 7 then multiplied by 100. The TLFB permits capturing data in a subsequent 
visit if a visit is missed; however, if fewer than 7 days are observed, then the denominator is the 
number of days observed in the 7-day period. At least 3 days in a week must be observed; 
otherwise, the week is considered missing. 
Weekly percentage of days abstinent is similarly calculated by using the number of days 
abstinent instead of the number of heavy drinking days. 
5.1.6 Percentage of Subjects with No Heavy Drinking Days and the Percentage of 
Subjects Abstinent from Alcohol 
The percentage of subjects with no heavy drinking days is the number of subjects that have no 
heavy drinking days during the period of interest divided by the number of subjects with at least 
one day of non-missing drinking data during the period of interest, multiplied by 100.  
The percentage of subjects abstinent from alcohol is calculated similarly, except the numerator is 
the number of subjects that have no drinking days during the period of interest. 
5.1.7  Weekly Mean Number of Drinks and Weekly Mean Number of Drinks per Drinking 
Day 
Weekly mean number of drinks is the sum of SDUs calculated to the tenths over 7 calendar days 
divided by the number of days with non-missing data. The quotient is multiplied by 7. At least 3 
days in a week must be observed; otherwise, the week is considered missing.  
Weekly mean number of drinks per drinking days utilizes the same numerator, and the 
denominator is the number of days with greater than 0 SDUs. Weeks where all days within the 
week are abstinent are assigned a value of 0 for weekly drinks per drinking day.  


 
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5.1.8 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 et al, 
2015). Two dichotomous endpoints will be analyzed: WHO 1-level and WHO 2-level decrease 
in alcohol consumption. The WHO 1-level and 2-level decrease endpoints are the percentage of 
subjects experiencing at least a 1-level or 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 period of interest. 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 (WHO2000). In computing the alcohol consumption level, average drinks 
per day will be used, computed as the sum of all drinking 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. A subject must have at least 1 week of data during a 
month to be considered non-missing. 
5.2 
Alcohol Use Disorder (MINI Version 7 – DSM5) 
The AUD module of the MINI Neuropsychiatric Interview (MINI) specifies the severity of AUD 
into 3 categories based on the total number of symptoms to which the subject is coded “Yes” as 
follows: 
 
Mild = 2 to 3 symptoms 
Moderate = 4 to 5 symptoms 
Severe = 6 or more symptoms 
Subjects must have at least 4 symptoms to be eligible to participate in the study. The total 
number of symptoms being scored is 11. No imputation for missing values will be used. 
 
5.3 
Barrett Impulsiveness Scale 
 
The Barratt Impulsiveness Scale (BIS) 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. Separate subscale scores for Self-Control and Impulsive behavior will also be calculated. 
The BIS is among the baseline assessments that are performed only at Week 1. 
 


 
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5.4 
Smoking and Cigarettes Smoked per Week 
A quantity frequency interview at baseline and during treatment will include two questions to 
assess cigarette smoking behavior: 1) Over the past week, on how many days did you smoke 
cigarettes?; and 2) On the days you smoked during the past week, how many cigarettes did you 
smoke on average? At baseline subjects that answer “0” to question #1 are considered non-
smokers for the study. Cigarettes per week is the answer to question #2 multiplied by the answer 
to question #1. No imputation for missing values will be used. 
5.5 
Nicotine use and Days of Other Nicotine Use per Week 
The cigarette smoking questionnaire will include a third question: 3) Over the past week, on how 
many days did you use other nicotine products (ex. chew, cigars, cigarillos, e-cigarettes, vape, 
gum, patch, etc...). A subject is positive for any nicotine use if the number of smoking days or 
the number of any other nicotine use days is greater than zero.  
5.6 
Experiences in Close Relationships – Relationship Structures Questionnaire 
(ECR-RS) 
 
The Experiences in Close Relationships-Relationship Structures scale (Farley et al, 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 
only the first 18-item attachment-related anxiety scale will be assessed and evaluated. The 
presentation of the items were 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. However, items 9 and 11 are 
“reverse keyed”.  
 
5.7 
Hyperkatifeia 
 
Hyperkatifeia is defined as a greater intensity of negative emotional/motivational signs and 
symptoms during withdrawal from drugs of abuse in the withdrawal/negative affect stage of the 
addiction cycle (Koob 2021).  Hyperkatifeia or negative emotional state is considered to be one 
of stages of addiction in the context of drug withdrawal (Koob and Le Moal 1997, Koob 2019). 
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 anxiety, depression, stress, irritability and 
pain. Each item is is 5-point Likert scale assessing the intensity of the feelings and sensations 
experienced when not drinking alcohol. Higher scores are indicative of greater intensity of 
hyperkatifeia. 
  
5.8 
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 (Mann et al, 2018). Fifteen items measure reward drinking 


 
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tendencies and 15 items measure relief drinking tendencies.  A subsequent evaluation of IDS-30 
refined the definition of reward drinking to five items and relief drinking to five items (Votaw et 
al, 2022) 
 
The reward drinking score is determined by summing the scores for these items: 6, 18, 21, 23, 
27. 
 
The relief drinking score is determined bu summing the scores for these items: 9, 14, 15, 22, 25 
 
Missing data is not imputed. All five questions within each scale must be answered for a score to 
be computed; otherwise, the scale is missing. 
 
5.9 
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 (https://www.healthmeasures.net/explore-measurement-systems/promis). Three of these 
assessments, described below, will be utilized in this study.  
5.9.1 PROMIS – Alcohol-related Negative Consequences 
 
For negative consequences for alcohol use, the PROMIS Alcohol Negative Consequences – 
Short Form 7a questionnaire will be used to assess outcomes of alcohol use over the past 30 
days. Each of the 7-items assesses the frequency of the negative alcohol-related consequence on 
5-point Likert scale with higher scores indicating greater frequency.  The scoring manual will be 
used to compute T-scores for each evaluation. All 7 questions must be answered for the form to 
be considered non-missing. 
5.9.2 PROMIS – Sleep Disturbances 
 
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 [<55], mild [55.0 – 59.9], moderate 
[60 – 69.9] or severe [70 or higher] based on the T-score derived from a conversion table) {add 
reference to APA website|. At least 5 questions must be answered to be considered non-missing. 
5.9.3 PROMIS – Pain Interference 
 
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 the degree to which pain interferes with various activities. 
Each item on the measure is rated on a 5-point scale with higher scores indicating greater pain 


 
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interference. The scale ranges from 8 to 40. The scoring manual will be used to compute T-
scores for each evaluation. At least 5 questions must be answered to be considered non-missing. 
5.10 Profile of Mood States (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 
(0)” to “extremely (5).” 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 Tension-Anxiety, Depression-Dejection, Anger-Hostility, Fatigue-Inertia, and 
Confusion-Bewilderment scores then subtracting the Vigor-Activity subscale score. A missing 
value within a subscale will be replaced by the average score of the answered items within the 
subscale; if 2 or more items within a subscale are missing then the entire subscale will be 
considered missing. 
 
5.11 Urge to Drink Scale (UDS) 
The UDS 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. This measure has been 
shown to be a valid and reliable instrument for assessing an individual’s urge to drink alcohol. 
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. 
Total scores of 10 or higher during treatment have been reported to be associated with increased 
risk for relapse. Missing values will not be imputed. 
6.0 
HYPOTHESES TO BE TESTED 
6.1 
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 period (study weeks 3-12). This hypothesis 
will be tested using other time periods during treatment. 
6.2 
Secondary Efficacy Endpoints 
Over the 10-week maintenance period (study weeks 3-12), 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: 
a.  1-level 
b.  2-levels  
4. Increase the percentage of days abstinent per week 


 
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5. Decease the weekly mean number of drinks per week  
6. Decrease the weekly mean drinks per drinking day 
7. Decrease the number of MINI AUD symptoms 
8. Decrease the cigarettes smoked per week among smokers 
9. Increase the smoking abstinence rate among smokers 
10. Decrease the weekly number of days of other nicotine use among other nicotine users 
11. Increase the nicotine use abstinence rate among nicotine users (includes cigarettes) 
12. Decrease in attachment related anxiety scores of the ECR-RS (attachment related 
anxiety) 
13. Decrease in PROMIS sleep disturbance, alcohol-related negative consequences, and pain 
interference scores 
14. Decrease in POMS subscales total mood disturbance, anger-hostility, fatigue-inertia, 
confusion-bewilderment, tension-anxiety and depression scores and/or increase vigor-
activity 
15. Decrease in the Urge to Drink scale scores 
7.0 
SAMPLE SIZE CONSIDERATIONS 
 
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. 
8.0 
DATA QUALITY ASSURANCE 
 
Data quality assurance will start with training of clinical investigative staff on data collection and 
assessment procedures including a Manual of Operations that describes what data to collect and 
procedures for completion of electronic case report form (eCRFs.) Completed eCRFs will be 
reviewed by Fast-Track Drugs and Biologics clinical monitors on a regular basis throughout the 
trial by comparison against the source documents. 
All study data will come from the eCRFs and no other source data. eCRFs for this study were 
created using an electronic data management system (EDMS) based on Merge eClinicalOS. 
eCRFs were created using an established data dictionary for each variable including the field 
name, field type, field attributes, and coding for variables. Range checks, alpha-numeric 
requirements, and null/not null parameters were programmed as applicable. The back end 
database application is Oracle. Data entered into the EDMS system will be reviewed by Fast-
Track clinical monitors and data managers. If incomplete or inaccurate data are found, the data 
will be queried in the system for site staff to address. The site will resolve data inconsistencies 
and errors using the EDMS with full audit trail of corrections being maintained within the 


 
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system. Corrections and changes to the data will be reviewed by Fast-Track clinical monitors and 
data managers.  
Additional edit checks will be written to detect anomalies in the database. These checks will 
address inconsistencies (within visits, across visits), invalid/unusual values, missing values, and 
protocol violations. Edit checking will be validated on test data or actual clinical trial data. In 
addition to programmed edit checks, quality control examination of data will also be performed 
on reviews of data listings. 
9.0 
STATISTICAL CONSIDERATIONS 
9.1 
General Considerations 
 
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. 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 using either a square root, logarithmic, or inverse 
transformation, the selection of which is determined by skewness and kurtosis statistics with 
values closest to zero and normalization of histograms. Cohen’s d will be used to calculate the 
effect size for means. Odds ratios will be provided for all dichotomous outcomes. 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. All analyses will be performed in the full analysis set. 
9.2 
Participant Accountability and Protocol Deviations 
 
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. Protocol deviations will be presented as summaries by type of deviation. 
9.3 
Demographics and Other Baseline Characteristics 
Summaries of the characteristics of the subjects in each of the study groups at baseline will be 
prepared for the full analysis set. Demographic characteristics (e.g., age, gender, race, and 
ethnicity) and other baseline characteristics including Barratt Impulsiveness scale (BIS), mood 
scales (e.g., Spielberger Trait Anxiety Inventory (STAI), Buss-Perry Aggression Questionnaire 
(BPAQ), POMS total and subscale scores), hyperkatifeia questionnaire, ECR-RS, Simplified 
Nutritional Appetite Questionnaire (SNAQ), PROMIS scales for alcohol negative consequences, 
sleep disturbances, and pain interference, University of Pennsylvania Smell Identification Test 
(UPSIT), and drinking goal) will be summarized by treatment group.  
Baseline drinking parameters in the 28-days prior to the start of screening, age started drinking 
regularly, medical treatments for drinking in the past year, and other services used for alcohol 
problems in the past 4 weeks prior to consent will be summarized by treatment group. The 


 
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number and percentage of subjects with mild, moderate and severe symptoms of AUD and 
summary statistics for total number of symptoms will also be presented. 
The numbers and percentages of subjects who are smokers, used any nictonine, used any other 
nicotine products, and any THC will be presented. The quantity of cigarettes smoked per week 
will be presented among smokers, and the number of days of other nicotine products used per 
week will be presented among subjects with any other nicotine product use. 
Baseline drinking-associated consequences (CIWA-AR), alcohol craving (Urge to Drink Scale) 
total score, and Inventory of Drinking Situations (IDS) subscales of reward drinking and relief 
drinking will be summarized in a table.   
Continuous variables will be summarized using means, standard deviations, medians, min, and 
max values. Categorical variables will be summarized using counts and percentages. 
The comparability among the treatment groups with respect to the demographic and baseline 
variables will be evaluated by appropriate statistical methods. These will include t-tests for 
continuous variables, chi-square tests for categorical variables, and Fisher’s exact test for binary 
variables. If a continuous variable is skewed, then the Wilcoxon rank sum test will be used on 
the raw data or a t-test on an appropriately transformed variable. 
9.4 
Efficacy Analysis 
9.4.1 Primary Analysis of Primary Efficacy Endpoint 
 
The primary efficacy endpoint is the weekly percentage of heavy drinking days during the 10-
week maintenance period (study weeks 3-12). The primary analysis of the primary endpoint will 
be a fully covaried, mixed-effect model for repeated measures employed on the Full Analysis Set 
(using an appropriate transformation of the endpoint, if needed; see Section 9.1). 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. The analyses 
will be performed using SAS PROC MIXED procedure Subjects are treated as a class variable 
and not continuous. The week, treatment group, and clinical site are also treated as class 
variables. Additional covariates may be selected using the method described in Section 9.4.3.The 
solution statement from SAS PROC MIXED is requested to provide the solution for the fixed 
effects parameters. A REPEATED statement specifies that values are repeated each week and 
subjects are nested within treatment group. The covariance structure is specified.  
 
The selection of the covariance structure is performed using a simple repeated mixed effects 
model that includes treatment group as the only fixed effect and subject nested within treatment 
group as the only random effect. The covariance structure is selected from autoregressive, 
compound symmetry, Toeplitz, and unstructured. The Akaike Information Criterion (AICc) 
corrected for a finite sample is obtained from each of the four models for the four possible 
covariance structures to determine model fit. The smallest (minimum) AICc associated with one 
of the covariance structures is selected and the difference for each of the other three covariance 
structures is calculated. A graph is produced of the model fit statistics and relative difference for 
the four possible covariance structures.  
 


 
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If the primary endpoint requires a transformation, another mixed effect model that is identical to 
the primary analysis model will be run using the untransformed endpoint. Results based on the 
primary analysis model and the model of the untransformed endpoint will be presented in tabular 
form. The overall least squares means and least square means for each time point along with the 
95% confidence intervals (CI) will be presented for the untransformed endpoint only (for 
descriptive purposes), while two-tailed p-values and Cohen’s d will be presented for both the 
untransformed and transformed data. Inference and Cohen’s d will be based upon the results 
using appropriately transformed data. A graph of the primary endpoint will be produced using 
the LSMEANs from the untransformed endpoint with p-values and Cohen’s d comparing weekly 
differences obtained from the appropriately transformed variable. 
Descriptive statistics will be reported for all study weeks (1-12) by treatment group.  
9.4.2 Analysis of Secondary Endpoints 
Continuous secondary efficacy endpoints with repeated measures will also be analyzed based on 
data collected during the treatment period, including TLFB and other questionnaire data assessed 
at Week 13 that reflect data collected during this period.  
In general, every continuous secondary efficacy endpoint with repeated measures is analyzed 
using a repeated measures mixed effects model as discussed in Section 9.4.1. Results will be 
presented using the same tabular and graphical formats detailed in Section 9.4.1.The primary 
analysis model is: 
 
appropriately transformed endpoint = treatment + week + treatment*week + clinical site + 
baseline equivalent of endpoint + other covariates (identified in Section 9.4.3).  
 
It is anticipated that the covariance structure selected for the primary endpoint will also be used 
for secondary endpoints; however, the selection process detailed in Section 9.4.1 will be 
followed for each continuous secondary endpoint. 
 
The primary analysis model for continuous endpoints measured at one time is a general linear 
model (GLM): appropriately transformed endpoint = treatment + clinical site + baseline 
equivalent of the endpoint + other covariates (identified in Section 9.4.3). 
 
The primary analysis model for dichotomous endpoints is a logistic regression model that 
includes treatment + clinical site + other covariates (identified in Section 9.4.3). If fewer than 5 
events are observed for a dichotomous endpoint then no logistic regression will be performed. In 
this situation Fisher’s exact test will be used to compare treatment groups. 
 
All analyses of secondary endpoints will use the Full Analysis Set.  
 
Descriptive statistics of all secondary endpoints will be reported for all study weeks (1-12) or 
times at which they were measured within the treatment period, by treatment group.  
 
 


 
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9.4.2.1 Secondary Drinking Endpoints 
The continuous endpoints – percentage of days abstinent per week, weekly mean number of 
drinks per week, and weekly mean number of drinks per drinking day – will be analyzed using 
the mixed effects model specified in Section 9.4.2. Covariates for these models will be identified 
as in Section 9.4.3.  
The dichotomous endpoints –percentage of subjects with a WHO 1-level decrease, and WHO 2-
level decrease in alcohol consumption risk category, percentage of subjects with no heavy 
drinking days, and percentage of subjects abstinent from alcohol – will be assessed for the entire 
10-week maintenance period, with 1- and 2-month grace periods, and Month 2 and Month 3. 
These endpoints will be analyzed with the logistic regression model specified in Section 9.4.2. 
Covariates for these models will be identified as in Section 9.4.3.  
 
 
9.4.2.2 Alcohol Use and Craving Endpoints 
 
The MINI AUD module is assessed at screening and Week 13. The number of AUD symptoms 
at Week 13 is a continuous variable and will be modeled using a GLM specified in Section 9.4.2. 
Covariates for these models will be identified as in Section 9.4.3.  
Craving is assessed using the Urge to Drink Scale which is assessed repeatedly during the 
treatment period. The total score will be analyzed using the mixed effect model approach 
detailed in Section 9.4.2. Covariates for this model will be identified as in Section 9.4.3. 
9.4.2.3 Psychosocial Endpoints 
 
The POMS, ECR-RS, and the three PROMIS scales (including negative alcohol-related 
consequences, sleep disturbance, and pain interference) are continuous variables assessed 
repeatedly throughout the treatment period. The POMS includes the overall Total Mood 
Disturbance and other subscales, and each will be individually analyzed. The ECR-RS is a 36-
item questionnaire of which only the first 18-item attachment-related anxiety scale will be 
assessed and analyzed. The three PROMIS scales employed in this study will be transformed 
into T-scores prior to analysis. The POMS, ECR-RS and PROMIS scores will be analyzed using 
the mixed effect model approach detailed in Section 9.4.2. Covariates for these models will be 
identified as in Section 9.4.3. 
9.4.2.4 Nicotine-Related Endpoints  
 
The dichotomous endpoints – abstinence from smoking and abstinence from nicotine use – will 
be analyzed with the logistic regression model described in Section 9.4.2. Covariates for these 
models will be identified as in Section 9.4.3. 
 
The mean number of cigarettes smoked in the past week is a continuous variable measured 
repeatedly during the treatment period. This endpoint will be analyzed only for those subjects 
who smoked at baseline. The data will be analyzed using the mixed effects described in Section 
9.4.2. Covariates for this endpoint will be identified in Section 9.4.3. 
 


 
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The mean numbers of days of other nicotine product use is a continuous variable measured 
repeatedly during the treatment period. This endpoint will be analyzed only for those subjects 
who used other nicotine products at baseline. The data will be analyzed as described in Section 
9.4.2. Covariates for this endpoint will be identified in Section 9.4.3. 
9.4.3 Covariate Adjustment for the Analysis of Endpoints 
Covariates for the continuous efficacy endpoints measured repeatedly include the baseline 
equivalent of the endpoint, clinical site, treatment, time and the treatment by time interaction. 
Covariates for the continuous efficacy endpoints measured at a single time point include the 
baseline equivalent of the endpoint, clinical site, and treatment. Covariates for the dichotomous 
endpoints include treatment and clinical site; however, the number of covariates will depend 
upon the number of events. In general, 10 events per covariate are necessary for a stable logistic 
regression model (Peduzzi et al, 1996). If the number of events permits the inclusion of a 
baseline drinking covariate, the percentage of days abstinent will be used as the covariate for the 
percent subjects abstinent endpoint; the percentage of heavy drinking days will be used as the 
covariate for the percent subjects with no heavy drinking days endpoint; however, no baseline 
drinking covariate will be employed for the endpoint, percent subjects with a WHO decrease in 
alcohol consumption, as this endpoint already adjusts for baseline drinking in its calculation. If 
there are only 5-9 events in one of the dichotomous endpoints then a logistic regression will be 
performed with treatment group as the only covariate. 
 
Clinical site is included as a covariate because it was chosen as a stratification variable to 
account for between site variability in outcome. Prior to conducting the logistic regression, a 
blinded analysis of site by treatment group by dichotomous secondary outcome will be 
performed to determine if every site has an outcome. Clinical sites with fewer than 3 events will 
be combined for the purpose of conducting the logistic regression. The baseline equivalent of the 
endpoint is a strong predictor of the endpoint and will generally be included as a covariate.  
 
Additional covariates for the efficacy endpoints may include baseline characteristics with a 
theoretical and/or empirical basis for a relationship with a particular endpoint. Such 
characteristics may include, but are not limited to, drinking goal, age, and years of regular 
drinking (age minus age first started drinking alcohol regularly). Prior to the unblinding of the 
data, matrices of correlations between these baseline characteristics and each of the secondary 
efficacy endpoints, pooled across blinded treatment assignment, will be produced (using Pearson 
for continuous variables, Spearman for categorical outcomes). Selection of baseline variables to 
include as covariates in the models will be based on consideration of the following criteria: at 
least modest correlation with outcome (i.e., r>0.20), and clinical expertise. Each endpoint may 
have a unique set of covariates. Care is taken to only select a limited number of covariates such 
that the models are not over fitted. 
 


 
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9.5 
Handling of Missing Data 
9.5.1 Missing Data for Continuous Endpoints 
Drinking data is collected in the TLFB. Prior to the subject dropping out of the study, every 
attempt will be made to continue to collect TLFB data.  However, if the subject no longer wishes 
to participate in the collection of the TLFB, but agrees to a shorter drinking assessment using the 
Brief Drinking Questionnaire (BDQ), then,  answers from the BDQ will be used in conjunction 
with the TLFB (if some TLFB data were provided by the subject) or in lieu of the TLFB (if no 
data were provided by the subject) to otherwise avoid missing data for drinking endpoints. 
Specifically, the BDQ has two questions assessing whether the subject had any heavy drinking 
days or drinking days during the period covered and will be used to assess the presence of a 
heavy drinking day or  or a drinking day, respectively, for the drinking endpoints percentage of 
subjects with no heavy drinking days and percentage of subjects abstinent, respectively.  
The primary analysis of the primary endpoint will be performed on available data in the Full 
Analysis Set with no imputation for missing data. However, a sensitivity analysis will be 
performed on the primary endpoint using multiple imputation for missing drinking data 
(Jakobsen et al, 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 multiple 
imputation method will be performed on transformed endpoint data, if a transformation is 
deemed necessary. The data will be evaluated for the pattern of missingness. If the data have 
monotone missingness then the regression method will be used. If the data have non-monotone 
missingness then the Monte Carlo method will be used (Ratitch et al, 2013). 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. The “m” imputed datasets each will be analyzed using 
mixed effects models then SAS PROC MIANALYZE will be used to combine the parameter 
estimates.  
 
No imputation will be done for analysis of secondary endpoints.  
 
 
9.6 
Safety Analysis 
9.6.1 Adverse Events 
 
AEs will be coded using the most recent version of the Medical Dictionary for Regulatory 
Activities (MedDRA) and will be grouped by system, organ, and 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 to IP, outcome, action taken (including any treatment administered), 
and duration will be provided. 
 
Every AE will be assessed for whether or not it qualifies as an SAE. All SAEs will be 
categorized and listed according to the following categories: Congenital Anomaly or Birth 
Defect; Persistent or Significant Disability/Incapacity; Results in Death; Requires or Prolongs 


 
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Hospitalization; Other Medically Important Serious Event; or Life-Threatening. For deaths, the 
date and cause of death will be collected and listed. For hospitalizations, the dates of admission 
and release (discharge) will be collected and listed. 
 
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. Tabulation of suicidal ideation by CSSRS will be 
presented without hypothesis testing; answers to the C-SSRS will be provided in a subject 
listing. 
9.6.2 Clinical Laboratory and Point of Care Tests 
For clinical laboratory data, descriptive statistics will be generated for all tests performed at 
screening and at each clinic visit. If a laboratory analysis is repeated, the last measurement 
performed prior to the clinic visit will be used in the summary statistics for that clinic visit. If an 
unscheduled clinical laboratory visit occurs prior to a scheduled visit that is missed due to 
dropout, then the unscheduled visit will be used in the summary statistics for the missed 
scheduled clinical visit. If an unscheduled clinical laboratory visit occurs between two scheduled 
clinical visits, then the data from the unscheduled visit will only be presented in the listings and 
not in summary statistics. In addition, at each post-randomization clinic visit descriptive statistics 
for change from baseline will be generated. Laboratory values will be plotted as mean ± standard 
error over time. All laboratory measurements will be presented in the listings. 
Number and percentage of positive urine drug tests and pregnancy tests for screening visits and 
all treatment and follow-up visits will be tabulated. Results of all urine drug tests and pregnancy 
tests will be presented in the listings. The percentage of subjects with a positive urine drug test at 
any time post start of treatment will also be presented by test type and treatment group. 
9.6.3 Vital Signs, Weight, and ECG 
Vital signs will be presented as summary statistics and change from baseline. The percentage of 
ECG results considered abnormal and clinically significant will be provided. Body weight will 
be presented as summary statistics and change from screening. No statistical tests will be 
performed. Vital signs, ECG results, and weight measurements for all visits will be presented in 
the listings. 
9.6.4 Blood Alcohol Concentration 
The number and percent of subjects at any clinic visit that have a BAC > 0 will be tabulated. All 
BAC measurements will be presented in the listings. 
9.6.5 CIWA-AR Scores 
 
The number and percentage of subjects who reported CIWA-AR scores ≥ 10 at any time after the 
start of dosing will be presented. Fisher’s exact test will be performed. No modeling or 
imputation will be performed. 


 
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9.6.6 Buss-Perry Aggression Questionnaire (BPAQ) 
 
The short form version of the BPAQ is used in this study and is a 12-item self-report measure 
aggression. Each item is assessed on a 5-point Likert scale assessing the degree to which 
agreesion-related statements are characterisitic of the subject during the past week.  The BPAQ 
includes four subscales: physical aggression (4 items), verbal aggression (3 items), anger (2 
items), and hostility (3 items) (Diamond and Magaletta, 2006). Scores for each subscale, which 
are the sum of the items, will be assessed individually. There is no total score for this scale.  
 
 Because the BPAQ is a repeated continuous measure, the BPAQ subscales wil be analyzed 
using the mixed effects described in Section 9.4.2. Descriptive statistics will be presented for 
each assessment by treatment group. No imputation will be performed. 
9.6.7 Simplified Nutritional Appetite Questionnaire (SNAQ)  
 
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. The number and percentages of subjects in each 
group with a SNAQ score ≤14 at each visit will be summarized. Fisher’s exact test will be used 
at each visit. No imputation for missing data will be performed. A mixed effects analysis on the 
continuous SNAQ score, as described in Section 9.4.2, will be used to evaluate change over time. 
No imputation will be performed. 
 
9.6.8 University of Pennsylvania Smell Identification Test (UPSIT) 
 
The UPSIT will be assessed at screening and other clinic visits throughout the study 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. Outcomes will be captured in Adverse 
Event tables.  
9.7 
Drug Exposure and Retention 
 
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 IU per day of investigational product taken based on the the 
vial weight difference prior to and after dispensment will also be reported overall and weekly 
will be reported for the oxytocin and placebo groups. Exposure and compliance averages will be 
compared across treatment groups using t-tests at each week and overall. If the data are 
meaningfully skewed then the Wilcoxon rank-sum test will be used. The same test will be used 
for each week and overall. The research participation rate, defined as percentage of subjects with 
complete drinking data, will be compared between treatment groups. A Fisher’s Exact test will 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
28 
 
be used for the overall participation rate, weekly tests will not be performed. 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. No statistical inference will be performed 
for reasons of discontinuation. 
9.8 
Analysis of Other Services Used 
 
Weekly days of attendance at self-help meetings or other professional service providers to help 
reduce/quit drinking at study week 13 will be presented as summary statistics by treatment 
group. All other services used data will be presented in the listings. 
9.9 
Concomitant Medications, Medical History, and Pregnancy Tests 
 
Concomitant and prior medications are collected at screening and at all study weeks and will be 
presented in a subject listing, as will pregnancy tests. Medical History will be coded using 
MedDRA, summarized in a table by treatment group and will be presented in subject listings. No 
statistical inference will be performed. 
9.10 Eligibility and Screen Failures 
 
Screen failures will be summarized in a table and provided in subject listings. Answers to 
eligibility criteria will be provided in the subject listings. 
9.11 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. The model identified 
in Section 9.4.1 will be amended to include the potential moderator variable and the moderator 
by treatment group interaction. To aid with interpretation, continuous moderator variables will be 
dichotomized based on clinically accepted levels available from the literature. In the event a 
clinically meaningful cutoff is not available, LOESS curves will be used to identify a cut point. 
The LOESS curve analysis will use averaged PHDD data over study weeks 3-12, treatment 
group and the moderator of interest. In all approaches, an appropriate cutoff will be one that 
ensures a sufficient sample size in all resultant subgroups.  The potential moderator variables are 
assessed at baseline and include: sex, IDS-30 reward/relief drinking, baseline drinks per week, 
measures of anxiety and depression (ECR-RS anxiety-related attachment, POMS subscales of 
depression and anxiety, Spielberger Trait Anxiety Inventory), Barratt Impulsiveness Scale, 
history 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 an efficacy endpoint and 
moderator of drug response. Hyperkatifeia scores are assessed at Week 1 and Week 13 (EOS 
Visit 9). Exploratory analyses utilizing Hyperkatifeia Scale scores will include: 1) using the total 
score and subscales as an endpoints to assess treatment efficacy; and 2) conducting moderator 
analyses using total score and the subscales. The total score and subscales are the sum of the 
items. 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
29 
 
 9.12 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 alcohol-related outcomes; 2) conducting mediator analyses; 3) factor analysis to 
better understand the underlying dimensions of hyperkatifeia; 4) validity of the Hyperkatifeia 
Scale by comparing to other measures (e.g., POMS and PROMIS scales or subscale scores); and 
5) and further evaluation of the scales as endpoints to assess treatment efficacy. 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. 
 
Ad hoc analyses may also be performed on the Drinking Goal questionnaire as a predictor and 
moderator of alcohol-related outcomes. Cutpoints for IDS-30 reward and relief drinkers have 
been proposed for high and low levels of each, creating 4 categories (Votaw et al, 2022). These 
categories will be related to drinking outcomes if there are sufficient sample sizes within each 
category. 
10. 
VALIDATION OF PROGRAMMING CODE 
 
All SAS codes used to generate tables and listings will be validated and reviewed before being 
finalized. The validation process will be used to determine that the numbers are produced by a 
statistically valid method and that the execution of the computations is correct. Qualified 
personnel who have not previously been involved in the production of the original programming 
codes will perform the validation procedures. Methods of validation include independent 
programming and comparison to data listings. Tables will be reviewed for accuracy, consistency 
with this plan, consistency within tables, and consistency with corresponding output. Once 
validation is complete, a quality control reviewer will perform a final review of the documents 
for accuracy and consistency. Upon completion of validation and quality review procedures, all 
documentation will be collected and filed in the study documentation files at Fast-Track. 
11.0 REFERENCES 
 
Aubin HJ, Reimer J, Nutt DJ, Bladstrom A, Torup L, Francois C, Chick J. Clinical relevance of 
as-needed treatment with nalmefene in alcohol dependent patients. Eur Addict Res. 
2015;21:160–68 
Carey KB. Reliability and validity of the time-line follow-back interview among psychiatric 
outpatients: a preliminary report. Psych Addic Behav. 1997;11, 26-33. 
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 
1976;16:31-41. 
Diamond PM, Magaletta PR. The short-form Buss-Perry aggression questionnaire (BPAQ-SF): 
A validation study with federal offenders. Assessment. 2006;13:227-240 


 
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Fraley RC, Heffernan ME, Vicary AM, and Brumbaugh C. The experiences in close 
relationships—relationship structures questionnaire: A method for assessing attachment 
orientations across relationships. Psychological Assessment. 2011;23:615-625. 
Jakobsen JC, Gluud C, Wetterslev J, Winkel P. When and how should multiple imputation be 
used for handling missing data in randomised clinical trials - a practical guide with flowcharts. 
BMC Med Res Methodol. 2017 Dec 6;17(1):162.  
Koob GF, Le Moal M. Drug abuse: hedonic homeostatic dysregulation. Science. 1997. 278:52–
58. 
Koob GF. Neurobiology of opioid addiction: opponent process, hyperkatifeia, and negative 
reinforcement. Biol Psychiatry. 2019;87:44–53. 
Koob GF. Drug Addiction: Hyperkatifeia/negative reinforcement as a framework for 
medications development. Pharmacol Rev. 2021;73:163-201. 
Mann K, Roos CR, Hoffman S, Namovics H, Leménager T, Heinz A, Witkiewitz K. Precision 
medicine in alcohol dependence: A controlled trial testing pharmacotherapy response among 
reward and relief drinking phenotypes. Neuropsychopharmacology. 2018:1-9. 
Morean ME, DeMartini KS, Leeman RF, Pearlson GD, Anticevic A, Krishnan-Sarin S, Krystal 
JH, O’Malley S. Psychometrically improved, abbreviated versions of three classic measures of 
impulsivity and self control. Psych Assess 2014;26:1003-1020.  
McNair DM, Heuchert JWP. Profile of Mood States (POMS) Multi-Health Systems, Tonawanda, 
NY. 2005. 
Peduzzi P, Concato J, Kemper E, Holford TR, Feinstein AR. A simulation study of the number 
of events per variable in logistic regression analysis. J Clin Epidemiol. 1996 Dec;49(12):1373-9.  
Ratitch B, O'Kelly M, Tosiello R. Missing data in clinical trials: from clinical assumptions to 
statistical analysis using pattern mixture models. Pharm Stat. 2013 Nov-Dec;12(6):337-47. 
Sobell LC, Sobell MB. Timeline followback: a technique for assessing self-reported alcohol 
consumption. In Litten, R. Z. and Allen, J.P. (Eds.) Measuring alcohol consumption: 
psychosocial and biochemical methods. Totowa, NJ: Humana Press (pp. 41-72) 1992. 
Sobell LC, Sobell MB, Leo GI, Cancilla A. Reliability of a timeline method: assessing normal 
drinkers' reports of recent drinking and a comparative evaluation across several populations. Br J 
Addict. 1988;83:393-402. 
Sobell LC, Brown J, Leo GI, Sobell MB. The reliability of the Alcohol Timeline Followback 
when administered by telephone and by computer. Drug Alcohol Depend 1996;42:49-54. 
Spielberger, C. D., Gorsuch, R. L., Lushene, R., Vagg, P. R., & Jacobs, G. A. (1983). Manual for 
the State-Trait Anxiety Inventory. Palo Alto, CA: Consulting Psychologists Press. 
Votaw VR, Mann K, Kranzler HR, Roos CR, Nakovics H, Witkiewitz K. Examining a brief 
measure and observed cutoff scores to identify reward and relief drinking profiles: Psychometric 
properties and pharmacotherapy response. Drug Alcohol Depend. 2022 Mar 1;232:109257.  


 
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Wilson M-MG, Thomas DR, Rubenstein LZ, Chibnall JT, Anderson S, Baxi A, Diebold MR, 
Morley JE. Appetite assessment: simple appetite questionnaire predicts weight loss in 
community-dwelling adults and nursing home residents. Am J Clin Nutr 2005;82:1074–81. 
World Health Organization (WHO): International Guide for Monitoring Alcohol Consumption 
and Related Harm. Geneva, WHO, 2000. Available at: 
http://whqlibdoc.who.int/hq/2000/who_msd_msb_00.4.pdf. 
 
 
 
 
 
 
 
 
 
 
 


 
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12.0 TABLE, LISTING, AND FIGURE SHELLS 
 
Table 1: 
Subject Disposition - All Consented Subjects .......................................................... 38 
Table 2: 
Reasons for Screen Failure – All Consented Subjects .............................................. 39 
Table 3: 
Exposure to Investigational Products Based on Subject Diary ................................. 39 
Table 4: 
Percent Compliance to Investigational Products Based on Subject Diary ............... 40 
Table 5:  
Exposure to Investigational Products Based on Weight of Vials ............................. 40 
Table 6: 
Percent Compliance to Investigational Products Based on Weight of Vials ............ 40 
Table 7:  
Summary of Medical History.................................................................................... 40 
Table 8:` 
Exit Interview............................................................................................................ 41 
Table 9: 
 Research Participation by Treatment Group and Week ........................................... 43 
Table 10: 
Number and Percent of Subjects with Drinking Data Provided by the Brief Drinking 
Questionnaire instead of the TLFB ............................................................................................... 44 
Table 11: 
Demographic Characteristics .................................................................................... 45 
Table 12: 
Baseline DSM-5 Disorders ....................................................................................... 48 
Table 13: 
Baseline Drinking-related Behavior and Characteristics .......................................... 49 
Table 14: 
Baseline Drinking by TLFB...................................................................................... 51 
Table 15: 
Baseline Other Substance Use .................................................................................. 53 
Table 16: 
Baseline POMS ......................................................................................................... 54 
Table 17: 
Baseline Alcohol-Related Craving, Consequences, and Withdrawal ....................... 55 
Table 18: 
Baseline Mood Questionnaires ................................................................................. 56 
Table 19: 
Baseline ECR-RS ...................................................................................................... 58 
Table 20: 
Baseline SNAQ ......................................................................................................... 58 
Table 21: 
Baseline PROMIS Subscales .................................................................................... 59 
Table 22: 
Baseline UPSIT ......................................................................................................... 60 
Table 23: 
Weekly Percentage of Heavy Drinking Days from Baseline to Week 12 ................ 62 
Table 24: 
Percentage of Heavy Drinking Days per Week –Mixed Effects , Weeks 3-12, No 
Imputation 62 
Table 25: Percentage of Heavy Drinking Days per Week – Multiple Imputation for Missing 
Values, Mixed Effects, Weeks 3-12 ............................................................................................. 64 
Table 26: 
Drinks per Week from Baseline to Week 12 ............................................................ 66 
Table 27: 
Drinks per Week – Mixed Effects, Weeks 3-12 ....................................................... 66 
Table 28: 
Drinks per Drinking Day from Baseline to Week 12 ............................................... 68 
Table 29: 
Drinks per Drinking Day – Mixed Effects, Weeks 3-12 .......................................... 68 
Table 30: 
Percent Days Abstinent from Baseline to Week 12 .................................................. 68 
Table 31: 
Percent Days Abstinent – Mixed Effects, Weeks 3-12 ............................................. 68 
Table 32: 
WHO Shift Baseline to Weeks 3-12 ......................................................................... 69 
Table 33: 
WHO 1-Level Decrease in Alcohol Consumption – Weeks 3-12 ............................ 69 
Table 34: 
WHO 1-Level Decrease in Alcohol Consumption  – Full Model, Logistic 
Regression, Weeks 3-12................................................................................................................ 70 
Table 35: 
WHO 1-Level Decrease in Alcohol Consumption – Weeks 9-12 (2 Month Grace) 70 
Table 36: 
WHO 1-Level Decrease in Alcohol Consumption – Full Model, Logistic Regression, 
Weeks 9-12 (2 Month Grace) ....................................................................................................... 70 
Table 37: 
WHO 1-Level Decrease in Alcohol Consumption – Weeks 5-12 (1 Month Grace) 70 
Table 38: 
WHO 1-Level Decrease in Alcohol Consumption – Full Model, Logistic Regression, 
Weeks 5-12 (1 Month Grace) ....................................................................................................... 70 


 
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Table 39: 
WHO 1-Level Decrease in Alcohol Consumption Monthly..................................... 71 
Table 40: 
Monthly Summary of WHO 1-Level Decrease in Alcohol Consumption – Full 
Model 
71 
Table 41: 
WHO 2-Level Decrease in Alcohol Consumption – Weeks 3-12 ............................ 72 
Table 42: 
WHO 2-Level Decrease in Alcohol Consumption – Full Model, Logistic Regression, 
Weeks 3-12 72 
Table 43: 
WHO 2-Level Decrease in Alcohol Consumption – Weeks 9-12 (2 Month Grace) 72 
Table 44: 
WHO 2-Level Decrease in Alcohol Consumption – Full Model, Logistic Regression, 
Weeks 9-12 (2 Month Grace) ....................................................................................................... 72 
Table 45: 
WHO 2-Level Decrease in Alcohol Consumption – Weeks 5-12 (1 Month Grace) 72 
Table 46: 
WHO 2-Level Decrease in Alcohol Consumption – Full Model, Logistic Regression, 
Weeks 5-12 (1 Month Grace) ....................................................................................................... 72 
Table 47: 
WHO 2-Level Decrease in Alcohol Consumption Monthly..................................... 72 
Table 48: 
Monthly Summary of WHO 2-Level Decrease in Alcohol Consumption – Full 
Model 
72 
Table 49: 
Subjects Abstinent from Alcohol – Weeks 3-12....................................................... 73 
Table 50: 
Subjects Abstinent from Alcohol – Full Model, Logistic Regression, Weeks 3-12 . 73 
Table 51: 
Subjects Abstinent from Alcohol – Weeks 9-12 (2 Month Grace) ........................... 73 
Table 52: 
Subjects Abstinent from Alcohol – Full Model, Logistic Regression, Weeks 9-12 (2 
Month Grace) ................................................................................................................................ 73 
Table 53: 
Subjects Abstinent from Alcohol – Weeks 5-12 (1 Month Grace) ........................... 74 
Table 54: 
Subjects Abstinent from Alcohol – Full Model, Logistic Regression, Weeks 5-12 (1 
Month Grace) ................................................................................................................................ 74 
Table 55: 
Subjects Abstinent from Alcohol Monthly ............................................................... 74 
Table 56: 
Monthly Summary of Subjects Abstinent from Alcohol – Full Model .................... 74 
Table 57: 
Subjects No Heavy Drinking Days – Weeks 3-12 .................................................... 75 
Table 58: 
Subjects No Heavy Drinking Days – Full Model, Logistic Regression, Weeks 3-12
 
75 
Table 59: 
Subjects No Heavy Drinking Days – Weeks 9-12 (2 Month Grace) ........................ 75 
Table 60: 
Subjects No Heavy Drinking Days – Full Model, Logistic Regression, Weeks 9-12 
(2 Month Grace) ............................................................................................................................ 76 
Table 61: 
Subjects No Heavy Drinking Days – Weeks 5-12 (1 Month Grace) ........................ 76 
Table 62: 
Subjects No Heavy Drinking Days – Full Model, Logistic Regression, Weeks 5-12 
(1 Month Grace) ............................................................................................................................ 76 
Table 63: 
Subjects No Heavy Drinking Days -- Monthly ......................................................... 76 
Table 64: 
Monthly Summary of Subjects No Heavy Drinking Days – Full Model ................. 76 
Table 65: 
Urge to Drink Scale – Each Evaluation During Maintenance Period ....................... 76 
Table 66: 
Urge to Drink Scale – Full Model, Mixed Effects, Weeks 6-13 ............................... 77 
Table 67: 
ECR-RS (attachment related anxiety) – Each Evaluation During Maintenance Period
 
78 
Table 68: 
ECR-RS Attachment-Related Anxiety – Full Model, Mixed Effects, Weeks 6-13.. 78 
Table 69: 
POMS – Each Evaluation During Maintenance Period ............................................ 78 
Table 70: 
POMS Tension-Anxiety – Full Model, Mixed Effects, Weeks 6-13 ........................ 79 
Table 71: 
POMS Depression-Dejection – Full Model, Mixed Effects, Weeks 6-13 ................ 80 
Table 72: 
POMS Anger-Hostility – Full Model, Mixed Effects, Weeks 6-13 ......................... 80 
Table 73: 
POMS Vigor-Activity – Full Model, Mixed Effects, Weeks 6-13 ........................... 80 


 
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Table 74: 
POMS Fatigue-Inertia – Full Model, Mixed Effects, Weeks 6-13 ........................... 80 
Table 75: 
POMS Confusion-Bewilderment – Full Model, Mixed Effects, Weeks 6-13 .......... 80 
Table 76: 
POMS Total Mood Disturbance – Full Model, Mixed Effects, Weeks 6-13 ........... 80 
Table 77: 
PROMIS – Each Evaluation During Maintenance Period ........................................ 80 
Table 78: 
PROMIS Alcohol Use Negative Consequences – Full Model, Mixed Effects, Weeks 
6-13 
81 
Table 79: 
PROMIS Sleep Disturbances – Full Model, Mixed Effects, Weeks 6-13 ................ 81 
Table 80: 
PROMIS Pain Interference – Full Model, Mixed Effects, Weeks 6-13 ................... 81 
Table 81: 
Mean Cigarettes Smoked per Week (among smokers) – Each Evaluation During 
Maintenance Period ...................................................................................................................... 81 
Table 82: 
Mean Cigarettes Smoked per Week (among Smokers) – Full Model, Mixed Effects, 
Weeks 6-13 82 
Table 83: 
Mean Days Use of Other Nicotine Products – Each Evaluation During Maintenance 
Period 
82 
Table 84: 
Mean Use of Other Nicotine Products – Full Model, Mixed Effects, Weeks 6-13 .. 82 
Table 85: 
Subjects Abstinent from Cigarettes among Smokers Weeks 6-13 ........................... 82 
Table 86: 
Subjects Abstinent from Cigarettes (among Smokers) – Logistic Regression, Weeks 
6-13 
83 
Table 87: 
MINI AUD Number of Symptoms ........................................................................... 83 
Table 88: 
MINI AUD Number of Symptoms – Analysis of Covariance, Week 13 ................. 83 
Table 89: 
Overall Summary of Adverse Events ....................................................................... 86 
Table 90: 
 Number and Percentage of Subjects with Adverse Events ...................................... 86 
Table 91: 
Number and Percentage of Subjects with Adverse Events During Weeks 1 & 2..... 87 
Table 92: 
Number and Percentage of Subjects with Adverse Events During Weeks 3-12 ...... 87 
Table 93: 
Summary of Subjects with Adverse Events by Severity and Relationship – Oxytocin
 
87 
Table 94: 
Summary of Subjects with Adverse Events by Severity and Relationship – Placebo
 
87 
Table 95: 
Number and Percentage of Subjects with Adverse Events by Maximum Severity .. 88 
Table 96: 
Number and Percentage of Subjects with Adverse Events by Maximum Severity 
During Weeks 1& 2 ...................................................................................................................... 88 
Table 97: 
Number and Percentage of Subjects with Adverse Events by Maximum Severity 
During Weeks 3-12 ....................................................................................................................... 88 
Table 98: 
Number and Percentage of Subjects with Adverse Events Occurring in >= 5% ...... 89 
Table 99: 
Number and Percentage of Subjects with Adverse Events Leading to 
Discontinuation of Study .............................................................................................................. 89 
Table 100: 
Number and Percentage of Subjects with Adverse Events Leading to 
Discontinuation of Study Medication ........................................................................................... 90 
Table 101: 
 CIWA-AR Score > 10 at Least Once During Treatment ..................................... 90 
Table 102: 
Summary of Vital Signs and Body Weights ......................................................... 91 
Table 103: 
Incidence of Abnormal Findings on Physical Exam in Nasal Mucosa ................. 91 
Table 104: 
Summary of Other Services Used During Treatment Period ................................ 91 
Table 105: 
Summary of ECG Results ..................................................................................... 92 
Table 106: 
Summary of Blood Chemistries ............................................................................ 92 
Table 107: 
Summary of Positive Urine Drug Tests, Pregnancy Test or BAC > 0.000 Any 
Time During the Study.................................................................................................................. 93 


 
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Table 108: 
BPAQ  – Each Evaluation During Maintenance Period ....................................... 93 
Table 109: 
 BPAQ Physical Aggression Score -- Full Model, Mixed Effects,  Entire 
Maintenance Period ...................................................................................................................... 94 
Table 110: 
BPAQ Verbal Aggression Score -- Full Model, Mixed Effects, Entire 
Maintenance Period ...................................................................................................................... 95 
Table 111: 
BPAQ Anger Score -- Full Model, Mixed Effects, Entire Maintenance Period... 95 
Table 112: 
BPAQ Hostility Score -- Full Model, Mixed Effects, Entire Maintenance Period95 
Table 113: 
SNAQ – Untransformed, Each Evaluation During Maintenance Period .............. 96 
Table 114: 
SNAQ Score < 14 at Each Visit During Treatment .............................................. 96 
Table 115: 
SNAQ Total Score -- Full Model, Mixed Effects, Entire Maintenance Period .... 96 
Table 116: 
Frequency of Subjects with Suicidal Ideation Any Time During the Study ......... 96 
Table 117: 
Moderator: MINI AUD (Percent Heavy Drinking Days Weeks 3-12) ................. 98 
Table 118: 
Moderator: POMS Tension-Anxiety (Percent Heavy Drinking Days Weeks 3-12)
 
98 
Table 119: 
Moderator: POMS Depression-Dejection (Percent Heavy Drinking Days Weeks 
3-12) 
99 
Table 120: 
Moderator: ECR-RS Attachment-Related Anxiety (Percent Heavy Drinking Days 
Weeks 3-12) 99 
Table 121: 
Moderator: STAI (Percent Heavy Drinking Days Weeks 3-12) ........................... 99 
Table 122: 
Moderator: Drinking Goal (Percent Heavy Drinking Days Weeks 3-12) ............ 99 
Table 123: 
Moderator: BIS Self Control (Percent Heavy Drinking Days Weeks 3-12) ......... 99 
Table 124: 
Moderator: BIS Impulsive Behavior (Percent Heavy Drinking Days Weeks 3-12)
 
99 
Table 125: 
Moderator: Hyperkatifeia (Percent Heavy Drinking Days Weeks 3-12) .............. 99 
Table 126: 
Hyperkatifeia Total Score ..................................................................................... 99 
Table 127: 
Hyperkatifeia Total Score– Generalized Linear Model, Week 13 ..................... 100 
Table 128: 
Hyperkatifeia Stress/Anxiety Score .................................................................... 100 
Table 129:  
Hyperkatifeia Stress/Anxiety Score– Generalized Linear Model, Week 13 ...... 100 
Table 130: 
Hyperkatifeia Depression Score ......................................................................... 101 
Table 131: 
Hyperkatifeia Depression Score– Generalized Linear Model, Week 13 ............ 101 
Table 132: 
Hyperkatifeia Irritable Score............................................................................... 101 
Table 133: 
Hyperkatifeia Irritable Score– Generalized Linear Model, Week 13 ................. 101 
Table 134: 
Hyperkatifeia Pain Score .................................................................................... 101 
Table 135: 
Hyperkatifeia Pain Score– Generalized Linear Model, Week 13 ....................... 101 
 
Listing 1:  
Subject Disposition - All Subjects ...................................................................... 103 
Listing 2: 
Enrollment and Randomization – All Consented Subjects ..................................... 103 
Listing 3: 
Reason not Eligible – Screen Failures .................................................................... 104 
Listing 4: 
Protocol Deviations ................................................................................................. 104 
Listing 5: 
 Subjects Excluded from the Efficacy Analysis ...................................................... 105 
Listing 6: 
 Demographics Data ................................................................................................ 105 
Listing 7: 
Baseline Drinking Characteristics ........................................................................... 106 
Listing 8: 
MINI DSM5 Disorders ........................................................................................... 107 
Listing 9: 
MINI DSM5 AUD .................................................................................................. 108 
Listing 10: 
MINI AUD End of Study .................................................................................... 109 
Listing 11:  Medical History ....................................................................................................... 110 


 
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36 
 
Listing 12: 
Surgical History .................................................................................................. 111 
Listing 13: 
Physical Exam ..................................................................................................... 112 
Listing 14: 
 Drinking Treatment History ............................................................................... 112 
Listing 15: 
Drinking Goal ..................................................................................................... 113 
Listing 16: 
Daily and Weekly Standard Drink Units (TLFB) During Treatment ................. 114 
Listing 17: 
Drinking Question ............................................................................................... 114 
Listing 18: 
Drinking Consequences, Craving, Appetite, and Anxiety .................................. 114 
Listing 19: 
UPSIT Scores ...................................................................................................... 115 
Listing 20: 
POMS Scores ...................................................................................................... 115 
Listing 21: 
PROMIS Scale Scores ........................................................................................ 116 
Listing 22: 
Smoking Data...................................................................................................... 116 
Listing 23: 
 Exit Interview..................................................................................................... 117 
Listing 24: 
Other Services Use .............................................................................................. 118 
Listing 25: 
Drug Exposure .................................................................................................... 119 
Listing 26: 
 Adverse Events .................................................................................................. 120 
Listing 27: 
 Adverse Events Leading to Subject Discontinuation from Study ..................... 121 
Listing 28: 
 Adverse Events Leading to Discontinuation of Investigational Product ........... 122 
Listing 29: 
Serious Adverse Events ...................................................................................... 123 
Listing 30: 
Columbia-Suicide Severity Scale ....................................................................... 124 
Listing 31: 
BPAQ Scores ...................................................................................................... 126 
Listing 32: 
Blood Chemistries ............................................................................................... 126 
Listing 33: 
Pregnancy Test/Birth Control Data ..................................................................... 127 
Listing 34: 
 Blood Alcohol Concentration ............................................................................ 128 
Listing 35: 
Urine Drug Screen .............................................................................................. 128 
Listing 36: 
Vital Signs and Body Weights ............................................................................ 129 
Listing 37: 
Prior and Concomitant Medications ................................................................... 129 
 
Figure 1: 
Percent Heavy Drinking Days per Week Least Squares Means – Untransformed . 130 
Figure 2: 
Mean Drinks per Week Least Squares Means – Untransformed ............................ 130 
Figure 3: 
Mean Drinks per Drinking Day by Week Least Squares Means – Untransformed 130 
Figure 4: 
Percentage of Subjects No Heavy Drinking Days Weeks 3-12 .............................. 131 
Figure 5: 
Percentage of Subjects Abstinent Weeks 3-12 ....................................................... 131 
Figure 6: 
Percentage of Subjects with WHO 1-Level Decrease in Alcohol Consumption 
Weeks 3-12 131 
Figure 7: 
Percentage of Subjects with WHO 2-Level Decrease in Alcohol Consumption 
Weeks 3-12 131 
Figure 8: 
Cumulative Grace Periods for Percentage of Subjects No Heavy Drinking Days . 132 
Figure 9: 
Cumulative Grace Periods for Percentage of Subjects Abstinent ........................... 132 
Figure 10: 
Cumulative Grace Periods for Percentage WHO 1-Level Decrease in Alcohol 
Consumption 132 
Figure 11: 
Cumulative Grace Periods for Percentage WHO 2-Level Decrease in Alcohol 
Consumption 132 
Figure 12: 
Percentage Days Abstinent per Week Least Squares Means – Untransformed .. 133 
Figure 13: 
Weekly Number of Cigarettes Smoked in Smokers Least Squares Means – 
Untransformed ............................................................................................................................ 133 
Figure 14: 
POMS Total Score Least Squares Means by Visit – Untransformed ................. 133 


 
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Figure 15: 
POMS Tension-Anxiety Least Squares Means by Visit – Untransformed......... 133 
Figure 16: 
POMS Depression-Dejection Least Squares Means by Visit – Untransformed . 134 
Figure 17: 
POMS Vigor-Activity Least Squares Means by Visit – Untransformed ............ 134 
Figure 18: 
POMS Fatigue-Inertia Least Squares Means by Visit – Untransformed ............ 134 
Figure 19: 
POMS Anger-Hostility Least Squares Means by Visit – Untransformed .......... 134 
Figure 20: 
POMS Confusion-Bewilderment Least Squares Means by Visit – Untransformed
 
134 
Figure 21: 
PROMIS Alcohol Negative Consequences Least Squares Means by Visit – 
Untransformed ............................................................................................................................ 134 
Figure 22: 
PROMIS Sleep Disturbances Least Squares Means by Visit – Untransformed . 134 
Figure 23: 
PROMIS Pain Interference Least Squares Means by Visit – Untransformed .... 134 
Figure 24: 
ECR-RS Attachment-Related Anxiety Least Squares Means by Visit – 
Untransformed ............................................................................................................................ 134 
Figure 25: 
Clinical Chemistry Values Over Time ................................................................ 135 
 
12.1 Tables 
12.1.1 Subject Disposition, Participation, Compliance 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
38 
 
 
Table 1: 
Subject Disposition - All Consented Subjects 
 
           Treatment Group 
 
 
Placebo 
Oxytocin 
Total 
 
 
n (%) 
n (%) 
n (%) 
p-value1 
Number of Subjects Consented 
 
 
xxx 
 
Number of Subjects Screen Failed 
 
 
xxx (xx.x%) 
 
Number of Subjects Randomized 
xxx 
xxx 
xxx 
 
Number of Subjects Randomized but Did Not Take Medication 
x (xx.x%) 
x (xx.x%) 
x (xx.x%) 
 
Number of Subjects Randomized and Took at Least One Dose of Study 
Medication (Full Analysis Set) 
xx (xx.x%) 
xx (xx.x%) 
xxx (xx.x%) 
0.xxx 
Number of Completed Subjects2 
xx (xx.x%) 
xx (xx.x%) 
xxx (xx.x%) 
0.xxx 
Number of Subjects Discontinuing Medication, Remain in Study 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
Number of Subjects Discontinuing Medication, Drop out of  Study 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
Reason for Discontinuation 
 
 
 
 
   Lost to follow up 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   Died 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   Adverse Event  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   Logistical or practical reasons 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   Lack of perceived efficacy 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   Absent from the protocol due to confinement in a controlled 
environment 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   Subject withdrew consent 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   Clinical deterioration 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   Prefer another treatment 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   Protocol non-compliance 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   Other reason 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
1 p-value from Fisher’s exact test for binary 2Subjects completing Week 13 visit by phone or clinic 
Programmer Notes: The discontinuation reasons are as given on the CRF. Include only the reasons actually used for the subjects in the study. If a 
subject discontinued, but the specific reason is missing, include ‘Missing’ as a row in the table. Use the order of discontinuation reasons as 
presented on the CRF page 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
39 
 
 
Table 2: 
Reasons for Screen Failure – All Consented Subjects 
Category 
Reason 
n (%)  
   Inclusion 
Too young 
xxx (xx.x%) 
 
… Refuse to take study medication 
xxx (xx.x%) 
   Exclusion 
Current substance abuse disorder 
xxx (xx.x%) 
 
… Other reason 
xxx (xx.x%) 
Programmer list all reasons identified for screen failure with denominator being all consented subjects 
 
 
 
 
 
Table 3: 
Exposure to Investigational Products Based on Subject Diary  
 
Placebo 
Oxytocin 
 
Period 
N 
Mean 
SD 
Med 
Min 
Max 
n 
Mean 
SD 
Med 
Min 
Max 
p-value1 
  Insufflations2 
 
 
 
 
 
 
 
 
 
 
 
 
 
    Week 1 (xx)3 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
0.xxx 
    Week 2 (xx) 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
0.xxx 
    Week 3 (xx) … Week 12 (xx) 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
0.xxx 
Overall (Weeks 1-12) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total number of insufflations  
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
0.xxx 
Total number of insufflations 
Weeks 1-2  
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
0.xxx 
Total number of insufflations 
Weeks 3-12  
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
0.xxx 
 1 p-value from t-test for continuous variables (t) – skewed continuous data uses the Wilcoxon rank-sum test (w). 
2Number of insufflations per week  
3xx maximum  number.possibible in week 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
40 
 
 
Table 4: 
Percent Compliance to Investigational Products Based on Subject Diary  
 
Placebo 
Oxytocin 
 
Period 
n 
Mean 
SD 
Med 
Min 
Max 
n 
Mean 
SD 
Med 
Min 
Max 
p-value1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  Insufflations2 
 
 
 
 
 
 
 
 
 
 
 
 
 
    Week 1 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
0.xxx 
    Week 2 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
0.xxx 
    Week 3 … Week 12 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
0.xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Overall (Weeks 1-12) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Total number of insufflations  
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
0.xxx 
Total number of insufflations 
Weeks 1-2  
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
0.xxx 
Total number of insufflations 
Weeks 3-12  
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
0.xxx 
1 p-value from t-test for continuous variables (t) – skewed continuous data uses the Wilcoxon rank-sum test (w). 
2 percent is the # of sprays taken/#of sprays presecribed in a period 
Table 5:  
Exposure to Investigational Products Based on Weight of Vials  
Note that this is the same as Table 2 except using IU for dosing 
 
Table 6: 
Percent Compliance to Investigational Products Based on Weight of Vials  
Note that this is the same as Table 3 except using IU for dosing and percent is based upon IU taken/IU presecribed 
 
Table 7:  
Summary of Medical History 
MedDRA SOC/ 
Placebo 
Oxytocin 
  Preferred Term 
(N=xx) 
(N=xx) 
SOC 
nn (xx.x%) 
nn (xx.x%) 
   - Overall -  
 
 
      Preferred term 1 
nn (xx.x%) 
nn (xx.x%) 
      Preferred term 2 
nn (xx.x%) 
nn (xx.x%) 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
41 
 
Table 8:` 
Exit Interview  
 
Placebo 
Oxytocin 
Total 
 
Question 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
What medication do you believe you were taking? 
 
 
 
0.xxx 
  Placebo 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Active 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Both Active & Placebo 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  No Idea 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Other substance 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Refuse to answer 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Missing 
xx 
xx 
xx 
 
 
 
 
 
 
Correctly Guessed Medication (Subjects that guessed a medication) 
 
 
 
0.xxx 
   Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
Why did you answer above? 
 
 
 
0.xxx 
  Had side effects 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Had no side effects 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Staff treated me different 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  No improvement  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Had improvement 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Had a hunch  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  I just felt different 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Other 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Refuse to answer 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Missing 
xx 
xx 
xx 
 
 
 
 
 
Do you feel the medication helped you to reduce drinking? 
 
 
0.xxx 
  Very Much  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Much  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Moderately  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  A little  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Not at all 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Refuse to answer 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Missing 
xx 
xx 
xx 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
42 
 
 
Placebo 
Oxytocin 
Total 
 
Question 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
How would you describe your experience taking the medication? 
 
 
0.xxx 
 Experienced no unwanted side effects and benefited 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 Experienced some unwanted side effects but benefited 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 Experienced a lot unwanted side effects but benefited 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 Experienced no unwanted side effects but did not benefit 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 Experienced some unwanted side effects and did not benefit 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 Experienced a lot of unwanted side effects and did not benefit 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Refuse to answer 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 Missing 
xx 
xx 
xx 
 
 
 
 
 
 
If a friend were in need of help for a drinking problem, would you recommend taking the medication to him/her? 
0.xxx 
  Yes, definitely 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Yes, generally 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Neither yes nor no 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  No, not really 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  No, definitely not 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Refuse to answer 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Missing 
xx 
Xx 
xx 
 
 
 
 
 
 
If you were to need treatment in the future, would you choose to take the medication again? 
0.xxx 
  Definitely yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Generally yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Neither yes or no 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  No, not really 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Definitely not 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Refuse to answer 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Missing 
xx 
Xx 
xx 
 
 
 
 
 
 
How much do you think of yourself as wanting to please other people (people pleaser)? 
 
0.xxx 
  More than average 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Average 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Less than average 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Refuse to answer 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Missing 
xx 
Xx 
xx 
 
1 p-value from t-test for continuous variables (t) – skewed continuous data uses the Wilcoxon rank-sum test (w) - chi-square test for 
categorical variables (c). 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
43 
 
Table 9: 
 Research Participation by Treatment Group and Week  
 
 
 
 
 
 
 
 
 
Placebo (N=xx) 
Oxytocin (N=xx) 
 
Study Week2 
n 
Cumulative n 
Cumulative % 
n 
Cumulative n 
Cumulative % 
p-value1 
 
 
 
 
 
 
 
 
Week 1 
xx 
xx 
 xx.x% 
xx 
xx 
 xx.x% 
0.xxx 
Week 2 
xx 
xx 
 xx.x% 
xx 
xx 
 xx.x% 
0.xxx 
Week 3 
xx 
xx 
 xx.x% 
xx 
xx 
 xx.x% 
0.xxx 
Week 4 
xx 
xx 
 xx.x% 
xx 
xx 
 xx.x% 
0.xxx 
Week 5 
xx 
xx 
 xx.x% 
xx 
xx 
 xx.x% 
0.xxx 
Week 6 
xx 
xx 
 xx.x% 
xx 
xx 
 xx.x% 
0.xxx 
Week 7 
xx 
xx 
 xx.x% 
xx 
xx 
 xx.x% 
0.xxx 
Week 8 
xx 
xx 
 xx.x% 
xx 
xx 
 xx.x% 
0.xxx 
Week 9 
xx 
xx 
 xx.x% 
xx 
xx 
 xx.x% 
0.xxx 
Week 10 
xx 
xx 
 xx.x% 
xx 
xx 
 xx.x% 
0.xxx 
Week 11 
xx 
xx 
 xx.x% 
xx 
xx 
 xx.x% 
0.xxx 
Week 12 
xx 
xx 
 xx.x% 
xx 
xx 
 xx.x% 
0.xxx 
Week 13 
xx 
xx 
 xx.x% 
xx 
xx 
 xx.x% 
0.xxx 
1 Fisher’s exact test 
2Numbers and percentages are based on subjects that participated through a given week 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
44 
 
Table 10: 
Number and Percent of Subjects with Drinking Data Provided by the Brief Drinking Questionnaire instead of 
the TLFB  
 
Placebo 
Oxytocin 
 
Study Week 
n 
% 
n 
% 
p-value1 
Week 3 
xx 
 xx.x% 
xx 
 xx.x% 
0.xxx 
Week 4 
xx 
 xx.x% 
xx 
 xx.x% 
0.xxx 
Week 5 
xx 
 xx.x% 
xx 
 xx.x% 
0.xxx 
Week 6 
xx 
 xx.x% 
xx 
 xx.x% 
0.xxx 
Week 7 
xx 
 xx.x% 
xx 
 xx.x% 
0.xxx 
Week 8 
xx 
 xx.x% 
xx 
 xx.x% 
0.xxx 
Week 9 
xx 
 xx.x% 
xx 
 xx.x% 
0.xxx 
Week 10 
xx 
 xx.x% 
xx 
 xx.x% 
0.xxx 
Week 11 
xx 
 xx.x% 
xx 
 xx.x% 
0.xxx 
Week 12 
xx 
 xx.x% 
xx 
 xx.x% 
0.xxx 
Overall 
xx 
 xx.x% 
xx 
 xx.x% 
0.xxx 
1Fisher’s exact test 
Note only rows with values above 0 will be presented 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
45 
 
Table 11: 
Demographic Characteristics  
 
Placebo 
Oxytocin 
Total 
 
Characteristic 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
Age (years) 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 
 
 
 
 
Gender at Birth 
 
 
 
0.xxx 
  N 
 
 
 
 
  Male 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Female 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
Race 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
 
  White 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  African-American or Black  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Asian 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Native Hawaiian or Other Pacific Islander 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  American Indian or Alaskan Native 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  More than one race or other race  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Unknown or not reported 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Other 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
Ethnicity 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
 
  Hispanic or Latino 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Not Hispanic or Latino 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Not reported 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Unknown 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Other 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
Race/Ethnicity 
 
 
 
0.xxx 
   White 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   Black 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   Hispanic 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
46 
 
 
Placebo 
Oxytocin 
Total 
 
Characteristic 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
   Other 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
Education (years) 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
 
 
 
 
 
 
Education 
 
 
 
0.xxx 
  ≤ High School 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  > High School 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
Marital Status 
 
 
 
0.xxx 
  Legally Married 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Living with Partner / Cohabitating 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Widowed 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Separated 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Divorced 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Never Married 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Unknown 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
Marital Status 
 
 
 
0.xxx 
  Married 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Not Married 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
Employment Pattern (last 30 days) 
 
 
 
0.xxx 
  Full-time > 35 hrs /week 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Part-time regular 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Part-time irregular 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Student 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Military Service 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Unemployed 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Retired/Disabled 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Homemaker 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  In controlled environment 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Unknown 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
47 
 
 
Placebo 
Oxytocin 
Total 
 
Characteristic 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
Employment 
 
 
 
0.xxx 
  Employed 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  Unemployed  
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
Income 
 
 
 
0.xxx 
   $0-$15,000 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   $15,001-$30,000 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   $30,001-$45,000 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   $45,001-60,000 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   $60,001-75,000 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   $75,001-90,000 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   $90,001-105,000 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   $105,001-120,000 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   >$120,000 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   Missing 
xx 
xx 
xx 
 
 
 
 
 
 
Occupation 
 
 
 
0.xxx 
   Corporate Executive or Major Professional 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   Business Manager or Minor Professional 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   Business Administrator, Small Business 
Owner, or Semi-professional 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   Clerical Worker, Sales, or Technician 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   Skilled Worker 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   Semi-skilled Worker 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   Unskilled Worker 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   Other Occupation 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   Unemployed (not paid for services) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   Never Worked 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   Missing/ Not Given 
xx 
xx 
xx 
 
1 p-value from chi-square test (c), t-test for continuous data, and Fisher’s exact test for binary categories (f) 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
48 
 
 
Table 12: 
Baseline DSM-5 Disorders  
 
Placebo 
Oxytocin 
Total 
 
(N=xx) 
(N=xx) 
(N=xxx) 
DSM-5 Disorders1 
 
 
 
  Major Depressive Episode 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Major Depressive Disorder 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Suicidality 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Suicide Behavior Disorder 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Manic episode 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Hypomanic episode 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Bipolar I Disorder 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Bipolar II Disorder 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Other Specified Bipolar Disorder 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Panic Disorder 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Agoraphobia 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Social Anxiety Disorder (Social Phobia) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Obsessive Compulsive Disorder (Past month) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Posttraumatic Stress Disorder (Past month) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Alcohol Use Disorder 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 Substance Abuse Disorder (Non-alcohol) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Any Psychotic Disorder 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Mood Disorder with Psychotic Features 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Major Depressive Disorder with Psychotic 
Features 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Bipolar I Disorder with Psychotic Features 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Anorexia Nervosa (past 3 months) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Bulemia Nervosa (past 3 months) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Binge-eating Disorder (past 3 months) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Generalized Anxiety Disorder (past 6 months) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Medical, Organic, Drug Case Ruled Out 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  Antisocial Personality Disorder 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
1 As assessed by MINI 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
49 
 
 
 
Table 13: 
Baseline Drinking-related Behavior and Characteristics  
 
Placebo 
Oxytocin 
Total 
 
Characteristic 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
Drinking Goal (n, %) 
 
 
 
0.xxx 
   Total Abstinence 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   Reduce but not stop 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Goal of no Heavy Alcohol Use (n, %)2 
 
 
 
0.xxx 
   Yes 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
   No 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
 
Goal of at least 50% Reduction in Drinks Per Week3 
 
 
 
   N 
xx 
xx 
xx 
0.xxx 
   Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
   Median 
xx 
xx 
xx 
 
   Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
Motivation to Reach Goal 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
  Scale Min-Max 
 
 
(xx – xx) 
 
Confidence to Reach Goal 
 
 
 
 
  N 
xx 
xx 
xx 
0.xxx 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
  Scale Min-Max 
 
 
(xx – xx) 
 
AUD Symptom Severity 
 
 
 
0.xxx 
    Moderate (4 or 5 symptoms) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
    Severe (6 or more symptoms) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
AUD Number of Symptoms 
 
 
 
0.xxx 
  4 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  5   
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  6 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
50 
 
 
Placebo 
Oxytocin 
Total 
 
Characteristic 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
  7 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  8 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  9 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 10 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 11 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
AUD Number of Symptoms (continuous) 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
 
Age when first started drinking 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
 
   Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 
 
 
 
 
Number Lifetime Hospitalizations to 
Reduce/Quit Drinking 
 
 
 
 
   N 
xx 
xx 
xx 
0.xxx 
   Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
   Median 
xx 
xx 
xx 
 
   Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
Number Lifetime Hospitalizations for Illness/ 
Injuries due to Drinking 
 
 
 
 
   N 
xx 
xx 
xx 
0.xxx 
   Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
   Median 
xx 
xx 
xx 
 
   Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
Number Outpatient Visits to Reduce/Quit 
Drinking in Last 12 Months 
 
 
 
 
   N 
xx 
xx 
xx 
0.xxx 
   Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
   Median 
xx 
xx 
xx 
 
   Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
Number Lifetime Medical Detoxifications 
 
 
 
 
   N 
xx 
xx 
xx 
0.xxx 
   Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
51 
 
 
Placebo 
Oxytocin 
Total 
 
Characteristic 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
   Median 
xx 
xx 
xx 
 
   Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
Past Year Number of Support Group Meetings4  
 
 
 
 
   N 
xx 
xx 
xx 
0.xxx 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
   Median 
xx 
xx 
xx 
 
   Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 
Note: Percentages are based on the number of non-missing values in each variable.  
1 p-value from t-test for continuous variables (t) – skewed continuous data uses the Wilcoxon rank-sum test (w) - chi-square test for categorical variables (c) – 
Fisher’s exact test for dichotomous variables (f) 
2 No HDD and <=14 drinks per week for men or <=7 drinks per week women 
3 Calculated using the subject's drinks per week during 28-day pre-screen period and the drinks per week obtained from the 7-day period on the Drinking Goal 
assessment. 
4 Examples include Alcoholics Anonymous (AA), 12 step, Save Ourselves, or similar group meetings attended for alcohol problems or drinking  
 
Table 14: 
Baseline Drinking by TLFB  
 
Placebo 
Oxytocin 
Total 
 
Parameter 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
Percentage of Heavy Drinking Days (Pre-screening Days -1 to -28) 
 
 
 
0.xxx 
   Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx_ 
xx.x (xx.xx) 
 
   Median 
xx.x 
xx.x 
xx.x 
 
   (Min – Max) 
(xx.x – xx.x) 
(xx.x – xx.x) 
(xx.x – xx.x) 
 
 
 
 
 
 
Percentage of Heavy Drinking Days (7 Days Prior to Randomization) 
 
 
 
0.xxx 
   Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx_ 
xx.x (xx.xx) 
 
   Median 
xx.x 
xx.x 
xx.x 
 
   (Min – Max) 
(xx.x – xx.x) 
(xx.x – xx.x) 
(xx.x – xx.x) 
 
 
 
 
 
 
Percentage of Heavy Drinking Days (Percent Change Pre-screening 
Days -1 to -28 to 7 Days Prior to Randomization) 
 
 
 
0.xxx 
   Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx_ 
xx.x (xx.xx) 
 
   Median 
xx.x 
xx.x 
xx.x 
 
   (Min – Max) 
(xx.x – xx.x) 
(xx.x – xx.x) 
(xx.x – xx.x) 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
52 
 
 
Placebo 
Oxytocin 
Total 
 
Parameter 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
  Drinks/Week (Pre-screening Days -1 to -28) 
 
 
 
0.xxx 
   Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx_ 
xx.x (xx.xx) 
 
   Median 
xx.x 
xx.x 
xx.x 
 
   (Min – Max) 
(xx.x – xx.x) 
(xx.x – xx.x) 
(xx.x – xx.x) 
 
 
 
 
 
 
  Drinks/Week (7 Days Prior to Randomization) 
 
 
 
0.xxx 
   Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx_ 
xx.x (xx.xx) 
 
   Median 
xx.x 
xx.x 
xx.x 
 
   (Min – Max) 
(xx.x – xx.x) 
(xx.x – xx.x) 
(xx.x – xx.x) 
 
 
 
 
 
 
  Drinks/Week (Percent Change Pre-screening Days -1 to -28 to 7 Days 
Prior to Randomization) 
 
 
 
0.xxx 
   Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx_ 
xx.x (xx.xx) 
 
   Median 
xx.x 
xx.x 
xx.x 
 
   (Min – Max) 
(xx.x – xx.x) 
(xx.x – xx.x) 
(xx.x – xx.x) 
 
 
 
 
 
 
  Drinks/Drinking Day (Pre-screening Days -1 to -28) 
 
 
 
0.xxx 
   Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx_ 
xx.x (xx.xx) 
 
   Median 
xx.x 
xx.x 
xx.x 
 
   (Min – Max) 
(xx.x – xx.x) 
(xx.x – xx.x) 
(xx.x – xx.x) 
 
 
 
 
 
 
  Drinks/Drinking Day (7Days Prior to Randomization) 
 
 
 
0.xxx 
   Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx_ 
xx.x (xx.xx) 
 
   Median 
xx.x 
xx.x 
xx.x 
 
   (Min – Max) 
(xx.x – xx.x) 
(xx.x – xx.x) 
(xx.x – xx.x) 
 
 
 
 
 
 
  Drinks/Drinking Day (Percent Change Pre-screening Days -1 to -28 to 
7 Days Prior to Randomization) 
 
 
 
0.xxx 
   Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx_ 
xx.x (xx.xx) 
 
   Median 
xx.x 
xx.x 
xx.x 
 
   (Min – Max) 
(xx.x – xx.x) 
(xx.x – xx.x) 
(xx.x – xx.x) 
 
 
 
 
 
 
Percentage Days Abstinent (Pre-screening Days -1 to -28) 
 
 
 
0.xxx 
   Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx_ 
xx.x (xx.xx) 
 
   Median 
xx.x 
xx.x 
xx.x 
 
   (Min – Max) 
(xx.x – xx.x) 
(xx.x – xx.x) 
(xx.x – xx.x) 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
53 
 
 
Placebo 
Oxytocin 
Total 
 
Parameter 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
Percentage Days Abstinent  (7 Days Prior to Randomization) 
 
 
 
0.xxx 
   Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx_ 
xx.x (xx.xx) 
 
   Median 
xx.x 
xx.x 
xx.x 
 
   (Min – Max) 
(xx.x – xx.x) 
(xx.x – xx.x) 
(xx.x – xx.x) 
 
 
 
 
 
 
Percentage Days Abstinent  (Percent Change Pre-screening Days -1 to -
28 to 7 Days Prior to Randomization) 
 
 
 
0.xxx 
   Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx_ 
xx.x (xx.xx) 
 
   Median 
xx.x 
xx.x 
xx.x 
 
   (Min – Max) 
(xx.x – xx.x) 
(xx.x – xx.x) 
(xx.x – xx.x) 
 
 
 
 
 
 
WHO Risk Level 
 
 
 
0.xxx 
  High Risk 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 Very High Risk 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Note: Percentages are based on the number of non-missing values in each variable.  
1 p-value from t-test for continuous variables (t) – skewed continuous data uses the Wilcoxon rank-sum test (w) - chi-square test for categorical variables (c)  
 
 
Table 15: 
Baseline Other Substance Use  
 
Placebo 
Oxytocin 
Total 
 
Parameter 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
Cigarette Smoker? 
 
 
 
0.xxx 
   Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
Any Nicotine Use? 
 
 
 
0.xxx 
   Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
Any Other Nicotine Product Use? 
 
 
 
0.xxx 
   Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
   No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
THC 
 
 
 
0.xxx 
  Negative 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
54 
 
 
Placebo 
Oxytocin 
Total 
 
Parameter 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
Cigarette Smoker? 
 
 
 
0.xxx 
  Positive 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Note: Percentages are based on the number of non-missing values in each variable. 1 p-value from t-test for continuous variables (t) – skewed continuous data 
uses the Wilcoxon rank-sum test (w) - chi-square test for categorical (c), Fisher’s exact test for binary variables (f) 
Programmer’s note: Place the parenthesis and character after each p-value to denote the test 
 
 
Table 16: 
Baseline POMS 
 
Placebo 
Oxytocin 
Total 
 
Characteristic 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
Tension-Anxiety 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 Scale Min-Max 
 
 
(xx-xx) 
 
 
 
 
 
 
Depression-Dejection 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 Scale Min-Max 
 
 
(xx-xx) 
 
 
 
 
 
 
Anger-Hostility 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 Scale Min-Max 
 
 
(xx-xx) 
 
 
 
 
 
 
Fatigue-Inertia 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
55 
 
 
Placebo 
Oxytocin 
Total 
 
Characteristic 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 Scale Min-Max 
 
 
(xx-xx) 
 
 
 
 
 
 
Confusion-Bewilderment 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 Scale Min-Max 
 
 
(xx-xx) 
 
Vigor-Activity 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 Scale Min-Max 
 
 
(xx-xx) 
 
 
 
 
 
 
Total Mood Disturbance 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
 
  Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
  Median 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 Scale Min-Max 
 
 
(xx-xx) 
 
Note: 1 p-value from t-test for continuous variables (t) – skewed continuous data uses the Wilcoxon rank-sum test (w) 
 
 
Table 17: 
Baseline Alcohol-Related Craving, Consequences, and Withdrawal 
 
Placebo 
Oxytocin 
Total 
 
Parameter 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
IDS Reward Drinking Score 
 
 
 
0.xxx 
   Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
   Median 
xx.x 
xx.x 
xx.x 
 
   (Min – Max) 
(xx.x – xx.x) 
(xx.x – xx.x) 
(xx.x – xx.x) 
 
   Scale Min-Max 
 
 
(xx.x – xx.x) 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
56 
 
 
Placebo 
Oxytocin 
Total 
 
Parameter 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
IDS Relief Drinker Score 
 
 
 
0.xxx 
   Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
   Median 
xx.x 
xx.x 
xx.x 
 
   (Min – Max) 
(xx.x – xx.x) 
(xx.x – xx.x) 
(xx.x – xx.x) 
 
   Scale Min-Max 
 
 
(xx.x – xx.x) 
 
 
 
 
 
 
IDS Reward Drinker N (%) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
 
 
 
 
 
 CIWA-AR 
 
 
 
0.xxx 
   Mean (SD) 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
   Median 
xx.x 
xx.x 
xx.x 
 
   (Min – Max) 
(xx.x – xx.x) 
(xx.x – xx.x) 
(xx.x – xx.x) 
 
   Scale Min-Max 
 
 
(xx.x – xx.x) 
 
 
 
 
 
 
No. Subjects with Withdrawal Symptoms (CIWA ≥ 10) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
Note: 1 p-value from t-test for continuous variables (t) – skewed continuous data uses the Wilcoxon rank-sum test (w); chi-squared test for 
symptoms (c) 
Programmer’s note: Place the parenthesis and character after each p-value to denote the test 
 
 
 
 
 
Table 18: 
Baseline Mood Questionnaires  
 
Placebo 
Oxytocin 
Total 
 
Scale 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
BIS Brief 
 
 
 
 
Total Score 
 
 
 
 
  N 
xx 
xx 
xx 
 
  Mean (SD) 
xx.x  (xx.x) 
xx.x  (xx.x) 
xx.x  (xx.x) 
 
  Median 
xxx.xx 
xxx.xx 
xxx.xx 
 
  (Min – Max) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 Scale Min-Max 
 
 
(xx-xx) 
 
 
 
 
 
 
STAI (T-Anxiety Scale) 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
57 
 
 
Placebo 
Oxytocin 
Total 
 
Scale 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
  Mean (SD) 
xx.x  (xx.x) 
xx.x  (xx.x) 
xx.x  (xx.x) 
 
  Median 
xxx.xx 
xxx.xx 
xxx.xx 
 
  (Min – Max) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 Scale Min-Max 
 
 
(xx-xx) 
 
 
 
 
 
 
BPAQ 
 
 
 
 
Physical Aggression 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
 
  Mean (SD) 
xx.x  (xx.x) 
xx.x  (xx.x) 
xx.x  (xx.x) 
 
  Median 
xxx.xx 
xxx.xx 
xxx.xx 
 
  (Min – Max) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 Scale Min-Max 
 
 
(xx-xx) 
 
Anger 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
 
  Mean (SD) 
xx.x  (xx.x) 
xx.x  (xx.x) 
xx.x  (xx.x) 
 
  Median 
xxx.xx 
xxx.xx 
xxx.xx 
 
  (Min – Max) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 Scale Min-Max 
 
 
(xx-xx) 
 
Verbal Aggression 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
 
  Mean (SD) 
xx.x  (xx.x) 
xx.x  (xx.x) 
xx.x  (xx.x) 
 
  Median 
xxx.xx 
xxx.xx 
xxx.xx 
 
  (Min – Max) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 Scale Min-Max 
 
 
(xx-xx) 
 
Hostility 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
 
  Mean (SD) 
xx.x  (xx.x) 
xx.x  (xx.x) 
xx.x  (xx.x) 
 
  Median 
xxx.xx 
xxx.xx 
xxx.xx 
 
  (Min – Max) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 Scale Min-Max 
 
 
(xx-xx) 
 
. 1 p-value from t-test for continuous variables (t) – skewed continuous data uses the Wilcoxon rank-sum test (w) 
 
 
 
 
 


 
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Table 19: 
Baseline ECR-RS  
 
Placebo 
Oxytocin 
Total 
 
Subscale 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
Attachment-related 
 
 
 
 
Anxiety 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
 
  Mean (SD) 
xx.x (xx.x) 
xx.x  (xx.x) 
xx.x  (xx.x) 
 
  Median 
xxx.xx 
xxx.xx 
xxx.xx 
 
  (Min – Max) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 Scale Min-Max 
 
 
(xx-xx) 
 
 
 
 
 
 
 1 p-value from t-test for continuous variables (t) – skewed continuous data uses the Wilcoxon rank-sum test (w) 
 
 
Table 20: 
Baseline SNAQ  
 
Placebo 
Oxytocin 
Total 
 
SNAQ 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
 
 
 
 
 
Total Score 
 
 
 
0.xxx 
  Mean (SD) 
xx.x (xx.x) 
xx.x (xx.x) 
xx.x (xx.x) 
 
  Median 
xxx.xx 
xxx.xx 
xxx.xx 
 
  (Min – Max) 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
Scale Min-Max 
 
 
(xx-xx) 
 
 
 
 
 
 
Dichotomized 
 
 
 
0.xxx 
  15+ 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
  ≤14 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 1 p-value from t-test for continuous variables (t) – skewed continuous data uses the Wilcoxon rank-sum test (w) Fisher’s exact test for binary variables (f) 
 
 
 
 
 


 
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Table 21: 
Baseline PROMIS Subscales  
 
Placebo 
Oxytocin 
Total 
 
Subscale 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
Alcohol Use Negative Consequences 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
 
  Mean (SD_ 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x(xx.xx) 
 
  Median 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 Scale Min-Max 
 
 
(xx-xx) 
 
 
 
 
 
 
Sleep Disturbances 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
 
  Mean (SD_ 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x(xx.xx) 
 
  Median 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 Scale Min-Max 
 
 
(xx-xx) 
 
 
 
 
 
 
Pain Interference 
 
 
 
0.xxx 
  N 
xx 
xx 
xx 
 
  Mean (SD_ 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x(xx.xx) 
 
  Median 
xx 
xx 
xx 
 
  Min-Max 
(xx-xx) 
(xx-xx) 
(xx-xx) 
 
 Scale Min-Max 
 
 
(xx-xx) 
 
1 p-value from t-test for continuous variables (t) – skewed continuous data uses the Wilcoxon rank-sum test (w) 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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Table 22: 
Baseline UPSIT  
 
Placebo 
Oxytocin 
Total 
 
UPSIT 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
 
 
 
 
 
Categories 
 
 
 
0.xxx 
  Normosmia 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 Mild microsmia 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 Moderate microsmia    
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 Severe microsmia 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 Anosmia 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
1 p-value from t-test for continuous variables (t) – skewed continuous data uses the Wilcoxon rank-sum test (w) 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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12.1.2 
Primary Efficacy Endpoint


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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Table 23: 
Weekly Percentage of Heavy Drinking Days from Baseline to Week 12 
 
Oxytocin 
Placebo 
Study Week 
N 
Mean (SD) 
Median 
Min - Max 
N 
Mean (SD) 
Median 
Min - Max 
p-value1 
Baseline 
xx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
1 
xx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
2 
xx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
3 
xx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
4 
xx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
5 
xx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
6 
xx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
7 
xx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
8 
xx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
9 
xx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
10 
xx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
11 
xx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
12 
xx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
3-12 
xx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
xxx (xx.xx) 
xxx 
xxx - xxx 
 
1t-tests for each  individual week. Week 3-12 is evaluated in modeling 
{programmer note: change test to Wilcoxon if the data are skewed} 
 
Table 24: 
Percentage of Heavy Drinking Days per Week –Mixed Effects , Weeks 3-12, No Imputation  
Type III Wald Tests1 
Parameter 
Num DF Den DF 
F Value 
 
p-value 
ARM 
1 
xxx 
xxx.xx 
0.xxx 
Week 
10 
xxx 
xxx.xx 
0.xxx 
Site 
9 
xxx 
xxx.xx 
0.xxx 
Cov 
x 
xxx 
xxx.xx 
0.xxx 
ARM*Week 
9 
xxx 
xxx.xx 
0.xxx 
 
 
 
 
1Values in Type III table are based upon transformed data {note to specify which transformation} 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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Least Squares Means1 
 
 
 
 
95% CI 
 
 
Untransformed 
Transformed 
Arm 
Week 
Estimate 
SE 
Lower CI 
Upper CI 
Difference 
SE 
p-value 
Cohen’s d 
p-value 
Cohen’s d 
Oxytocin 
3 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
3 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
Oxytocin 
4 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
4 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
Oxytocin 
5 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
5 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
Oxytocin 
6 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
6 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
Oxytocin 
7 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
7 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
Oxytocin 
8 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
8 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
Oxytocin 
9 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
9 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
Oxytocin 
10 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
10 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
Oxytocin 
11 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
11 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
Oxytocin 
12 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
12 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
Oxytocin 
Overall  
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
Overall 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
1Values are based on untransformed data unless otherwise specified 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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Table 25: Percentage of Heavy Drinking Days per Week – Multiple Imputation for Missing Values, Mixed Effects, Weeks 3-12 
Least Squares Means 
 
 
 
 
95% CI 
 
 
Untransformed 
Arm 
Week 
Estimate 
SE 
Lower CI 
Upper CI 
Difference 
SE 
p-value 
Cohen’s d 
Oxytocin 
3 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
Placebo 
3 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
Oxytocin 
4 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
Placebo 
4 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
Oxytocin 
5 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
Placebo 
5 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
Oxytocin 
6 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
Placebo 
6 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
Oxytocin 
7 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
Placebo 
7 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
Oxytocin 
8 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
Placebo 
8 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
Oxytocin 
9 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
Placebo 
9 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
Oxytocin 
10 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
Placebo 
10 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
Oxytocin 
11 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
Placebo 
11 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
Oxytocin 
12 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
Placebo 
12 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
Oxytocin 
Overall  
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
Placebo 
Overall 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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12.1.3 Secondary Efficacy Endpoints


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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Table 26: 
Drinks per Week from Baseline to Week 12 
 
Oxytocin 
Placebo 
Study Week 
N 
Mean (SD) 
Median 
Min - Max 
N 
Mean (SD) 
Median 
Min - Max 
p-value1 
Baseline 
xx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
1 
xx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
2 
xx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
3 
xx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
4 
xx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
5 
xx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
6 
xx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
7 
xx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
8 
xx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
9 
xx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
10 
xx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
11 
xx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
12 
xx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
3-12 
xx 
xxx (xx.xx) 
xxx 
xxx - xxx 
xxx 
xxx (xx.xx) 
xxx 
xxx - xxx 
 
1t-tests for each  individual week. Week 3-12 is evaluated in modeling 
{programmer note: change test to Wilcoxon if the data are skewed} 
 
 
Table 27: 
Drinks per Week – Mixed Effects, Weeks 3-12 
Type III Wald Tests1 
Parameter 
Num DF Den DF 
F Value 
 
p-value 
ARM 
1 
xxx 
xxx.xx 
0.xxx 
Week 
10 
xxx 
xxx.xx 
0.xxx 
Site 
9 
xxx 
xxx.xx 
0.xxx 
Cov 
x 
xxx 
xxx.xx 
0.xxx 
ARM*Week 
9 
xxx 
xxx.xx 
0.xxx 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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1Values in Type III table are based upon transformed data {note to specify which transformation} 
 
Least Squares Means1 
 
 
 
 
95% CI 
 
 
Untransformed 
Transformed 
Arm 
Week 
Estimate 
SE 
Lower CI 
Upper CI 
Difference 
SE 
p-value 
Cohen’s d 
p-value 
Cohen’s d 
Oxytocin 
3 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
3 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
Oxytocin 
4 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
4 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
Oxytocin 
5 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
5 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
Oxytocin 
6 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
6 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
Oxytocin 
7 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
7 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
Oxytocin 
8 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
8 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
Oxytocin 
9 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
9 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
Oxytocin 
10 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
10 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
Oxytocin 
11 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
11 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
Oxytocin 
12 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
12 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
68 
 
 
 
 
 
95% CI 
 
 
Untransformed 
Transformed 
Arm 
Week 
Estimate 
SE 
Lower CI 
Upper CI 
Difference 
SE 
p-value 
Cohen’s d 
p-value 
Cohen’s d 
Oxytocin 
Overall  
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
Overall 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
1Values are based on untransformed data unless otherwise specified 
 
 
Table 28: 
Drinks per Drinking Day from Baseline to Week 12 
Same format as Table 18 
 
Table 29: 
Drinks per Drinking Day – Mixed Effects, Weeks 3-12 
Same format as Table 19 
 
Table 30: 
Percent Days Abstinent from Baseline to Week 12 
Same format as Table 18 
 
Table 31: 
Percent Days Abstinent – Mixed Effects, Weeks 3-12 
Same format as Table 19 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
69 
 
Table 32: 
WHO Shift Baseline to Weeks 3-12 
 
 
Baseline 
Category 
Week 3-12 Categorya  
Abstinent 
n (%) 
Low Risk 
n (%) 
Medium Risk 
n (%) 
High Risk 
n (%) 
Very High Risk 
n (%) 
High Risk 
 
 
 
 
 
Very High Risk 
 
 
 
 
 
a Percent is based upon row denominator (eg # subjects with High Risk at baseline) 
Same table for Oxytocin subjects only 
Same table for Placebo subjects only 
 
 
 
 
Table 33: 
WHO 1-Level Decrease in Alcohol Consumption – Weeks 3-12 
 
 
 
 
 
 
Placebo 
Oxytocin 
Total 
 
(N=xx) 
(N=xx) 
(N=xxx) 
 
 
 
 
WHO 1-Level Decrease 
 
 
 
  Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
70 
 
Table 34: 
WHO 1-Level Decrease in Alcohol Consumption  – Full Model, Logistic Regression, Weeks 3-12 
 
 
 
 
 
 
 
 
95% CI 
Parameter 
  
DF 
Estimate 
Standard Error 
Wald Chi-Square 
Pr > Chi-Square 
OR 
Upper CI 
Lower CI 
Intercept 
  
1 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
 
 
 
Treatment 
Oxytocin 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
Site 
Overall 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
 
 
 
Site 
1 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
Site 
2..10 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
Cov 
 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
 
Table 35: 
WHO 1-Level Decrease in Alcohol Consumption – Weeks 9-12 (2 Month Grace)  
Same style as Table 33 
Table 36: 
WHO 1-Level Decrease in Alcohol Consumption – Full Model, Logistic Regression, Weeks 9-12 (2 Month 
Grace)  
Same style as Table 34 
 
Table 37: 
WHO 1-Level Decrease in Alcohol Consumption – Weeks 5-12 (1 Month Grace)  
Same style as Table 33 
Table 38: 
WHO 1-Level Decrease in Alcohol Consumption – Full Model, Logistic Regression, Weeks 5-12 (1 Month 
Grace)  
Same style as Table 34 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
71 
 
Table 39: 
WHO 1-Level Decrease in Alcohol Consumption Monthly  
 
Placebo 
Oxytocin 
Total 
 
(N=xx) 
(N=xx) 
(N=xxx) 
Mo 2 WHO 1-Level Decrease 
 
 
 
  Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Mo 3 WHO 1-Level Decrease 
 
 
 
  Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
Table 40: 
Monthly Summary of WHO 1-Level Decrease in Alcohol Consumption – Full Model 
 
 
 
 
 
 
 
 
95% CI 
Model 
Montha 
Parameter 
DF 
Estimate 
Standard 
Error 
Wald 
Chi-
Square 
Pr > Chi-
Square 
OR 
Upper CI 
Lower CI 
2 
Treatment 
Oxytocin 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
3 
Treatment 
Oxytocin 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
 
Adjusted Prevalence Estimates1 
 
 
 
 
 
OR 95% CI 
 
Arm 
Month 
Estimate 
SE 
OR 
Lower CI 
Upper CI 
p-value 
Oxytocin 
2 
xx.xx 
0.xxx 
0.xxx 
x.xxx 
0.xxx 
xx.xxx 
Placebo 
2 
xx.xx 
0.xxx 
0.xxx 
 
 
 
Oxytocin 
3 
xx.xx 
0.xxx 
0.xxx 
x.xxx 
0.xxx 
xx.xxx 
Placebo 
3 
xx.xx 
0.xxx 
0.xxx 
 
 
 
1The adjusted prevalence rates are obtained from the monthly logistic regression models 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
72 
 
Table 41: 
WHO 2-Level Decrease in Alcohol Consumption – Weeks 3-12 
Same as Table 33 
 
Table 42: 
WHO 2-Level Decrease in Alcohol Consumption – Full Model, Logistic Regression, Weeks 3-12 
Same as Table 34 
 
Table 43: 
WHO 2-Level Decrease in Alcohol Consumption – Weeks 9-12 (2 Month Grace) 
Same style as Table 33 
Table 44: 
WHO 2-Level Decrease in Alcohol Consumption – Full Model, Logistic Regression, Weeks 9-12 (2 Month 
Grace)  
Same style as Table 34 
Table 45: 
WHO 2-Level Decrease in Alcohol Consumption – Weeks 5-12 (1 Month Grace)  
Same style as Table 33 
 
Table 46: 
WHO 2-Level Decrease in Alcohol Consumption – Full Model, Logistic Regression, Weeks 5-12 (1 Month 
Grace)  
Same style as Table 34 
 
Table 47: 
WHO 2-Level Decrease in Alcohol Consumption Monthly 
Same style as Table 39 
 
Table 48: 
Monthly Summary of WHO 2-Level Decrease in Alcohol Consumption – Full Model 
Same style as Table 40 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
73 
 
Table 49: 
Subjects Abstinent from Alcohol – Weeks 3-12 
 
 
 
 
 
 
Placebo 
Oxytocin 
Total 
 
(N=xx) 
(N=xx) 
(N=xxx) 
 
 
 
 
Completely 
Abstinent 
 
 
 
  Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Table 50: 
Subjects Abstinent from Alcohol – Full Model, Logistic Regression, Weeks 3-12 
 
 
 
 
 
 
 
 
95% CI 
Parameter 
  
DF 
Estimate 
Standard 
Error 
Wald Chi-
Square 
Pr > Chi-
Square 
OR 
Upper CI 
Lower CI 
Intercept 
  
1 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
 
 
 
Treatment 
Oxytocin 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
Site 
Overall 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
 
 
 
Site 
1 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
Site 
2..10 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
Cov 
 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
 
Table 51: 
Subjects Abstinent from Alcohol – Weeks 9-12 (2 Month Grace) 
Same as Table 49 
 
 
Table 52: 
Subjects Abstinent from Alcohol – Full Model, Logistic Regression, Weeks 9-12 (2 Month Grace) 
Same as Table 50 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
74 
 
Table 53: 
Subjects Abstinent from Alcohol – Weeks 5-12 (1 Month Grace) 
Same as Table 49 
 
Table 54: 
Subjects Abstinent from Alcohol – Full Model, Logistic Regression, Weeks 5-12 (1 Month Grace) 
Same as Table 50 
 
 
Table 55: 
Subjects Abstinent from Alcohol Monthly 
 
 
 
 
 
 
 
Placebo 
Oxytocin 
Total 
 
(N=xx) 
(N=xx) 
(N=xxx) 
 
 
 
 
Mo 2 Drinking Days 
 
 
 
  Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
Mo 3 Drinking Days 
 
 
 
  Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
Table 56: 
Monthly Summary of Subjects Abstinent from Alcohol – Full Model 
 
 
 
 
 
 
 
 
95% CI 
Model 
Montha 
Parameter 
DF 
Estimate 
Standard 
Error 
Wald 
Chi-
Square 
Pr > Chi-
Square 
OR 
Upper CI 
Lower CI 
2 
Treatment 
Oxytocin 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
3 
Treatment 
Oxytocin 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
a Separate models are created for each month; only the treatment arm results are presented in the summary table 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
75 
 
 
Adjusted Prevalence Estimates1 
 
 
 
 
 
OR 95% CI 
 
Arm 
Month 
Estimate 
SE 
OR 
Lower CI 
Upper CI 
p-value 
Oxytocin 
2 
xx.xx 
0.xxx 
0.xxx 
x.xxx 
0.xxx 
xx.xxx 
Placebo 
2 
xx.xx 
0.xxx 
0.xxx 
 
 
 
Oxytocin 
3 
xx.xx 
0.xxx 
0.xxx 
x.xxx 
0.xxx 
xx.xxx 
Placebo 
3 
xx.xx 
0.xxx 
0.xxx 
 
 
 
1The adjusted prevalence rates are obtained from the monthly logistic regression models 
 
 
 
 
Table 57: 
Subjects No Heavy Drinking Days – Weeks 3-12 
 
 
 
 
 
 
 
Placebo 
Oxytocin 
Total 
 
(N=xx) 
(N=xx) 
(N=xxx) 
 
 
 
 
No Heavy Drinking 
Days 
 
 
 
  Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
Table 58: 
Subjects No Heavy Drinking Days – Full Model, Logistic Regression, Weeks 3-12 
Same as Table 50 
 
Table 59: 
Subjects No Heavy Drinking Days – Weeks 9-12 (2 Month Grace) 
Same as Table 49 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
76 
 
 
Table 60: 
Subjects No Heavy Drinking Days – Full Model, Logistic Regression, Weeks 9-12 (2 Month Grace) 
Sam as Table 50 
 
Table 61: 
Subjects No Heavy Drinking Days – Weeks 5-12 (1 Month Grace) 
Same as Table 49 
 
Table 62: 
Subjects No Heavy Drinking Days – Full Model, Logistic Regression, Weeks 5-12 (1 Month Grace) 
Same as Table 50 
 
Table 63: 
Subjects No Heavy Drinking Days -- Monthly 
Same style as Table 55 
 
Table 64: 
Monthly Summary of Subjects No Heavy Drinking Days – Full Model 
Same style as Table 56 
 
 
 
Table 65: 
Urge to Drink Scale – Each Evaluation During Maintenance Period 
 
 
Oxytocin 
Placebo 
Study Week 
N 
Mean 
SD 
Median 
Min 
Max 
N 
Mean 
SD 
Median 
Min 
Max 
Baseline 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
6 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
8 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
10 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
13 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
77 
 
 
Table 66: 
Urge to Drink Scale – Full Model, Mixed Effects, Weeks 6-13  
Type III Wald Tests1 
Parameter 
Num DF Den DF 
F Value 
 
p-value 
ARM 
1 
xxx 
xxx.xx 
0.xxx 
Week 
3 
xxx 
xxx.xx 
0.xxx 
Site 
9 
xxx 
xxx.xx 
0.xxx 
Cov 
X 
xxx 
xxx.xx 
0.xxx 
ARM*Week 
3 
xxx 
xxx.xx 
0.xxx 
1Values in Type III table are based upon transformed data {note to specify which transformation} 
Least Squares Means 
 
 
 
 
95% CI 
 
 
Untransformed 
Transformed 
Arm 
Week 
Estimate 
SE 
Lower CI 
Upper CI 
Difference 
SE 
p-value 
Cohen’s d 
p-value 
Cohen’s d 
Oxytocin 
6 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
6 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
Oxytocin 
8 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
8 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
Oxytocin 
10 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
10 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
Oxytocin 
13 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
13 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
Oxytocin 
Overall  
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
Overall 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
78 
 
Table 67: 
ECR-RS (attachment related anxiety) – Each Evaluation During Maintenance Period 
 
Oxytocin 
Placebo 
Study Week 
N 
Mean 
SD 
Median 
Min 
Max 
N 
Mean 
SD 
Median 
Min 
Max 
Anxiety 
 
 
 
 
 
 
 
 
 
 
Baseline 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
6 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
8 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
10 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
13 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
Table 68: 
ECR-RS Attachment-Related Anxiety – Full Model, Mixed Effects, Weeks 6-13 
Same as Table 66 
 
 
 
Table 69: 
POMS – Each Evaluation During Maintenance Period 
 
Oxytocin 
Placebo 
Study Week 
N 
Mean 
SD 
Median 
Min 
Max 
N 
Mean 
SD 
Median 
Min 
Max 
Tension-Anxiety 
 
 
 
 
 
 
 
 
 
 
Baseline 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
6 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
8 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
10 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
13 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Depression-Dejection 
 
 
 
 
 
 
 
 
 
 
Baseline 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
6 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
8 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
79 
 
10 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
13 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Anger-Hostility 
 
 
 
 
 
 
 
 
 
 
Baseline 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
6 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
8 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
10 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
13 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Vigor-Activity 
 
 
 
 
 
 
 
 
 
 
Baseline 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
6 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
8 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
10 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
13 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Fatigue-Inertia 
 
 
 
 
 
 
 
 
 
 
Baseline 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
6 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
8 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
10 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
13 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Confusion-Bewilderment 
 
 
 
 
 
 
 
 
 
 
Baseline 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
6 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
8 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
10 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
13 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Total Mood Disturbance 
 
 
 
 
 
 
 
 
 
 
Baseline 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
6 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
8 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
10 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
13 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Table 70: 
POMS Tension-Anxiety – Full Model, Mixed Effects, Weeks 6-13 
  Shell is the same style as Table 66 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
80 
 
Table 71: 
POMS Depression-Dejection – Full Model, Mixed Effects, Weeks 6-13  
Shell is same style as Table 66 
 
Table 72: 
POMS Anger-Hostility – Full Model, Mixed Effects, Weeks 6-13  
Shell is same style as Table 66 
 
Table 73: 
POMS Vigor-Activity – Full Model, Mixed Effects, Weeks 6-13  
Shell is same style as Table 66 
 
Table 74: 
POMS Fatigue-Inertia – Full Model, Mixed Effects, Weeks 6-13  
Shell is same style as Table 66 
 
Table 75: 
POMS Confusion-Bewilderment – Full Model, Mixed Effects, Weeks 6-13 
Shell is same style as Table 66 
 
Table 76: 
POMS Total Mood Disturbance – Full Model, Mixed Effects, Weeks 6-13  
Shell is same style as Table 66 
 
 
 
 
Table 77: 
PROMIS – Each Evaluation During Maintenance Period 
 
Oxytocin 
Placebo 
Study Week 
N 
Mean 
SD 
Median 
Min 
Max 
N 
Mean 
SD 
Median 
Min 
Max 
Alcohol Negative Consequences 
 
 
 
 
 
 
 
 
 
 
Baseline 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
6 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
8 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
10 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
81 
 
13 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Sleep Disturbances 
 
 
 
 
 
 
 
 
 
 
Baseline 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
6 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
8 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
10 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
13 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Pain Interference 
 
 
 
 
 
 
 
 
 
 
Baseline 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
6 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
8 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
10 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
13 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Table 78: 
PROMIS Alcohol Use Negative Consequences – Full Model, Mixed Effects, Weeks 6-13  
Shell is the same style as Table 66 
Table 79: 
PROMIS Sleep Disturbances – Full Model, Mixed Effects, Weeks 6-13  
Shell is the same style as Table 66 
Table 80: 
PROMIS Pain Interference – Full Model, Mixed Effects, Weeks 6-13  
Shell is the same style as Table 66 
 
Table 81: 
Mean Cigarettes Smoked per Week (among smokers) – Each Evaluation During Maintenance Period 
 
Oxytocin 
Placebo 
Study Week 
N 
Mean 
SD 
Median 
Min 
Max 
N 
Mean 
SD 
Median 
Min 
Max 
Baseline 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
6 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
8 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
10 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
13 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
82 
 
Table 82: 
Mean Cigarettes Smoked per Week (among Smokers) – Full Model, Mixed Effects, Weeks 6-13 
Same as Table 66 
 
 
 
Table 83: 
Mean Days Use of Other Nicotine Products – Each Evaluation During Maintenance Period 
Same as Table 81 
 
 
Table 84: 
Mean Use of Other Nicotine Products – Full Model, Mixed Effects, Weeks 6-13 
Same as Table 66 
 
 
Table 85: 
Subjects Abstinent from Cigarettes among Smokers Weeks 6-13  
 
 
 
 
 
Placebo 
Oxytocin 
Total 
 
(N=xx) 
(N=xx) 
(N=xxx) 
 
 
 
 
Completely Abstinent 
 
 
 
  Yes 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
  No 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
83 
 
Table 86: 
Subjects Abstinent from Cigarettes (among Smokers) – Logistic Regression, Weeks 6-13  
 
 
 
 
 
 
 
 
95% CI 
Parameter 
  
DF 
Estimate 
Standard 
Error 
Wald Chi-
Square 
Pr > Chi-
Square 
OR 
Upper CI 
Lower CI 
Intercept 
  
1 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
 
 
 
Treatment 
Oxytocin 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
Site 
Overall 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
Site 
1 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
 
 
 
Site 
2..10 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
 
 
 
Cov 
 
x 
xx.xxx 
xx.xxx 
xx.xxx 
0.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
 
 
Table 87: 
MINI AUD Number of Symptoms 
 
Oxytocin 
Placebo 
Study Week 
N 
Mean 
SD 
Median 
Min 
Max 
N 
Mean 
SD 
Median 
Min 
Max 
Baseline 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
13 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
 
Table 88: 
MINI AUD Number of Symptoms – Analysis of Covariance, Week 13 
Type III Wald Tests 
Parameter 
Num DF 
Den DF 
F Value 
 
p-value 
ARM 
1 
xxx 
xxx.xx 
0.xxx 
Site 
9 
xxx 
xxx.xx 
0.xxx 
MINI AUD 
1 
xxx 
xxx.xx 
0.xxx 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
84 
 
Least Squares Means 
 
 
 
95% CI 
 
 
Untransformed 
Transformed 
Arm 
Estimate 
SE 
Lower CI 
Upper CI 
Difference 
SE 
p-value 
Cohen’s d 
p-value 
Cohen’s d 
Oxytocin 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
85 
 
 
12.1.4 
Safety Analyses


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
86 
 
 
Table 89: 
Overall Summary of Adverse Events  
 
Placebo 
Oxytocin 
Total 
 
 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
Number of AEs 
xx 
xx 
xx 
 
Number of SAEs 
xx 
xx 
xx 
 
Number (%) of subjects with at least one AE 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
Number (%) of subjects with at least one SAE 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
Number (%) of subjects with at least one AE related2 to study product 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
Number of AEs by severity 
 
 
 
 
     Mild 
xx 
xx 
xx 
 
     Moderate 
xx 
xx 
xx 
 
    Severe 
xx 
xx 
xx 
 
   Life-threatening 
xx 
xx 
xx 
 
Number of AEs by relationship to study product 
 
 
 
 
     At least possibly related 
xx 
xx 
xx 
 
     Unrelated 
xx 
xx 
xx 
 
Number of AEs by SAE status 
 
 
 
 
     No 
xx 
xx 
xx 
 
     Yes 
xx 
xx 
xx 
 
1p-value from chi-square test   2 Related is possible, probable, or definite 
 
Table 90: 
 Number and Percentage of Subjects with Adverse Events  
 
 
 
 
MedDRA System Organ Class/ 
Placebo 
Oxytocin 
p-value1 
   Preferred Term 
(N=xx) 
(N=xx) 
 
 
 
 
 
- Any Adverse Events -  
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
SOC 
 
 
 
   - Overall -  
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
      Preferred term 1 
xx (xx.x%) 
xx (xx.x%) 
 
      Preferred term 2 
xx (xx.x%) 
xx (xx.x%) 
 
Notes: Percentages are based on the total number of subjects, as given in the column heading. 
Multiple occurrences of a specific adverse event for a subject are counted once in the frequency for the adverse event. Likewise, multiple occurrences of 
adverse events within a specific preferred term for a subject are counted once in the frequency for the preferred term. 
1 Fisher’s exact test 
Programmer’s Notes: Order System Organ Class alphabetically and preferred term alphabetically within System Organ Class. 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
87 
 
 
Table 91: 
Number and Percentage of Subjects with Adverse Events During Weeks 1 & 2 
Same as Table 90 except only the first 2 weeks 
 
Table 92: 
Number and Percentage of Subjects with Adverse Events During Weeks 3-12 
Same as Table 90 except only the last 10 weeks 
 
Table 93: 
Summary of Subjects with Adverse Events by Severity and Relationship – Oxytocin 
Number of Subjects (%) (N=x)  
 
 
Mild 
Moderate 
Severe 
Life-threatening 
All Grades 
SOC 
MedDRA 
PT 
R 
NR 
R 
NR 
R 
NR 
R 
NR 
R 
NR 
R + NR 
 
 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
Notes: Events are counted once per subject at the highest severity grade and closest relationship to the investigational product. R= related to investigational 
product (possibly, probably, definitely). NR = not related to investigational product (unrelated, unlikely). 
 
Table 94: 
Summary of Subjects with Adverse Events by Severity and Relationship – Placebo 
Number of Subjects (%) (N=x)  
 
 
Mild 
Moderate 
Severe 
Life-threatening 
All Grades 
SOC 
MedDRA 
PT 
R 
NR 
R 
NR 
R 
NR 
R 
NR 
R 
NR 
R + NR 
 
 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
xx 
(xx.x%) 
Notes: Events are counted once per subject at the highest severity grade and closest relationship to the investigational product. R= related to investigational 
product (possibly, probably, definitely). NR = not related to investigational product (unrelated, unlikely). 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
88 
 
Table 95: 
Number and Percentage of Subjects with Adverse Events by Maximum Severity  
 
 
 
 
 
 
MedDRA SOC/ 
Placebo 
Oxytocin 
  Preferred Term 
(N=xx) 
(N=xx) 
 
 
 
 
 
 
 
Mild 
Moderate 
Severe 
Life-
threatening 
Mild 
Moderate 
Severe 
Life-
threatening 
 
 
 
 
 
 
 
 
 
- Any Adverse Events -  
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
SOC 
 
 
 
 
 
 
 
 
   - Overall -  
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
      Preferred term 1 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
      Preferred term 2 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
nn (xx.x%) 
Notes: Percentages are based on the total number of subjects, as given in the column heading. 
Multiple occurrences of a specific adverse event for a subject are counted once in the frequency for the adverse event. Likewise, multiple occurrences of adverse 
events within a specific preferred term for a subject are counted once in the frequency for the preferred term. 
Programmer’s Notes: Order System Organ Class alphabetically and preferred term alphabetically within System Organ Class. 
 
 
 
 
Table 96: 
Number and Percentage of Subjects with Adverse Events by Maximum Severity During Weeks 1& 2 
Same as Table 95 using only first 2 weeks 
 
Table 97: 
Number and Percentage of Subjects with Adverse Events by Maximum Severity During Weeks 3-12 
Same as Table 95 using only weeks 3-12 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
89 
 
Table 98: 
Number and Percentage of Subjects with Adverse Events Occurring in >= 5%  
MedDRA SOC/ 
Placebo 
Oxytocin 
 
  Preferred Term 
(N=xx) 
(N=xx) 
p-value1 
 
 
 
 
 
 
 
SOC 
nn (xx.x%) 
nn (xx.x%) 
0.xxx 
   - Overall -  
 
 
 
      Preferred term 1 
nn (xx.x%) 
nn (xx.x%) 
0.xxx 
      Preferred term 2 
nn (xx.x%) 
nn (xx.x%) 
0.xxx 
Notes: Percentages are based on the total number of subjects, as given in the column heading. 
Multiple occurrences of a specific adverse event for a subject are counted once in the frequency for the adverse event. Likewise, multiple occurrences of 
adverse events within a specific preferred term for a subject are counted once in the frequency for the preferred term. At least 5% occurring in either arm 
to be included in the table. 
1 Fisher’s Exact test 
Programmer’s Notes: Order System Organ Class alphabetically and preferred term alphabetically within System Organ Class. 
 
 
Table 99: 
Number and Percentage of Subjects with Adverse Events Leading to Discontinuation of Study  
MedDRA SOC/ 
Placebo 
Oxytocin 
  Preferred Term 
(N=xx) 
(N=xx) 
 
 
 
 
 
SOC 
nn (xx.x%) 
nn (xx.x%) 
   - Overall -  
 
 
      Preferred term 1 
nn (xx.x%) 
nn (xx.x%) 
      Preferred term 2 
nn (xx.x%) 
nn (xx.x%) 
 
nn (xx.x%) 
nn (xx.x%) 
 
 
 
 
nn (xx.x%) 
nn (xx.x%) 
 
nn (xx.x%) 
nn (xx.x%) 
 
nn (xx.x%) 
nn (xx.x%) 
Notes: Percentages are based on the total number of subjects, as given in the column heading. 
Multiple occurrences of a specific adverse event for a subject are counted once in the frequency for the adverse event. Likewise, multiple occurrences of 
adverse events within a specific preferred term for a subject are counted once in the frequency for the preferred term. 
Programmer’s Notes: Order System Organ Class alphabetically and preferred term alphabetically within System Organ Class. 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
90 
 
Table 100: 
Number and Percentage of Subjects with Adverse Events Leading to Discontinuation of Study Medication  
MedDRA SOC/ 
Placebo 
Oxytocin 
  Preferred Term 
(N=xx) 
(N=xx) 
 
 
 
 
 
SOC 
nn (xx.x%) 
nn (xx.x%) 
   - Overall -  
 
 
      Preferred term 1 
nn (xx.x%) 
nn (xx.x%) 
      Preferred term 2 
nn (xx.x%) 
nn (xx.x%) 
 
nn (xx.x%) 
nn (xx.x%) 
 
 
 
 
nn (xx.x%) 
nn (xx.x%) 
 
nn (xx.x%) 
nn (xx.x%) 
 
nn (xx.x%) 
nn (xx.x%) 
Notes: Percentages are based on the total number of subjects, as given in the column heading. 
Multiple occurrences of a specific adverse event for a subject are counted once in the frequency for the adverse event. Likewise, multiple occurrences of 
adverse events within a specific preferred term for a subject are counted once in the frequency for the preferred term. 
Programmer’s Notes: Order System Organ Class alphabetically and preferred term alphabetically within System Organ Class. 
 
Table 101: 
 CIWA-AR Score > 10 at Least Once During Treatment  
 
 
 
 
 
 
 
95% CI 
 
Placebo 
Oxytocin 
Total 
 
 
 
 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
Cohen’s h 
Odds Ratio 
OR Lower CI 
OR Upper CI 
 
 
 
 
 
 
 
 
 
CIWA-AR Score >= 10 
 
 
 
 
 
 
 
 
  Never 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
 
  At Least Once 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
0.xx 
xx.xxx 
xx.xxx 
xx.xxx 
1 Chi-squared test 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
91 
 
Table 102: 
Summary of Vital Signs and Body Weights  
Parameter 
N 
Mean 
SD 
Med 
Max 
Min 
Vital Sign (units) 
 
 
 
 
 
 
 Screening 
 
 
 
 
 
 
   Placebo 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   Oxytocin 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Week 1 
 
 
 
 
 
 
   Placebo 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   Oxytocin 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Change from baseline 
 
 
 
 
 
 
   Placebo 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
   Oxytocin 
xx 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Weeks 1, 2, 3, 4, 6, 8, 10, 13 
 
 
 
 
 
 
Programmers note: vital signs include pulse rate, systolic blood pressure, and diastolic blood pressure. Body weight (lbs) will also be presented for screening, 
Weeks 6, 8, 10 and 13. 
 
 
Table 103: 
Incidence of Abnormal Findings on Physical Exam in Nasal Mucosa 
 
Placebo 
Oxytocin 
 
(N=xx) 
(N=xx) 
 
 
 
Abnomal Nasal Mucosa 
nn (xx.x%) 
nn (xx.x%) 
 
 
Table 104: 
Summary of Other Services Used During Treatment Period  
 
Placebo 
Oxytocin 
Services 
(N=xx) 
(N=xx) 
Self Help Meetings 
 
 
  N 
xx 
xx 
  Mean 
xx.x 
xx.x 
  SD 
xxx.xx 
xxx.xx 
  Median 
xx 
xx 
  Min-Max 
(xx-xx) 
(xx-xx) 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
92 
 
 
Placebo 
Oxytocin 
Services 
(N=xx) 
(N=xx) 
Have you visited another health professional to 
get help reducing drinking? 
 
 
  N 
Xx 
xx 
  Yes n (%) 
xx (xx) 
xx (xx) 
 
 
 
Programmer note: categorize type of professional for those categories reaching 5% 
 
Table 105: 
Summary of ECG Results 
 
ASP8062 
Placebo 
Result 
(N=xx) 
(N=xx) 
Screening 
 
 
  Normal 
nn (xx.x%) 
nn (xx.x%) 
  Abnormal, Not Clinically Significant 
nn (xx.x%) 
nn (xx.x%) 
  Abnormal, Clinically Significant 
nn (xx.x%) 
nn (xx.x%) 
End of Study 
 
 
  Normal 
nn (xx.x%) 
nn (xx.x%) 
  Abnormal, Not Clinically Significant 
nn (xx.x%) 
nn (xx.x%) 
  Abnormal, Clinically Significant 
nn (xx.x%) 
nn (xx.x%) 
 
 
 
Table 106: 
Summary of Blood Chemistries 
 
Placebo 
Oxytocin 
Test 
N 
Mean 
SD 
Med 
Min 
Max 
N 
Mean 
SD 
Med 
Min 
Max 
Test Name (units) 
 
 
 
 
 
 
 
 
 
 
 
 
 Screening 
 
 
 
 
 
 
 
 
 
 
 
 
Week 6 
 
 
 
 
 
 
 
 
 
 
 
 
Change from baseline 
 
 
 
 
 
 
 
 
 
 
 
 
Weeks 8, 10, 13 
 
 
 
 
 
 
 
 
 
 
 
 
Programmers note: table will include creatinine, ALT, AST, total bilirubin, creatinine, sodium, and potassium. 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
93 
 
 
 
Table 107: 
Summary of Positive Urine Drug Tests, Pregnancy Test or BAC > 0.000 Any Time During the Study 
 
Number (% Positive) 
Test 
Placebo 
Oxytocin 
THC 
xx (xx%) 
xx (xx%) 
Cocaine 
xx (xx%) 
xx (xx%) 
Opioids 
xx (xx%) 
xx (xx%) 
Methamphetamine 
xx (xx%) 
xx (xx%) 
Amphetamine 
xx (xx%) 
xx (xx%) 
Benzodiazapines 
xx (xx%) 
xx (xx%) 
Buprenorphine 
xx (xx%) 
xx (xx%) 
Methadone 
xx (xx%) 
xx (xx%) 
Oxycodone 
xx (xx%) 
xx (xx%) 
MDMA 
xx (xx%) 
xx (xx%) 
Barbiturates 
xx (xx%) 
xx (xx%) 
Pregnancy 
xx (xx%) 
xx (xx%) 
BAC > 0.000 
xx (xx%) 
xx (xx%) 
 
 
 
 
 
 
Table 108: 
BPAQ  – Each Evaluation During Maintenance Period 
 
 
Oxytocin 
Placebo 
Study Week 
N 
Mean 
SD 
Median 
Min 
Max 
N 
Mean 
SD 
Median 
Min 
Max 
Physical Aggression 
 
 
 
 
 
 
 
 
 
 
6 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
8 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
10 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
13 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Verbal Aggression 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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6 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
8 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
10 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
13 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Hostility 
 
 
 
 
 
 
 
 
 
 
6 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
8 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
10 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
13 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
Anger 
 
 
 
 
 
 
 
 
 
 
6 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
8 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
10 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
13 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Table 109: 
 BPAQ Physical Aggression Score -- Full Model, Mixed Effects,  Entire Maintenance Period 
Type III Wald Tests1 
Parameter 
Num DF Den DF 
F Value 
 
p-value 
ARM 
1 
xxx 
xxx.xx 
0.xxx 
Week 
3 
xxx 
xxx.xx 
0.xxx 
Site 
9 
xxx 
xxx.xx 
0.xxx 
Baseline 
Total Score 
x 
xxx 
xxx.xx 
0.xxx 
ARM*Week 
3 
xxx 
xxx.xx 
0.xxx 
1Values in Type III table are based upon transformed data {note to specify which transformation} 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
95 
 
 
Least Squares Means 
 
 
 
 
95% CI 
 
 
Untransformed 
Transformed 
Arm 
Week 
Estimate 
SE 
Lower CI 
Upper CI 
Difference 
SE 
p-value 
Cohen’s d 
p-value 
Cohen’s d 
Oxytocin 
6 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
6 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
Oxytocin 
8 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
8 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
Oxytocin 
10 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
10 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
Oxytocin 
13 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
13 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
Oxytocin 
Overall  
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
Overall 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
 
 
Table 110: 
BPAQ Verbal Aggression Score -- Full Model, Mixed Effects, Entire Maintenance Period 
Shell is same style as Table 109 
 
Table 111: 
BPAQ Anger Score -- Full Model, Mixed Effects, Entire Maintenance Period 
Shell is same style as Table 109 
 
Table 112: 
BPAQ Hostility Score -- Full Model, Mixed Effects, Entire Maintenance Period 
Shell is same style as Table 109 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
96 
 
Table 113: 
SNAQ – Untransformed, Each Evaluation During Maintenance Period 
 
 
Oxytocin 
Placebo 
Study Week 
N 
Mean 
SD 
Median 
Min 
Max 
N 
Mean 
SD 
Median 
Min 
Max 
6 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
8 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
10 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
13 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
Table 114: 
SNAQ Score < 14 at Each Visit During Treatment  
 
 
 
 
 
 
 
95% CI 
 
Placebo 
Oxytocin 
Total 
 
 
 
 
(N=xx) 
(N=xx) 
(N=xxx) 
p-value1 
Cohen’s h 
Odds Ratio 
OR Lower CI 
OR Upper CI 
 
 
 
 
 
 
 
 
 
SNAQ Score < 14 
 
 
 
 
 
 
 
 
  Week 6 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
0.xx 
xx.xxx 
xx.xxx 
xx.xxx 
  Week 8 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
0.xx 
xx.xxx 
xx.xxx 
xx.xxx 
  Week 10 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
0.xx 
xx.xxx 
xx.xxx 
xx.xxx 
  Week 13 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
0.xx 
xx.xxx 
xx.xxx 
xx.xxx 
1 Chi-squared test 
 
Table 115: 
SNAQ Total Score -- Full Model, Mixed Effects, Entire Maintenance Period 
Shell is same style as Table 109 
 
Table 116: 
Frequency of Subjects with Suicidal Ideation Any Time During the Study  
Number of Subjects Reporting Suicidal Ideation by C-SSRS (%) 
Placebo 
Oxytocin 
p-value 
(N=xx) 
(N=xx) 
 
xx (xx.x%) 
xx (xx.x%) 
0.xxx 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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12.1.5 
Exploratory Analyses


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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Table 117: 
Moderator: MINI AUD (Percent Heavy Drinking Days Weeks 3-12)  
 
Type III Wald Tests 
Parameter 
Num DF Den DF 
F Value 
 
p-value 
ARM 
1 
xxx 
xxx.xx 
0.xxx 
Week 
11 
xxx 
xxx.xx 
0.xxx 
Site 
9 
xxx 
xxx.xx 
0.xxx 
Baseline 
MINI AUD 
1 
xxx 
xxx.xx 
0.xxx 
ARM*MINI 
AUD 
1 
xxx 
xxx.xx 
0.xxx 
 
 
Least Squares Means 
 
 
 
 
 
95% CI 
 
 
 
AUD Split 
Arm 
Week 
Estimate 
SE 
Lower CI 
Upper CI 
Difference 
SE 
p-value 
Cohen’s d 
Yes 
Oxytocin 
Overall  
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
 
Placebo 
Overall 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
No 
Oxytocin 
Overall  
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
 
Placebo 
Overall 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
 
 
Table 118: 
Moderator: POMS Tension-Anxiety (Percent Heavy Drinking Days Weeks 3-12)  


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
99 
 
Shell style similar to Table 117 
 
Table 119: 
Moderator: POMS Depression-Dejection (Percent Heavy Drinking Days Weeks 3-12)  
Shell style similar to Table 117 
 
Table 120: 
Moderator: ECR-RS Attachment-Related Anxiety (Percent Heavy Drinking Days Weeks 3-12)  
Shell style similar to Table 117 
 
Table 121: 
Moderator: STAI (Percent Heavy Drinking Days Weeks 3-12)  
Shell style similar to Table 117 
 
Table 122: 
Moderator: Drinking Goal (Percent Heavy Drinking Days Weeks 3-12) 
Shell style similar to Table 117 
 
Table 123: 
Moderator: BIS Self Control (Percent Heavy Drinking Days Weeks 3-12)  
Shell style similar to Table 117 
 
Table 124: 
Moderator: BIS Impulsive Behavior (Percent Heavy Drinking Days Weeks 3-12)  
Shell style similar to Table 117 
 
Table 125: 
Moderator: Hyperkatifeia (Percent Heavy Drinking Days Weeks 3-12)  
Shell style similar to Table 117 
 
 
 
 
 
Table 126: 
Hyperkatifeia Total Score 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
100 
 
 
Oxytocin 
Placebo 
Study Week 
N 
Mean 
SD 
Median 
Min 
Max 
N 
Mean 
SD 
Median 
Min 
Max 
Baseline 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
13 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
 
 
Table 127: 
Hyperkatifeia Total Score– Generalized Linear Model, Week 13 
Type III Wald Tests 
Parameter 
Num DF 
Den DF 
F Value 
 
p-value 
ARM 
1 
xxx 
xxx.xx 
0.xxx 
Site 
9 
xxx 
xxx.xx 
0.xxx 
Hyperkatifeia 
1 
xxx 
xxx.xx 
0.xxx 
 
 
Least Squares Means 
 
 
 
95% CI 
 
 
Untransformed 
Transformed 
Arm 
Estimate 
SE 
Lower CI 
Upper CI 
Difference 
SE 
p-value 
Cohen’s d 
p-value 
Cohen’s d 
Oxytocin 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
x.xxx 
x.xxx 
0.xxx 
xx.xxx 
0.xxx 
xx.xxx 
Placebo 
xx.xx 
0.xxx 
0.xxx 
0.xxx 
 
 
 
 
 
 
 
 
Table 128: 
Hyperkatifeia Stress/Anxiety Score 
Same as Table 126 
 
Table 129:  
Hyperkatifeia Stress/Anxiety Score– Generalized Linear Model, Week 13 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
101 
 
Same as Table 127 
 
Table 130: 
Hyperkatifeia Depression Score 
Same as Table 126 
 
Table 131: 
Hyperkatifeia Depression Score– Generalized Linear Model, Week 13 
Same as Table 127 
 
Table 132: 
Hyperkatifeia Irritable Score 
Same as Table 126 
 
Table 133: 
Hyperkatifeia Irritable Score– Generalized Linear Model, Week 13 
Same as Table 127 
 
Table 134: 
Hyperkatifeia Pain Score 
Same as Table 126 
 
Table 135: 
Hyperkatifeia Pain Score– Generalized Linear Model, Week 13 
Same as Table 126 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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12.2 Listings


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
103 
 
 
Listing 1:  
Subject Disposition - All Subjects 
Subject 
ID  
Date of 
Consent  
Treatment 
Group 
Full 
Analysis 
Set  
Study 
Completi
on 
(Day) Date of 
Study Completion 
or Early 
Discontinuation 
Reason for Early 
Discontinuation 
Subject 
confined 
or incar-
cerated 
Start Date/ End 
Date of 
confinement 
xxx 
mm/dd/yyyy 
Oxytocin 
Yes 
Yes 
(xx) mm/dd/yyyy 
xxxxxx 
Yes 
mm/dd/yyyy / 
mm/dd/yyyy 
 
 
Placebo 
No 
No 
 
 
No 
 
 
 
None 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Day is relative to Study Day 0. 
 
 
 
 
 
 
 
Listing 2: 
Enrollment and Randomization – All Consented Subjects 
 
 
 
 
 
 
 
Subject 
ID  
Treatment 
Group 
Date of 
Consent 
Did the subject meet 
all eligibility criteria? 
Randomized? 
Date of 
Randomization 
Kit 
Number 
 
 
 
 
 
 
 
xxx 
Oxytocin 
mm/dd/yyyy 
Yes 
Yes 
mm/dd/yyyy 
xxx 
 
Placebo 
 
No 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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Listing 3: 
Reason not Eligible – Screen Failures 
 
 
 
 
Subject ID 
Criterion Type 
Criterion 
 
 
 
xxx 
Inclusion Criteria 
 
 
Exclusion Criteria 
 
 
 
 
 
Listing 4: 
Protocol Deviations  
 
 
 
 
 
Subject 
ID  
Treatment 
Group 
 
Deviation 
Date 
Protocol Deviation 
Details 
 
 
 
 
 
xxx 
Oxytocin 
mm/dd/yyyy 
Subject Failed to Meet the Inclusion/Exclusion Criteria 
 
 
Placebo 
 
Source Documentation was Not Available 
 
 
 
 
Pregnancy Test Not Performed 
 
 
 
 
Required study data was not obtained or obtained late 
due to site error 
 
 
 
 
Informed Consent Deviation 
 
 
 
 
AE/SAE Reporting Deviation 
 
 
 
 
Other Deviation: 
xxxxxxxxxxxxxxx 
 
 
 
 
 
Note: Only subjects with protocol deviation are listed. 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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Listing 5: 
 Subjects Excluded from the Efficacy Analysis  
 
 
 
Subject 
ID  
Treatment 
Group 
Reason for Exclusion from FA  
 
 
 
Xxx 
Oxytocin 
xxxxxx 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
Note: Only subjects excluded from the efficacy analysis are listed. 
 
Listing 6: 
 Demographics Data  
 
 
 
 
 
 
 
 
Subject 
ID  
Treatment 
Group 
Gender 
Age 
(yrs) 
Ethnicity 
 
Race 
Marital Status 
 
 
 
 
 
 
 
xxx 
Oxytocin 
Male 
xx 
Hispanic or Latino 
American Indian or Alaska Native 
  Married 
 
Placebo 
Female 
 
Not Hispanic or 
Latino 
Asian 
  Divorced 
 
 
 
 
Unknown 
Native Hawaiian or Other Pacific Islander 
  Living with Partner 
 
 
 
 
 
Black or African American 
  Widowed 
 
 
 
 
 
White 
  Separated 
 
 
 
 
 
Other 
  Never Married 
 
 
 
 
 
Unknown 
  Unknown 
 
 
 
 
 
 
  Missing 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
106 
 
 
 
 
 
 
 
 
Subject 
ID  
Treatment 
Group 
Years of 
Education 
Years of Formal Education 
(GED=12years) 
Usual Employment Pattern in 
the last 30 days 
 
 
 
 
 
xxx 
Oxytocin 
xx 
xxx 
Full-time, 35+ hrs/week 
 
Placebo 
 
 
Part-time, regular hours 
 
 
 
 
Part-time, irregular 
hours/daywork 
 
 
 
 
Student 
 
 
 
 
Military service 
 
 
 
 
Unemployed 
 
 
 
 
Retired/Disabled 
 
 
 
 
Homemaker 
 
 
 
 
In controlled environment 
 
 
 
 
Unknown 
 
 
 
 
 
 
 
Listing 7: 
Baseline Drinking Characteristics  
 
 
 
 
 
 
 
 
 
Subject 
ID  
Treatment 
Group 
Drinks/Week 
(Days -1 to -28) 
Drinks/Week  
(Days -1 to -7 
Pre- 
randomization) 
% Change 
Drinks per 
Week Pre-
screen to Pre-
randomization 
Drinks/ 
Drinking Day  
(Days -1 to -28) 
Drinks/Drinking 
Day (Days -1 to -
7 Pre-
randomization) 
% Change 
DPDD Pre-
screen to Pre-
randomization 
 
 
 
 
 
 
 
 
xxx 
Oxytocin 
xxx.x 
xxx.x 
xx.x 
xxx.x 
xxx.x 
xx.x 
 
Placebo 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
107 
 
 
 
 
 
 
 
 
 
Subject 
ID  
Treatment 
Group 
Weekly % Heavy 
Drinking Days  
(Days -1 to -28) 
Weekly % Days 
Abstinent 
 (Days -1 to -28) 
WHO Risk 
Level 
 
 
 
xxx 
Oxytocin 
xxx.x 
xxx.x 
High Risk 
 
Placebo 
 
 
Very High Risk 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 8: 
MINI DSM5 Disorders  
 
 
 
 
 
Subject 
ID  
Treatment 
Group 
Visit Date 
Diagnosis 
Timeframe 
 
 
 
 
 
xxx 
Oxytocin 
mm/dd/yyyy 
xxxxxx 
Current (2 weeks ) 
 
Placebo 
 
 
Past  
 
 
 
 
Recurrent  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Note: Only subjects with a diagnosis of a disorder will be listed. 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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Listing 9: 
MINI DSM5 AUD  
 
 
 
 
Subject 
ID  
Treatment 
Group 
Visit Date 
# of Symptoms 
 
 
 
 
xxx 
Oxytocin 
mm/dd/yyyy 
xx 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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Listing 10: 
MINI AUD End of Study  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject 
ID  
Treatment 
Group 
Item 
# of Symptoms 
 
 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
 
xxx 
Oxytocin 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
Y 
 
 
Placebo 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
 
 
 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
NA 
 
 
Item # 
List of Items 
1 
a. During the times when you drank alcohol, did you end up drinking more than you planned when you started? 
2 
b. Did you repeatedly want to reduce or control your alcohol use? Did you try to cut down or control your alcohol use, but 
failed? IF YES TO EITHER, MARK YES. 
3 
c. On the days that you drank, did you spend substantial time obtaining alcohol, drinking, or recovering from the effects of 
alcohol? 
4 
d. Did you crave or have a strong desire or urge to use alcohol? 
5 
e. Did you spend less time meeting your responsibilities at work, at school, or at home, because of your repeated drinking? 
6 
f. If your drinking caused problems with your family or other people, did you still keep on drinking? 
7 
g. Were you intoxicated more than once in any situation where you or others were physically at risk, for example, driving a car, 
riding a motorbike, using machinery, boating, etc.? 
8 
h. Did you continue to use alcohol, even though it was clear that the alcohol had caused or worsened psychological or physical 
problems? 
9 
i. Did you reduce or give up important work, social or recreational activities because of your drinking? 
10 
j. Did you need to drink a lot more in order to get the same effect that you got when you first started drinking or did you get 
much less effect with continued use of the same amount? 
11 
K1. When you cut down on heavy or prolonged drinking did you have any of the following: [increased sweating or heart rate; 
hand tremor or “the shakes”; trouble sleeping; nausea or vomiting; hearing or seeing things other people could not see or hear or 
having sensations in your skin for no apparent reason; agitation; anxiety; seizures]  (If yes to 2 or more of these, check yes for 
this question), OR 
 
K2. Did you drink alcohol to reduce or avoid withdrawal symptoms or to avoid being hung over? If K1 or K2 = yes, then score 
as yes. 
 
 
 


 
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Listing 11:  Medical History  
 
 
 
 
 
 
Subject 
ID No. 
Treatment 
Group 
SOC 
Specify (Preferred Term/ 
Verbatim Term) 
 
Start Date  
Ongoing 
 
 
 
 
 
 
xxx 
Oxytocin 
Blood and Lymphatic System 
Disorders 
Xxxxxxxxxxx/ xxxxxxxx 
mm/dd/yyyy No 
 
Placebo 
Cardiac Disorders  
 
 
Yes 
 
 
Congenital, Familial and Genetic 
Disorders 
 
 
 
 
 
Ear and Labyrinth Disorders 
 
 
 
 
 
Endocrine Disorders 
 
 
 
 
 
Eye Disorders 
 
 
 
 
 
Gastrointestinal Disorders 
 
 
 
 
 
General Disorders and 
Administration Site Conditions 
 
 
 
 
 
Hepatobiliary Disorders 
 
 
 
 
 
Immune System Disorders 
 
 
 
 
 
Infections and Infestations 
 
 
 
 
 
Injury, Poisoning and Procedural 
Complications 
 
 
 
 
 
Investigations 
 
 
 
 
 
Metabolism and Nutrition 
Disorders 
 
 
 
 
 
Musculoskeletal and Connective 
Tissue Disorders 
 
 
 
 
 
Neoplasms Benign, Malignant 
and Unspecified (incl Cysts and 
Polyps) 
 
 
 
 
 
Nervous system Disorders 
 
 
 
 
 
Pregnancy, Puerperium and 
Perinatal Conditions 
 
 
 
 
 
Psychiatric Disorders 
 
 
 


 
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Renal and Urinary Disorders 
 
 
 
 
 
Reproductive System and Breast 
Disorders 
 
 
 
 
 
Respiratory, Thoracic and 
Mediastinal Disorders 
 
 
 
 
 
Skin and Subcutaneous Tissue 
Disorders 
 
 
 
 
 
Social Circumstances 
 
 
 
 
 
Surgical and Medical Procedures  
 
 
 
 
Vascular Disorders 
 
 
 
 
 
Other:xxxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
Listing 12: 
Surgical History  
 
 
 
 
 
Subject 
ID No. 
Treatment 
Group 
Has the subject had any 
past surgeries? 
Date of Surgery Type of Surgery 
 
 
 
 
 
xxx 
Oxytocin 
Yes  
mm/dd/yyyy 
xxxxxxxxxxxxx 
 
Placebo 
No  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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Listing 13: 
Physical Exam  
 
 
 
 
 
 
 
Subject 
ID No. 
Treatment 
Group 
 
 
 
Exam Date  
 
 
Any abnormal finding 
during the physical exam?  
 
 
Describe  
 
 
 
 
 
 
 
xxx 
Oxytocin 
mm/dd/yyyy 
 
 
Yes  
xxxxxxxx 
 
Placebo 
 
 
 
No  
 
Programming Note: Only report the items that are abnormal 
 
Listing 14: 
 Drinking Treatment History  
Subject 
ID No. 
Treatment 
Group 
Age first 
started 
drinking 
alcohol 
regularly 
 
Number of 
lifetime 
inpatient visits 
to get help with 
reducing or 
quitting 
drinking 
Number of 
lifetime inpatient 
hospitalizations 
for illnesses, 
injuries, or 
accidents due to 
drinking 
Number of times 
in lifetime 
underwent 
alcohol 
detoxification 
using medication 
Number of 
lifetime 
outpatient visits 
with a health 
professional to 
get help with 
reducing or 
quitting drinking 
 
Number of group 
meetings 
attended for 
alcohol problems 
or drinking in 
the past year 
 
 
 
 
 
 
 
 
xxx 
Oxytocin 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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Listing 15: 
Drinking Goal  
 
 
 
 
Subjects wanting to reduce drinking, expected drinks per day 
Subject 
ID  
Treatment 
Group 
Visit Date 
Which treatment goal 
would you like to 
achieve by the end of the 
study? 
Mon 
Tues 
Wed 
Thur 
Fri 
Sat 
Sun 
 
 
 
 
 
 
 
 
 
 
 
xxx 
Oxytocin 
mm/dd/yyyy 
Abstinence 
x 
x 
x 
x 
x 
x 
x 
 
Placebo 
 
Reduction but not stop 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject 
ID  
Treatment 
Group 
Visit Date 
How motivated to reach 
your goal? 
How confident to achieve your goal? 
 
 
 
 
 
xxx 
Oxytocin 
mm/dd/yyyy 
1=Not Motivated 
1=Not Confident 
 
Placebo 
 
2, 3, 4, 5, 6, 7, 8, 9 
2, 3, 4, 5, 6, 7, 8, 9 
 
 
 
10=Extremely Motivated 
10=Extremely Confident 
 
 
 
Refuse to answer 
Refuse to answer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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Listing 16: 
Daily and Weekly Standard Drink Units (TLFB) During Treatment  
Subject 
ID 
Treatment 
Group 
Week 
D1 
D2 
D3 
D4 
D5 
D6 
D7 
Mean 
drinks/day 
Mean drinks/ 
drinking day 
Heavy 
drinking days 
% days 
abstinent 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxx 
Oxytocin 
1 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx.xx 
xx.xx 
xx.xx 
xx 
 
Placebo 
2 
 
 
 
 
 
 
 
 
 
 
 
 
 
3, etc 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 17: 
Drinking Question  
 
 
 
 
 
 
Subject 
ID  
Treatment 
Group 
Date of 
Assessment 
Did the subject have any 
drinking days since the 
last visit? 
Did the subject have any 
heavy drinking days since 
the last visit? 
Date of last visit 
 
 
 
 
 
 
xxx 
Oxytocin 
mm/dd/yyyy 
Yes 
Yes 
mm/dd/yyyy 
 
Placebo 
 
No 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 18: 
Drinking Consequences, Craving, Appetite, and Anxiety  
 
 
 
 
 
 
 
 
 
Subject 
ID 
Treatment 
Group 
Week 
Urge to Drink 
CIWA-AR 
STAI 
SNAQ 
ECR-RS 
Attachment-
Related Anxiety 
BIS Total Score 
 
 
 
 
 
 
 
 
 
xxx 
Oxytocin 
xx 
 
xx 
xx 
xx 
xx 
xx 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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Listing 19: 
UPSIT Scores 
 
 
 
 
 
Subject 
ID  
Treatment 
Group 
Week 
Total Score 
Category 
 
 
 
 
 
xxx 
Oxytocin 
xx 
xx 
Normosmia 
 
Placebo 
 
 
Mild microsmia 
 
 
 
 
Moderate microsmia 
 
 
 
 
Severe microsmia 
 
 
 
 
 Anosmia 
 
 
 
 
Normosmia 
 
 
Listing 20: 
POMS Scores  
 
 
 
Scores 
Subject 
ID 
Treatment 
Group 
Week 
Total Mood 
Disturbance  
Tension  
Depression  
Anger 
Fatigue 
Confusion  
Vigor  
 
 
 
 
 
 
 
 
 
 
xxx 
Oxytocin 
xx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
xxx 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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Listing 21: 
PROMIS Scale Scores  
Subject 
ID 
Treatment 
Group 
Week 
Sleep Disturbance 
Alcohol Negative 
Consequences 
Pain Interference 
 
 
 
 
 
 
xxx 
Oxytocin 
xx 
xx 
xx 
xx 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 22: 
Smoking Data 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject 
ID  
Treatment 
Group 
Week 
Visit Date 
Over the past 
week, how many 
days did you 
smoke 
cigarettes? 
On the days you 
smoked, how 
many cigarettes 
did you smoke 
on average? 
 How many days 
did you use other 
tobacco or 
nicotine products 
during the past 
week? 
 
 
 
 
 
 
 
xxx 
Oxytocin 
1, 6, 8, 10, 13 
mm/dd/yyyy 
x 
xx 
x  
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Listing 23: 
 Exit Interview  
 
 
 
 
 
 
 
Subject 
ID  
Treatment 
Group 
Visit Date 
What study drug do 
you believe you 
were taking? 
Why do you think you 
received that drug? 
Do you feel the study 
drug helped you to 
reduced drinking? 
How would you describe 
your experience taking the 
study drug? 
 
 
 
 
 
 
 
xxx 
Oxytocin 
mm/dd/yyyy 
Placebo 
Had side effects 
Very Much  
Experienced no unwanted side 
effects and benefited from 
taking the medication 
 
Placebo 
 
Active medication 
Had no side effects 
Much  
Experienced some unwanted 
side effects but benefited from 
taking the medication 
 
 
 
Both placebo and 
active 
Staff told me 
Moderately  
Experienced a lot unwanted 
side effects but benefited from 
taking the medication 
 
 
 
Don’t know 
Staff treatment me 
different  
A Little  
Experienced no unwanted side 
effects but did not benefit 
from taking the medication 
 
 
 
Other substance  
No improvement in 
drinking 
Not Little  
Experienced some unwanted 
side effects and did not benefit 
from taking the medication 
 
 
 
 
Had improvement in 
drinking  
Not at all  
Experienced a lot of unwanted 
side effects and did not benefit 
from taking the medication 
 
 
 
 
Had a hunch  
 
 
 
 
 
 
I just felt different  
 
 
 
 
 
 
Other: xxxxx 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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Subject 
ID  
Treatment 
Group 
Visit Date 
If a friend were in need of help 
for a drinking problem, would 
you recommend taking the study 
drug to him/her? 
If you were to need 
treatment in the future, 
would you choose to take 
the study drug again? 
How much do you think of 
yourself as wanting to 
please other people (people 
pleaser)? 
 
 
 
 
 
 
xxx 
Oxytocin 
mm/dd/yyyy 
Yes, definitely 
Definitely yes 
More than average 
 
Placebo 
 
Yes, generally 
Probably yes 
Average 
 
 
 
Neither yes nor no 
Maybe 
Less than average 
 
 
 
No, not really 
Probably not 
 
 
 
 
No, definitely not 
Definitely not 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 24: 
Other Services Use  
 
 
 
 
 
 
 
 
Subject 
ID  
Group 
Date 
Week 
Since your last visit 
did you attend any 
AA, 12-step, SOS, or 
similar group 
meeting? 
How 
many? 
Have you visited another 
health professional to get 
help reducing drinking? 
What type of 
professional? 
 
 
 
 
 
 
 
 
xxx 
Oxytocin 
mm/dd/yyyy 
xx 
Yes 
xxxx 
Yes 
xxxxx 
 
Placebo 
 
 
No 
 
No 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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Listing 25: 
Drug Exposure  
 
 
 
 
 
 
 
 
 
Subject 
ID No. 
Treatment 
Group 
Study 
Month 
Date Start of 
Month 
Date End of 
End of 
Month 
Volume of 
Drug 
Prescribed 
 
Volume of 
Drug 
Taken 
 
Reason for Discontinuation  
 
 
 
 
 
 
 
 
xxx 
Oxytocin 
1, 2, 3 
mm/dd/yyyy 
mm/dd/yyyy 
xx 
xx 
 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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Listing 26: 
 Adverse Events  
 
Notes: Day is relative to Study Day 0. 
 Severity: 1=Mild; 2=Moderate; 3=Severe; 4=Potentially Life-threatening. 
 Relationship: 1= Unrelated; 2=Unlikely; 3=Possibly; 4=Probably; 5=Definitely 
 Action Taken Due to AE: 1=None; 2=Treated with Drugs; 3=Non-drug treatment; 4=ER/Outpatient visit; 5=Hospitalization; 6=Referral for treatment 
 Outcome: 1=Resolved; 2=Recovered with sequelae; 3=Ongoing; 4=Required treatment; 5=Unknown 
 
Programmer’s Note: If “Were any AEs reported?” checkbox=No, then display “None Reported” in the Adverse Event column and SOC/PT column. If an AE 
started and stopped the same day, the duration is 1 day. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject 
ID 
Treatment 
Group 
Adverse 
Event 
(Verbatim) 
S: SOC 
P: PT 
Term 
Start Date/ 
Day 
Stop Date/ 
Day 
 
Duration 
in Days 
Severity Relation
-ship 
Actions 
Taken 
Outcome 
Serious 
 
 
 
 
 
 
 
 
 
 
 
xxx 
Oxytocin 
Verbatim 
mm/dd/yyyy  
mm/dd/yyyy   
1 
1 
1 
1 
Yes 
 
Placebo 
S: xxxx 
xx 
xx 
 
2 
2 
2 
2 
No 
 
 
P: xxxx 
 
 
 
3 
3 
3 
3 
 
 
 
 
 
 
 
4 
4 
4 
4 
 
 
 
 
 
 
 
 
5 
5 
5 
 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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Listing 27: 
 Adverse Events Leading to Subject Discontinuation from Study 
 
Notes: Day is relative to Study Day 0. 
 Severity: 1=Mild; 2=Moderate; 3=Severe; 4=Potentially Life-threatening. 
 Relationship: 1= Unrelated; 2=Unlikely; 3=Possibly; 4=Probably; 5=Definitely 
 Action Taken Due to AE: 1=None; 2=Treated with Drugs; 3=Non-drug treatment; 4=ER/Outpatient visit; 5=Hospitalization; 6=Referral for treatment 
 Outcome: 1=Resolved; 2=Recovered with sequelae; 3=Ongoing; 4=Required treatment; 5=Unknown 
 
Programmer’s Note: If “Were any AEs reported?” checkbox=No, then display “None Reported” in the Adverse Event column and SOC/PT column. If an AE 
started and stopped the same day, the duration is 1 day. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject 
ID 
Treatment 
Group 
Adverse 
Event 
(Verbatim) 
S: SOC 
P: PT 
Term 
Start Date/ 
Day 
Stop Date/ 
Day 
 
Duration 
in Days 
Severity Relation
-ship 
Actions 
Taken 
Outcome 
Serious 
 
 
 
 
 
 
 
 
 
 
 
xxx 
Oxytocin 
Verbatim 
mm/dd/yyyy  
mm/dd/yyyy   
1 
1 
1 
1 
Yes 
 
Placebo 
S: xxxx 
xx 
xx 
 
2 
2 
2 
2 
No 
 
 
P: xxxx 
 
 
 
3 
3 
3 
3 
 
 
 
 
 
 
 
4 
4 
4 
4 
 
 
 
 
 
 
 
 
5 
5 
5 
 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Listing 28: 
 Adverse Events Leading to Discontinuation of Investigational Product 
 
Notes: Day is relative to Study Day 0. 
 Severity: 1=Mild; 2=Moderate; 3=Severe; 4=Potentially Life-threatening. 
 Relationship: 1= Unrelated; 2=Unlikely; 3=Possibly; 4=Probably; 5=Definitely 
 Action Taken Due to AE: 1=None; 2=Treated with Drugs; 3=Non-drug treatment; 4=ER/Outpatient visit; 5=Hospitalization; 6=Referral for treatment 
 Outcome: 1=Resolved; 2=Recovered with sequelae; 3=Ongoing; 4=Required treatment; 5=Unknown 
 
Programmer’s Note: If “Were any AEs reported?” checkbox=No, then display “None Reported” in the Adverse Event column and SOC/PT column. If an AE 
started and stopped the same day, the duration is 1 day. 
 
 
 
 
 
 
 
 
 
 
 
 
Subject 
ID 
Treatment 
Group 
Adverse 
Event 
(Verbatim) 
S: SOC 
P: PT 
Term 
Start Date/ 
Day 
Stop Date/ 
Day 
 
Duration 
in Days 
Severity Relation
-ship 
Actions 
Taken 
Outcome 
Serious 
 
 
 
 
 
 
 
 
 
 
 
xxx 
Oxytocin 
Verbatim 
mm/dd/yyyy  
mm/dd/yyyy   
1 
1 
1 
1 
Yes 
 
Placebo 
S: xxxx 
xx 
xx 
 
2 
2 
2 
2 
No 
 
 
P: xxxx 
 
 
 
3 
3 
3 
3 
 
 
 
 
 
 
 
4 
4 
4 
4 
 
 
 
 
 
 
 
 
5 
5 
5 
 
 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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 Listing 29: 
Serious Adverse Events  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject 
ID No. 
SAE 
Continued 
Study 
Participation 
Study Drug 
Start Date 
Date of last 
administration 
of study drug 
prior to SAE 
SAE Abated 
after study 
drug 
stopped? 
Continued 
study drug 
Administration 
SAE 
reappeared 
after 
rechallenge? 
Outcome 
 
 
 
 
 
 
 
 
 
xxx 
Verbatim 
Yes 
mm/dd/yyyy 
mm/dd/yyyy 
Yes 
Yes 
Yes 
1 
 
 
No 
 
 
No 
No 
No 
2 
 
 
 
 
 
n/a 
 
n/a 
3 
 Notes: Day is relative to Study Day 0. 
Severity: 1=Mild; 2=Moderate; 3=Severe; 4=Potentially Life-threatening. 
Relationship: 1= Unrelated; 2=Unlikely; 3=Possibly; 4=Probably; 5=Definitely 
Outcome: 1=Recovered/Resolved; 2=Recovering/Resolving; 3=Not Recovered/Not Resolved; 4=Recovered/Resolved With Sequelae; 5=Fatal (Date of Death) 
 
 
. 
 
 
 
 
 
 
 
 
 
 
Subject 
ID  
Treatment 
Group 
SAE 
Verbatim 
S: SOC 
P: PT 
Start Date/ 
Day 
Stop Date/ 
Day 
SAE Category 
Severity 
Relationship 
 
 
 
 
 
 
 
 
xxx 
Oxytocin 
Verbatim 
mm/dd/yyyy  
mm/dd/yyyy  
Death 
1 
1 
 
Placebo 
S: XXX 
Xx 
Xx 
Life-threatening 
2 
2 
 
 
P: XX 
 
 
Hospitalization 
3 
3 
 
 
 
 
 
Disability 
4 
4 
 
 
 
 
 
Congenital Anomaly/Birth 
Defect 
5 
5 
 
 
 
 
 
Required Intervention to Prevent 
Permanent Impairment / Damage 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
 
 


 
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Listing 30: 
Columbia-Suicide Severity Scale  
 
 
 
 
Response 
to 
Question: 
 
 
 
 
 
 
 
 
 
 
 
 
Subjec
t ID  
Treatment 
Group 
Visit Date 
Study 
Week 
Q1 
Q2 
Q3 
Q4 
Q5 
Q6 
Q7 
Q8 
Q9 
Q10 
Q11 
Q12 
Q13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxx 
Oxytocin 
mm/dd/yyyy 
1, 2 , 5  
Yes 
Yes 
Yes 
Yes 
Yes 
Yes 
Type 1 
1 
1 
0 
0 
0 
Yes 
 
Placebo 
 
9, 13  
No 
No 
No 
No 
No 
No 
Type 2 
2 
2 
1 
1 
1 
No 
 
 
 
 
 
 
 
 
 
 
Type 3 
3 
3 
2 
2 
2 
 
 
 
 
 
 
 
 
 
 
 
Type 4 
4 
4 
3 
3 
3 
 
 
 
 
 
 
 
 
 
 
 
Type 5 
5 
5 
4 
4 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5 
5 
5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Suicide Ideation 
1. Have you wished you were dead or wished you could go to sleep and not wake up? 
2. Have you actually had any thoughts of killing yourself? 
3. Have you been thinking about how you might do this? 
4. Have you had these thoughts and had some intention of acting on them? 
5. Have you started to work out or worked out the details of how to kill yourself? 
6. Do you intend to carry out this plan? 
Intensity of Ideation 
7. The following features should be rated with respect to the most severe type of ideation (i.e. 1-5 with 1 being the least severe and 5 being the most 
severe) 
8. How many times have you had these thoughts?1=Less than once a week; 2=Once a week;  3=2-5 times a week;  4=Daily or almost;  
5=Many times each day 
9. When you have the thoughts, how long do they last? 1=Fleeting-few seconds or minutes; 2=Less than 1 hr-some of the time;  3=1-4 hrs/a lot of time;  
4=4-8 hrs/most of day;  5=More than 8 hours/persistent or continuous 
10. Could/can you stop thinking about killing yourself or wanting to die if you want to?  1=Easily; 2=Little Difficulty; 3=Some Difficulty; 
4=Lot of Difficulty;  5=Unable to control; 0=Does not attempt to control 
11. Are there things that stop you from wanting to die or acting on thoughts of committing suicide? 1=Definite deterrents; 2=Probably Deterrents;  
3=Uncertain Deterrents; 4=Unlikely Deterrents; 5=No Deterrents; 0=Does not apply 
12. What sort of reasons did you have for thinking about wanting to die or killing yourself? Was it to end pain or stop the way you were feeling or to get 
attention, revenge or reaction from others 1=Completely to get attention or revenge or reaction; 2=Mostly to get attention or revenge or reaction; 
3=Equally to get attention or revenge or reaction and stop pain; 4=Mostly to stop pain; 5=Completely to stop pain; 0=Does not apply 
Suicidal Behavior 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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13. Have you made a suicide attempt? 
14. Number of attempts 
15. Has the subject engaged in non-suicidal self-injurious behavior? 
16. Has there been a time when you started to do something to end your life but someone or something stopped you before actually did anything? 
17. Number interrupted 
18. Has there been a time when you stared to do something to try to end your life but you stopped yourself before you actually did anything? 
19. Number aborted 
20. Have you taken any step towards making a suicide attempt or preparing to kill yourself? 
21. Suicidal behavior was present during the assessment period 
22. Completed suicide? 
23. Actual Lethality/Medical Damage;  0=No physical damage; 1=Minor physical damage; 2=Moderate physical Damage; 3=Moderately severe physical 
damage; 4=Severe physical damage; 5=Death 
24. Potential Lethality;  0=Behavior not likely to result in injury; 1=Behavior likely to result in injury, but not death; 2=Behavior likely to result in death 
 
 


 
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Listing 31: 
BPAQ Scores  
 
 
 
Scores 
Subject 
ID 
Treatment 
Group 
Week 
Physical 
Aggression  
Verbal 
Aggression  Hostility  
Anger 
 
 
 
 
 
 
 
xxx 
Oxytocin 
xx 
xxx 
xxx 
xxx 
xxx 
 
Placebo 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 32: 
Blood Chemistries  
Subject 
ID  
Treatment 
Group 
Visit Date 
Test Name 
Result 
Units 
Flag 
Evaluation 
xxxx 
Oxytocin 
mm/dd/yyyy 
Creatinine 
x.xx 
mg/dL 
H (high) 
WNL 
 
Placebo 
 
Total Bilirubin 
xxx 
mg/dL 
L (low) 
Abnormal, NCS 
 
 
 
ALT 
xx.x 
U/L 
 
Abnormal, CS 
 
 
 
AST 
x.xx 
U/L 
 
 
 
 
 
sodium 
xx.x 
U/L 
 
 
 
 
 
Potassium 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Listing 33: 
Pregnancy Test/Birth Control Data  
 
 
 
 
 
 
Subject ID  Treatment Group 
Pregnancy Test 
Performed? 
 
Pregnancy Test 
Date 
Pregnancy 
Result 
Methods of birth control 
 
 
 
 
 
 
xxx 
Oxytocin 
Not Done 
mm/dd/yyyy 
Negative 
Oral Contraceptive 
 
Placebo 
 
 
Positive 
Contraceptive Sponge 
 
 
 
 
 
Contraceptive Skin Patch 
 
 
 
 
 
Double Barrier 
 
 
 
 
 
Intrauterine 
 
 
 
 
 
Etonogestrel implant 
 
 
 
 
 
Medroxyprogesterone 
 
 
 
 
 
Complete Abstinence 
 
 
 
 
 
Hormonal Vaginal contraceptive Ring  
 
 
 
 
 
Surgically Sterile 
 
 
 
 
 
Postmenopausal 
 
 
 
 
 
Partner surgically Sterile 
 
 
 
 
 
Other : xxxxxxxxxxxxxxxx 
 
 
 
 
 
 
  Programming note: Only indicate birth control methods that were indicated as Yes 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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Listing 34: 
 Blood Alcohol Concentration  
 
 
 
 
 
 
 
Subject 
ID  
Treatment 
Group 
Visit Date 
Study 
Week 
BAC 
Performed 
Time of 
BAC 
BAC % 
 
 
 
 
 
 
 
xxx 
Oxytocin 
mm/dd/yyyy 
Screen 
Done  
hh:mm 
x.xxx 
 
Placebo 
 
1, 2, 3 
Not Done  
 
 
 
 
 
4, 6, 8 
 
 
 
 
 
 
10, 13 
 
 
 
 
 
 
 
 
 
 
 
 
 
Listing 35: 
Urine Drug Screen  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject 
ID  
Treatment 
Group 
Visit Date 
Study 
Week 
AMP
a,b 
Benzos 
Barb 
Coc 
Bup 
EGT 
MDMA 
Meth 
Methadone 
Opioids 
Oxy 
THC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxx 
Oxytocin 
mm/dd/yyyy 
Screen 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
P 
 
Placebo 
 
1, 2, 3 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
N 
 
 
 
4, 6, 8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10, 13 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a P=positive; N=negative 
b AMP=amphetamine, Benzos=benzodiazepines, Coc=cocaine, Meth=methamphetamine, Oxy=oxycodone, Bup=buprenorphine, 
Barb=barbiturates 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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Listing 36: 
Vital Signs and Body Weights 
 
 
 Listing 37: 
Prior and Concomitant Medications  
Subject 
ID 
Treatment 
Group  
Prior 
Med?  
Verbatim Med 
 
Indication 
Route  
Frequency 
Dose  
Start Date  
Stop Date  
Continuing?  
xxx 
Oxytocin 
Yes  
xxx  
xxxxxx 
xxxxxx  
xxxxxx 
xxxxxx  
dd/mmm/yyyy 
dd/mmm/yyyy  
Yes  
xxx 
Placebo 
No  
xxx  
 
 
 
 
 
 
No  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject ID  
Treatment 
Group 
Visit Date 
Study 
Week 
Weight (Kg) 
Heart Rate 
(beats/min) 
Systolic Pressure 
(mmHg) 
Diastolic Pressure 
(mmHg) 
 
 
 
 
 
 
 
 
xxx 
Oxytocin 
mm/dd/yyyy 
Screening  
xxx 
xxx 
xxx 
xxx 
 
Placebo 
 
4 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
12, 16, 20 
 
 
 
 
 
 
 
24, 26, 27 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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12.3 Figures 
 
Figure 1: 
Percent Heavy Drinking Days per Week Least Squares Means – Untransformed  
 
Programmer note: connect the week estimates for each treatment group using linear line join, 95% CI at each estimate, add Cohen’s d to each point and * p-value <0.05 
 
Figure 2: 
Mean Drinks per Week Least Squares Means – Untransformed  
Shell style similar to Figure 1 
Figure 3: 
Mean Drinks per Drinking Day by Week Least Squares Means – Untransformed  
Shell style similar to Figure 1 
 
 
 
 
 
0 
0.2 
0.4 
0.6 
0.8 
1 
1.2 
0 
4 
8 
12 
Placebo 
Oxytocin 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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Figure 4: 
Percentage of Subjects No Heavy Drinking Days Weeks 3-12  
 
Programmer note: Use percent on y-axis, bar graph of PSNHDD add Cohen’s h, * a significant p-value, put values on graph 
 
Figure 5: 
Percentage of Subjects Abstinent Weeks 3-12 
Shell style similar to Figure 4 
 
Figure 6: 
Percentage of Subjects with WHO 1-Level Decrease in Alcohol Consumption Weeks 3-12  
Shell style similar to Figure 4 
 
Figure 7: 
Percentage of Subjects with WHO 2-Level Decrease in Alcohol Consumption Weeks 3-12 
0 
0.2 
0.4 
0.6 
0.8 
1 
Oxytocin 
Placebo 
PSNHDD 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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Shell style similar to Figure 4 
 
Figure 8: 
Cumulative Grace Periods for Percentage of Subjects No Heavy Drinking Days  
Shell style similar to Figure 4 
 
Programmer note put all of the grace periods (full treatment period, 1 month, 2 months) on the same graph 
Figure 9: 
Cumulative Grace Periods for Percentage of Subjects Abstinent  
Shell style similar to Figure 4 
 
Figure 10: 
Cumulative Grace Periods for Percentage WHO 1-Level Decrease in Alcohol Consumption 
Shell style similar to Figure 4 
 
 
Figure 11: 
Cumulative Grace Periods for Percentage WHO 2-Level Decrease in Alcohol Consumption 
Shell style similar to Figure 4 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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Figure 12: 
Percentage Days Abstinent per Week Least Squares Means – Untransformed  
 
Programmer note: connect the week estimates for each treatment group using linear line join, add Cohen’s d to each point and * p-value <0.05 
 
 
 
 
Figure 13: 
Weekly Number of Cigarettes Smoked in Smokers Least Squares Means – Untransformed 
Shell style similar to Figure 12 
 
Figure 14: 
POMS Total Score Least Squares Means by Visit – Untransformed  
Shell style similar to Figure 12 
 
Figure 15: 
POMS Tension-Anxiety Least Squares Means by Visit – Untransformed  
0 
0.2 
0.4 
0.6 
0.8 
1 
1.2 
0 
4 
8 
12 
Placebo 
Oxytocin 


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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Shell style similar to Figure 12 
 
Figure 16: 
POMS Depression-Dejection Least Squares Means by Visit – Untransformed  
Shell style similar to Figure 12 
 
Figure 17: 
POMS Vigor-Activity Least Squares Means by Visit – Untransformed  
Shell style similar to Figure 12 
 
Figure 18: 
POMS Fatigue-Inertia Least Squares Means by Visit – Untransformed  
Shell style similar to Figure 12 
 
Figure 19: 
POMS Anger-Hostility Least Squares Means by Visit – Untransformed  
Shell style similar to Figure 12 
 
Figure 20: 
POMS Confusion-Bewilderment Least Squares Means by Visit – Untransformed  
Shell style similar to Figure 12 
 
Figure 21: 
PROMIS Alcohol Negative Consequences Least Squares Means by Visit – Untransformed  
Shell style similar to Figure 12 
 
Figure 22: 
PROMIS Sleep Disturbances Least Squares Means by Visit – Untransformed  
Shell style similar to Figure 12 
 
Figure 23: 
PROMIS Pain Interference Least Squares Means by Visit – Untransformed  
Shell style similar to Figure 12 
 
Figure 24: 
ECR-RS Attachment-Related Anxiety Least Squares Means by Visit – Untransformed  


 
Statistical Analysis Plan: Protocol NCIG-007R, Version 1.0  Dated: 7 Sep 2023 
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Shell style similar to Figure 12 
 
Figure 25: 
Clinical Chemistry Values Over Time