Clinical trial NCT04051619
Conditions: Opioid Use Disorder
Sponsor: Brown University
Start date: 2020-01-06; Completion date: 2023-12-23
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Although stress has long been linked to substance use, craving and relapse, there are no available medications that target stress-induced substance use disorder (SUD). In particular, with the rise in opioid use, there is still a crucial need for developing effective pharmacological treatments that target and integrate the complexity of this disease. The long term goal of this project is to identify the key neuroendocrine pathways that are responsible for stress-induced craving in individuals with opioid use disorder (OUD) in order to better understand how they can be effectively treated.

Detailed description:
The goal of this research is to evaluate whether oxytocin, a hormone with anti-stress properties, dampens the effects of stress and opioid-associated cues on opioid craving and thus may be an effective adjunctive treatment for OUD.

The central hypothesis of this research is that oxytocin will reduce stress-induced opioid craving in patients with OUD treated with buprenorphine/naloxone as opioid replacement therapy (ORT). This hypothesis is based on the model of addiction (Koob, Neuron 2008) in which chronic substance use and stress lead to neurobehavioral counter-adaptations that dysregulate biobehavioral response.

In this double-blind, cross-over, placebo controlled, randomized trial, individuals with OUD (N=20 who are currently receiving treatment with buprenorphine/naloxone or methadone will be randomized to intranasal oxytocin (40 international units, IU) and oxytocin-matched placebo, administered twice/day for 7 days with a minimum of two days between the opposite condition (oxytocin or placebo). On days 5 and 7, and on days 14 and 16, participants will complete two counter-balanced sessions in which they receive yohimbine (32.4 mg) or yohimbine-matched placebo.

Arms: arm 1: Oxytocin was administered as 40 IU/0.12 mL nasal spray in each nostril once in the morning and once in the afternoon for 7 days. After a 2 day washout period, Placebo was administered as nasal spray in each nostril once in the morning and once in the afternoon for 7 days. arm 2: Placebo was administered as nasal spray in each nostril once in the morning and once in the afternoon for 7 days. After a 2 day washout period, oxytocin was administered as 40 IU/0.12 mL nasal spray in each nostril once in the morning and once in the afternoon for 7 days.
Interventions: intervention 1: intranasal oxytocin, 40 IU, twice a day for 7 days
Intervention descriptions: intervention 1: Adjunct therapy

Protocol documents:
ICF_002.pdf: 
Oxytocin reduces noradrenergic-induced opioid-like withdrawal symptoms 
in individuals on opioid agonist therapy  
 
 
 
INFORMED CONSENT DOCUMENT 
 
 
 
Carolina L. Haass-Koffler, PharmD, PhD 
121 South Main Street 
Providence, RI 02903 
Tel: 401-863-6624; Fax: 401-863-6697 
carolina_haass-koffler@brown.edu 
 
 
ORIGINAL: 2019 AUGUST 08 
REVISED: 2022 MAY 05 
 
 
Clinical trial registration: Clinicaltrials.gov; NCT04051619 
 
IND/FDA: 135570, oxytocin and yohimbine (Holder: Haass-Koffler) 
 
 
 
 
 
 
 


 
Initials_________ 
BROWN UNIVERSITY 
CONSENT FOR RESEARCH PARTICIPATION 
  
Oxytocin to reduce stress-induced craving in individuals with opioid use disorder 
Primary Participation 
                               Version #8, May 4, 2022 
 
Principal Investigator: Carolina Haass-Koffler, PharmD 
Co-Investigator: Robert Swift, MD, PhD  
 
INFORMED CONSENT FORM  
  
1. You are invited to participate in the following research study:  
  
Oxytocin to reduce stress-induced craving in individuals with opioid use disorder  
Key Information  
You are invited to take part in a Brown University research study. Your participation is voluntary.  
• 
PURPOSE: The purpose of the study is to evaluate the safety and efficacy of oxytocin in 
opioid craving after a stress induced condition resulted by a single dose of yohimbine.  
• 
PROCEDURES: You will receive both 40 IU twice a day of oxytocin and oxytocin-placebo.  
There are two sessions where you will receive a single dose of yohimbine and two sessions 
where you will receive a single oral dose of yohimbine-placebo. You will be exposed to non-
invasive cues, will complete other lab assessments and will have blood drawn at multiple 
study sessions.   
• 
TIME INVOLVED: There will be seven visits total over the course of 20 days.  
• 
COMPENSATION: Total maximum possible compensation is $550.  
• 
RISKS: Answering questions about your drug and alcohol use may cause you discomfort 
and/or put you at risk for loss of confidentiality. You may notify a researcher if you feel 
discomfort. We will also protect your information in locked filing cabinets and on password 
protected computers.  
• 
BENEFITS: There are no benefits to be expected by your participation in this study.  
• 
ALTERNATIVES TO PARTICIPATION: This is a research study and your participation is 
completely voluntary.  
  
This consent form may contain words that are used in ways you may not understand. Please ask the 
study doctor or the study staff to explain anything that you do not clearly understand.  
  
   The goal of this study is to determine if, under stress, opioid craving is reduced using a medication.  
  
You are being asked to take part in this study because you have stated that you are receiving 
Suboxone, which is the trade name for the generic formulation of the buprenorphine/naloxone, or 
methadone as opioid replacement therapy (ORT). This study is being done to determine if a drug 


 
Initials ________  
  
called oxytocin reduces your desire to use opioids while also receiving a single oral dose of yohimbine 
that increases your stress level.  
 
• 
Oxytocin is a naturally occurring substance in your body and when administered has been 
shown to be well tolerated with minimal to no side effects.  
• 
Yohimbine is an investigational drug that has been shown to increase nervous system 
activity. As in other similar studies, we will use yohimbine to increase stress. 
 
During the study, you will receive either 40 IU twice a day of oxytocin (or placebo) for 7 days. Which 
medication that you receive will be determined by a process called randomization (a process that is 
similar to flipping of a coin) and gives each participant in the study an equal chance to receive either 
oxytocin or placebo.   
  
To test if oxytocin reduces your desire to consume opioids under stress, we will give you yohimbine 
or placebo (sugar pill) to produce a stress-like condition on 2 occasions, separated by 2 days, after 
you have taken either oxytocin or placebo. A similar randomization procedure will be used for 
yohimbine, but you will receive both yohimbine and placebo, the order of which you will receive first 
will also be randomized. The two yohimbine periods are separated by 2 days (plus or minus 2 days 
to accommodate your schedule) during which there are no study procedures; we will call/email you 
to check how you are doing and remind you of your next visit.  
  
This study is called a double-blind study. This means that neither you nor the study staff will know 
which medication (oxytocin, yohimbine or placebo) you are taking. In case of an emergency, the 
study staff can find out which group you are in. Neither you nor the study staff will know what you 
received until all the participants have completed the study. At that time, you may be told about the 
order of your condition and your response.  
  
In order for you to decide whether or not you wish to be a part of this research study, you should 
consider the risks and benefits so that you can make an informed decision. This consent form gives 
you important information about the research study and a member of the research team will discuss 
this information with you. This discussion will go over all parts of this research: its purpose, the 
procedures that will be done, and possible benefits and risks. Once you understand what this study 
is about, you will then be asked if you wish to participate. If so, you will be asked to read and initial 
each page and sign the last page of this informed consent document.  
  
2. If you decide to participate, the procedures to be followed are explained below:  
This study is expected to last approximately 20 days and will consist of a total of 7 visits. You will 
be assigned a specific ID number for the study to protect your privacy. We will use your ID number 
rather than your name on all study documents. All information collected during each visit will be 
kept in a locked cabinet in our locked office here at Brown University. Your data will be entered 
and saved in password-protected computer files. All lab samples (saliva and blood) using your 
study ID number will be sent to an outside laboratory and will be tested for possible important 
clinical conditions (e.g. liver and kidney damage, altered blood analysis, etc.), which could prevent 
you from participation in the study.  
  
No information from this study will become part of any permanent medical record. 
  


 
Initials ________  
  
You can stop your participation in this part of the study at any time. If the blood, saliva and urine 
samples have not yet been analyzed, we will destroy them upon your request. However, if we have 
already analyzed the samples, you can tell us whether we may keep the information about the results 
or if you would like us to destroy them.   
 
STUDY PLAN  
In order to determine if you are eligible to participate in the study, you must have a breath alcohol 
content of =0.00% at each visit when you arrive to our office. If able to become pregnant, we will 
perform a pregnancy test at each visit and it must be negative to participate.  
Below is a Table that briefly describes what will occur at each visit and compensation. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A urine drug screen on the first and follow-up visits will be performed at Brown University. 
Visit 
Procedures and Estimated Time 
Compensation  
 
1  
Screening  
Physical exam, three small tubes of blood will be drawn for screening tests 
(once), for (buprenorphine/naloxone or methadone) levels (once), and for 
hormones levels (once). Saliva tests (by spitting three different times in a 
tube), urine (drug screen) and urine pregnancy test (if applicable). Medical 
and psychiatric history, ECG, vital signs and questionnaires (3 hours) 
  
$40  
2  Randomization 
(day 1)  
We will give you 5 days of the study medication (oxytocin or placebo) and will 
explain how to take the medication.  Vital signs and questionnaires, urine 
pregnancy test (if applicable) (1 hour) 
 
$40  
 
3  
Lab  
Session I  
(day 5)  
You will fill out questionnaires, a small tube of blood will be drawn to test for 
hormones levels (once), saliva tests (by spitting three different times in a 
tube), urine test (drug screen), and urine pregnancy test (if applicable). We 
will measure your vital signs, give you the yohimbine or placebo dose and will 
start the cue-reactivity for opioid craving (3 hours) 
  
 
$100  
Days 6-7  
No study procedures are scheduled; we will call to check how you are doing and to remind you 
of your next visit 
 
4  
Lab  
Session II  
(day 7)  
The procedures are identical to those described for Visit #3 above but with the 
opposite condition for yohimbine or placebo (3 hours) 
 
$100  
 
Days 8-9 
There will be a two day wash out period where no study procedures are scheduled. We will 
call to check in how you are doing. On day 10, you will begin taking the next dose of oxytocin 
or oxytocin-matched placebo. 
5 
Lab session III 
(day 14) 
The procedures are identical to those described for Visit #3 above. You 
will take yohimbine or placebo. 
 
$100 
 
Days 15-16 
 
No study procedures are scheduled; we will call to check how you are doing and to remind 
you of your next visit. 
 
6 
Lab session 
IV (day 17) 
The procedures are identical to those described for Visit #3 above. You 
will take yohimbine or placebo. 
 
$100 
 
Days 18-19 
 
No study procedures are scheduled; we will call to check how you are doing and to remind 
you of your final visit. 
 
7  Follow up (day 
20)  
Questionnaires, urine (drug screen), urine pregnancy test (if applicable) 
and vital signs (2 hours) 
END of STUDY 
$20 + $50 
bonus = 
$70 


 
Initials ________  
  
You will be also reimbursed for travel via parking validation or public transportation.   
  
Please note that blood will be drawn at five visits: Visits 1, 3, 4, 5 and 6 
NOTE: In the event that research staff are unable to give cash, you will be compensated the full 
amount via a ClinCard, or via an Amazon e-giftcard, emailed to the email address of your choice.  
 
ClinCard Information 
We will mail you the card. You will be given one card for the entire time of your participation and this 
card may be used to pay you in any future Brown University studies that uses ClinCard. You will also 
get information about how to use this card and whom to call if you have any questions. Be sure to 
read this information, including the cardholder agreement from Greenphire.  
Money will be added to your card based on the study’s payment schedule. You may use this card 
online or at any store that accepts Mastercard. Please read the FAQ information sheet from your 
study coordinator for details about the ways you can use the card, some of which may involve fees 
that will reduce the amount of money on the card. This card is administered by an outside company 
called Greenphire. Greenphire will be given your name, address, and date of birth. They will use this 
information only as part of the payment system, and it will not be given or sold to any other company. 
Greenphire will not receive any information about your health status or the study in which you are 
participating. If your card is lost or stolen, please call the study coordinator for a free replacement 
card. If you request a replacement card from Greenphire directly, you may be charged a fee. 
 
VISIT#1 Screening  
• 
Before starting any study procedure, a breath alcohol test will be performed and must be 
0.00%. Breath alcohol is measured by blowing into a machine called a breathalyzer. If your 
breath alcohol is 0.00%, the study will be discussed with you, and you will have an opportunity 
to ask questions about the study.   
• 
If your breath alcohol is above 0.00% you may wait until it is 0.00% or return another day.   
• 
If you agree to participate, you will be asked to sign this consent form. You will receive a copy 
of the signed consent form.  
• 
You will be asked to provide your contact information.  
• 
You will have a physical exam and your blood pressure, pulse, weight, height, and 
temperature will be recorded. You will also have an electrocardiogram (ECG) that measures 
the electrical activity of your heart.  
• 
You will be asked about any medications that you are taking. For your safety, it is 
IMPORTANT to discuss all medications that you are taking with the study staff. This includes 
over the counter medications and vitamins. Drug interactions are serious and could cause 
harm.  
• 
There are no known drug-drug interactions between Suboxone (buprenorphine/naloxone) 
and or methadone and yohimbine. To protect you against any risk of additional drug-drug 
interactions, we will ask you of any prescriptions or over-the-counter medications to ensure 
that there are no interaction with oxytocin and yohimbine.   
• 
We will be collecting blood samples to conduct screening tests (approximately 2 teaspoons, 
one tube) and to test for hormones levels (less than 1 teaspoon, small vial). Saliva tests are 
done by spitting three different times into a tube. We will collect saliva three times total: upon 
arrival, after the dose of yohimbine 45 minutes later, and at the end of the session. You will 
be asked to provide urine samples for drug screening and routine analysis.  
• 
You will be examined to determine if you are having any opioid withdrawal symptoms.  


 
Initials ________  
  
• 
You will complete a number of questionnaires asking you about your drug use, family history 
of drug use, mood, urge and craving for drugs.  
• 
If applicable, you will be asked about your periods or menopausal status and will be tested 
for pregnancy at each visit.  
• 
You will be asked about your medical history as well as about your traumatic and psychiatric 
history, including past use of any substances of abuse. If answering these questions makes 
you uncomfortable, you can decide not to answer these questions and this does not affect 
your participation in the study.  
  
VISIT#2 (Randomization) - Day 1. Upon your arrival, a breath alcohol test will be performed and 
must be 0.00%. After medical clearance, you will be randomized to either oxytocin or the oxytocin 
matched placebo group that will be dispensed as a nasal spray and the session will include a 30 
minute discussion of the proper administration of the nasal spray, the potential side effects and drug-
drug interactions. Those who are able to become pregnant will provide a urine sample for a 
pregnancy test.  
 
In the event that we determine (based upon a case by case basis) that study session 2 can safely 
and effectively be conducted remotely, we will set up a time for a study session phone call and ask 
you the paper assessments typically filled out by you in lab over the telephone. If a remote session 
occurs, you will not be asked to come into the lab, and all procedures will be conducted over the 
telephone.  
  
Visit 3 (Laboratory Session I) – Day 5. Upon your arrival, a breath alcohol test will be performed 
and must be 0.00% and you will provide a urine sample for drug toxicology screening (which will be 
kept confidential and not shared with your Suboxone (buprenorphine/naloxone) prescriber). A 
pregnancy test will be conducted (if applicable). Blood will be collected to test for hormone levels 
(one small tube), and the first sample of salivary cortisol (small tube) will be collected. You will then 
complete a series of assessments and receive a single oral dose of yohimbine or yohimbine-
matched placebo. Fifteen minutes later, we will administer a dose of oxytocin or oxytocin-matched 
placebo (40 IU, 4 sprays per nostril), and the cue-reactivity will begin. The Cue-Reactivity (CR) Task 
will be administered with cues selected based on your drug experience. To measure cue-induced 
opioid craving, you will a view images of neutral stimuli and then images of opioid drug use. You will 
rate your craving, then the second sample of salivary cortisol will be collected (30 min later). Vital 
signs will be monitored during the entire procedure. Finally, you will complete post-Cue measures, 
will have your vital signs measured, and the last sample of salivary cortisol will be collected (for a 
total of 3 samples of saliva for the visit).  
During Study Days 6-7 there are no study procedures, but we will call you to check how you are 
doing. We will also contact you either by phone or email to remind you of your next visit.  
  
Visit 4 (Laboratory Session II) – Day 7 You will come back after two days. The procedure will be 
identical to Visit 3, but you will receive the opposite condition (yohimbine or yohimbine-matched 
placebo).  
  
There will be a two day wash out period where there will be no study visits. We will mail you 
the next intranasal medication (i.e. oxytocin or placebo) which you will take for one week. 
Whichever you did not take the first week, you will take the second week. 
 


 
Initials ________  
  
Visit 5 (Laboratory Session III) – Day 14 You will come back for the third lab visit after taking the 
second round of medication for 5 days. The procedure will be identical to Visits #3-4, and you will 
receive yohimbine or placebo.  
 
Visit 6 (Laboratory Session IV) – Day 17 You will come back for the fourth and final lab visit two 
days after the third lab visit. The procedure will be identical to Visits #3-5, and you will receive 
yohimbine or placebo.  
 
 
Visit 7 (follow-up) – Day 20 After three days, you will come to the lab for the final assessments. 
END of STUDY  
  
3. Risks and Discomforts:  
The following complications or risks have been reported, are known, or may occur:  
Please take your time with this section and feel free to discuss any words you may not understand 
with the research staff.  
  
Answering questions about your drug use may cause you discomfort and/or put you at risk for 
loss of confidentiality. You may notify a researcher if you feel discomfort. We will also protect your 
information in locked filing cabinets and on password-protected computers.  
  
Both oxytocin and yohimbine have been given to many research participants, including healthy 
individuals, individuals affected by chronic or serious medical conditions (i.e. obesity, gastric 
surgery, chronic heart failure, diabetes, malnutrition, digestive disorders, cancer, and others), and 
individuals affected by mental illness (i.e. psychotic major depression, Post-traumatic Stress 
Disorder). Also, both drugs have been used in studies with individuals with alcohol and opioid use 
disorders.  
 
Some discomfort may occur during the blood draw. 
  
Oxytocin: there are usually no side effects in individuals that administer intranasal oxytocin spray 
at the dose provided in this proposed project. Common side effects include: relaxation, irritability 
and stomach cramps. Less common side effects that are reported at higher doses include: mild 
dizziness, dry mouth, nausea, vomiting, nasal irritation, runny nose, or tearing of the eyes. These 
are common with medications given by nasal spray.   
  
You will be instructed on how to properly administer the nasal spray with an empty spray bottle and 
you will administer the first dose while at the laboratory to ensure correct administration.  
 
With your copy of the informed consent, you are given a list of mental health resources that are 
available in the State of Rhode Island. Some participants may have suicidal thoughts or actions. 
Should you have thoughts of suicide for any reason before you are randomized, the study physician 
will be notified and he will assess the best course of action to take, including coming here to talk with 
you or referring you to receive appropriate medical or psychiatric interventions. For your safety we 
will monitor your mood or any thoughts of suicide closely during the entire course of the study. 
Between visits, however, if you feel a change in your mood or if you feel depressed or feel you may 
harm yourself, please contact us, or one of the resources provided to you. The principal investigator, 


 
Initials ________  
  
the study physician, and the nurse will be monitoring your mood and behavior as a way to measure 
your risk of suicide and to measure depression. Should you develop any medical or psychiatric 
problems that require clinical attention, the study physician will refer you to receive appropriate 
medical or psychiatric interventions. However, there is no provision for any medical or monetary 
compensation in the event of physical or psychological injury resulting from these research 
procedures. Brown University does not routinely provide any compensation for these events.  
  
4. The benefits, which can be expected, have been described as: There are no benefits to be 
expected by your participation in this study. You will have the chance to contribute to research 
that may prove beneficial to you or to others in the future.  
  
5. Financial Considerations: There will be no cost(s) to participate in this study. The study 
medications and all procedures that are required for the study will be provided to you. If eligible 
for the study, you will be compensated for your time and travel costs. The amounts of 
compensation that can be received are described in the study table on pages 2-3. The maximum 
amount of compensation that can be received if you complete all study procedures is $350. 
However this amount can vary depending upon missed appointments.   
  
6. De-identified data will be kept and used for future research. This includes your biospecimens. 
We may share your de-identified data and biospecimens with researchers at Brown or other 
institutions. It is unlikely but possible that biospecimens may be used to generate discoveries or 
other applications for commercial profit. You will not share in any profit arising from such uses.  
  
7. We may learn things about your health as part of the research. If this happens this information 
will be provided to you. For example, if you become pregnant or if your blood test results or ECG 
reveal any abnormalities. You may need to meet with professionals with expertise to help you 
learn more about your research results. The study team/study will not cover the costs of any 
follow-up consultations or actions.   
  
8. Should any problems arise or you experience any side effects during the study, you can contact 
our lab at (401) 863-6624 during normal business hours. After hours, you may call (401) 273-
7100 and ask to have the study physician paged.  
  
9. Your confidentiality will be maintained as follows:  
• This study will ask potentially sensitive information about your alcohol and drug use. Every attempt 
will be made to keep this information confidential. All reasonable efforts will be made to protect the 
confidentiality of your participation in the study. However, it is possible that your confidentiality may 
be violated.  
  
• In order to protect your confidentiality, all your records collected during the study will be kept in a 
locked file under a code number rather than your name. None of the information, including this 
consent form, will become part of your medical record. Your name will not be publicly disclosed at 
any time, and the records will be strictly maintained according to current legal requirements. 
However, please note that state law mandates reporting of any incidents of child or elder abuse 
(age 60 or older).  
  
• If you give us your permission by signing this document, information (including biospecimens) 
which does not identify you by name, may be used for medical and scientific purposes including 


 
Initials ________  
  
teaching and/or publication. No one at Brown University who is unaffiliated with this research 
project will have access to information that identifies you.  
  
By signing this document you give Dr. Haass-Koffler permission to share your de-identified data 
collected (including biospecimens) during this study.  
The results of the study will be analyzed, and the results of this study may be used for other research 
purposes, including:  
o reviewing the safety or effectiveness of the study drug and other products or therapies; 
o developing a better understanding of disease; o improving the design of future clinical 
trials  
Because this research involves articles regulated by the Food and Drug Administration (FDA), the 
FDA may choose to inspect and copy medical or research records that identify individual research 
subjects.  
  
10. Certificate of Confidentiality from the National Institutes of Health (NIH)  
This research is covered by a Certificate of Confidentiality (CoC) from the National Institutes of Health. 
The researchers with this Certificate may not disclose or use information, documents, or 
biospecimens that may identify you in any federal, state, or local civil, criminal, administrative, 
legislative, or other action, suit, or proceeding, or be used as evidence, for example, if there is a court 
subpoena, unless you have consented for this use. Information, documents, or biospecimens 
protected by this Certificate cannot be disclosed to anyone else who is not connected with the 
research except, if there is a federal, state, or local law that requires disclosure (such as to report 
child abuse or communicable diseases but not for federal, state, or local civil, criminal, administrative, 
legislative, or other proceedings); if you have consented to the disclosure, including for your medical 
treatment; or if it is used for other scientific research, as allowed by federal regulations protecting 
research subjects.  
  
The Certificate cannot be used to refuse a request for information from personnel of the United 
States federal or state government agency sponsoring the project that is needed for auditing or 
program evaluation by NIH which is funding this project or for information that must be disclosed in 
order to meet the requirements of the federal Food and Drug Administration (FDA). You should 
understand that a Certificate of Confidentiality does not prevent you from voluntarily releasing 
information about yourself or your involvement in this research. If you want your research information 
released to an insurer, medical care provider, or any other person not connected with the research, 
you must provide consent to allow the researchers to release it. The Certificate of Confidentiality will 
not be used to prevent disclosure as required by federal, state, or local law of child or elder abuse 
and neglect, or harm to self or others. 
 
11. If you have questions about your rights as a research subject or otherwise, please contact 
the Brown University Human Research Protection Program at (401) 863-3050 or toll-free at 1- 
866- 309-2095 (for use within the Continental United States and Canada).  
  
12. You are making a decision whether or not to participate in this study.  
Your participation in this study is voluntary. Your decision whether or not to participate will not hurt 
your future relationship with Brown University. If you decide to participate, you are free to withdraw 
your consent and to discontinue your participation without prejudice. If you choose not to participate 
or if you withdraw from this study, it will not adversely affect your relationship with the doctors and 


 
Initials ________  
  
staff at Brown University. If you so choose you may also withdraw your permission for Dr. Haass- 
Koffler to use and share your collected research data.  
  
If you start the study and then cancel your permission, you will not be able to continue to participate 
in the study. This is because the study staff and/or the study doctor would not be able to collect the 
information needed to evaluate the goals of the study.  
If you wish to withdraw, it is important to notify the study physician because this may involve a visit 
to the clinic for an exit assessment.  
  
13. You understand that you do not have to participate in this study.  
If it is in your best interest medically, or if you do not follow the study procedures required of the 
study, the study doctors, the PI, and her staff can stop your participation in the study without your 
consent. This could be because you have had an unexpected reaction, or have not followed 
instructions, or because the entire study has been stopped. Regardless of whether you choose to 
withdraw or if your participation in the study is terminated, certain procedures must be followed in 
ending your participation in the study in order to protect your safety. You may be asked questions 
about any reactions you may have had during this study and may be asked to cooperate in certain 
tests such as physical examination and laboratory testing.  
  
You have read and understand the preceding information describing this medical research study. 
It has been explained you in detail by the study doctor or the study staff and all of your questions 
have been answered to your satisfaction. You voluntarily consent to participate in this study. You 
have read this informed consent and agree to participate in the study. You will receive a copy of 
this consent form.  
 
A description of this clinical trial is available on http://www.clinicaltrials.gov, as required by  
U.S. Law. This website will not include information that can identify you. At most, the website will 
include a summary of the results. You can search this website at any time.  
 
14. May we contact you for future studies?  
  
 
Yes  
No  
Initial   
  
  
15. May we store your de-identified blood and saliva samples (biospecimens) 
for future studies?  
  
 
Yes  
No  
Initial   
  
  
 
 
 
 
 
 
 


 
Initials ________  
  
 
 
 
 
 
THIS EVIDENCE OF INFORMED CONSENT MUST BE SIGNED BY THE SUBJECT.  
  
  
PARTICIPANT AGREES TO HAVING HIS/HER BLOOD SAMPLES STORED FOR TESTING 
ADDITIONAL HORMONAL LEVEL FOR FUTURE STUDIES:  YES   NO  
  
       PARTICIPANT (printed name):___________________  DATE: ___________ TIME: __________ 
 
 
I have explained this study to the participant. 
 
PERSON EXPLAINING THE STUDY:________________    DATE: ___________ TIME:________ 
 
PARTICIPANT SIGNATURE: ___________________   DATE: ___________  TIME: _______ 


  
  
 
 Attachment #1  
 
Substance Use & Mental Health 
• 
Services for Adults: BH Link at (401) 414-LINK (5465) 
• 
Services for children: Kids Link at (855) 543-5465 
• 
RI's Hope & Recovery Support Line: (401) 942-STOP (7867) 
• 
National Suicide Prevention Lifeline: (800) 273-TALK (8255) 
• 
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• The Rhode Island Department of Labor and Training COVID-19 Assistance Line and email 
address (401-462-2020; dlt.covid19@dlt.ri.gov) to provide support regarding employment 
issues. The phone line is staffed Monday to Friday during business hours. 
 
 
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• Rhode Islanders seeking food assistance may locate their local food pantry online through the 
RI Community Food Bank or call (401) 942-6325 for a pantry near you.  
 
 
Resources for People Experiencing Homelessness 
• For those in our community experiencing homelessness, you can call the Rhode Island 
Coalition for the Homeless coordinated entry system hotline at (401) 277-4316. 
 
 
Domestic Violence 
• 
The Rhode Island Coalition Against Domestic Violence and all of its member agencies are 
open, as are domestic violence shelters. Rhode Islanders seeking help can call 1-800-494-
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Health Insurance Information 
• 
If you have lost your employer-sponsored coverage due to job loss, or if you have experienced 
another qualifying life-changing event, you may qualify to sign up for coverage 
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call 1-855-840-4774 for assistance. 
 

Prot_000.pdf: 
Oxytocin reduces noradrenergic-induced opioid-like withdrawal symptoms 
in individuals on opioid agonist therapy  
CLINICAL PROTOCOL 
Carolina L. Haass-Koffler, PharmD, PhD 
121 South Main Street 
Providence, RI 02903 
Tel: 401-863-6624; Fax: 401-863-6697 
carolina_haass-koffler@brown.edu 
ORIGINAL: 2019 AUGUST 08 
REVISED: 2022 MAY 05 
Clinical trial registration: Clinicaltrials.gov; NCT04051619 
IND/FDA: 135570, oxytocin and yohimbine (Holder: Haass-Koffler) 


  
Brown University  
Application for Full Board / Expedited IRB Review 
 
 
Protocol Title:   
Oxytocin to reduce stress-induced craving in individuals with opioid use disorder 
Principal Investigator (PI):  Carolina Haass-Koffler 
Department:  CAAS, Psychiatry and Human Behavior 
 
PI Phone number & email address: 401-836-6624; carolina_haass-koffler@brown.edu 
Is this an undergraduate student project?1 ☐  Yes   ☒ No  
If yes, name of undergraduate student:       
 
 
Human Subjects CITI training is complete (PI, student & advisor): ☒  Yes   ☐ No 
Good Clinical Practices (GCP) training is complete (clinical trials only):  ☒  Yes   ☐ No   ☐ N/A 
HIPAA training is complete (if using PHI): ☐  Yes   ☐ No   ☒ N/A 
 
Are there multiple sites involved with this study?  ☐  Yes   ☒ No 
• If “yes,” review the Application for IRB Authorization Agreement 
 
Funding Source(s):  
 If there is no external funding for the project, write "University;" if funded by a specific internal funding 
mechanism (e.g., Mellon Mays Fellowship, Royce Fellowship, UTRA, OVPR Seed funds, etc.) please 
specify:  NIH 
 If externally funded, the project title and grant/contract # must be provided: Centers of Biomedical 
Research Excellence (COBRE) P20 GM130414-01 
 
 
PART I. HUMAN SUBJECTS RESEARCH SCREENING 
 
Full Board/Expedited studies must meet the federal definition of “Human Subjects Research.” Answer the 
following questions to determine if your proposed study meets the federal definitions of both “Research” 
and “Human subjects.” 
  ☒ Yes   ☐ No 
Is this study a systematic investigation? 
  ☒ Yes   ☐ No 
Is the primary design intent of this study to contribute to generalizable knowledge? 
  ☒ Yes   ☐ No 
Is the information being obtained about living individuals? 
  ☒ Yes   ☐ No 
Will you collect information through some type of intervention or interaction? OR 
Will you have access to individually identifiable information? OR 
Will you have access to private information? 
If you answered “no” to any of the above questions, your study does not meet the definition of 
“Human Subjects Research.” You are not required to submit an Application for IRB review to the 
Brown HRPP. 
1 Most Undergraduate student projects do not require IRB/HRPP review and oversight. Before completing this application, please 
refer to Brown’s Guidance Regarding Undergraduate Work Involving Human Subjects Research. 
 
STOP 
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Before proceeding, be sure to review the revised Common Rule categories for Exemption to determine if 
your study meets criteria for Exempt review and the Application for Exemption. 
 
 
PART II.  RISK ASSESSMENT & EXPEDITED ELIGIBILITY SCREENER 
1. Minimal Risk means that the probability and magnitude of harm or discomfort anticipated in the 
research are not greater in and of themselves than those ordinarily encountered in daily life or during 
the performance of routine physical or psychological examination or tests. 
 
Using this definition, do you believe this research presents: 
  ☐ No greater than 
minimal risk 
(Expedited) 
Briefly justify this selection (and proceed to Question 2):  
 ☒ Greater than 
minimal risk (Full 
Board) 
Briefly justify this selection (and proceed to Part III): 
This protocol include the administration of two medications; oxytocin intranasal (IN) 
and yohimbine oral (PO).   
 
2. Below are Research Categories eligible for Expedited Review. Select one or more of the categories 
that are applicable to your proposed research, if any. 
  ☐ Category 1 
Clinical studies of drugs and medical devices only when condition (a) or (b) is met (please select 
one): 
 ☐ (a) research on drugs for which an IND application is not required. (Note: Research on 
marketed drugs that significantly increases the risks or decreases the acceptability of the risks 
associated with the use of the product is not eligible for expedited review); OR 
 
☐ (b) research on medical devices for which (i) an IDE exemption application is not required; or 
(ii) the medical device is cleared/approved for marketing and the medical device is being used in 
accordance with its cleared/approved labeling. 
 ☐ Category 2 
Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture as follows: 
 ☐ (a) from healthy, non-pregnant adults who weigh at least 110 pounds. For these participants, the 
amounts drawn must not exceed 550 ml in an 8-week period and collection may not occur more 
frequently than 2 times per week; OR 
 
☐ (b) from other adults and children, considering the age, weight, and health of the participants, 
the collection procedure, the amount of blood to be collected, and the frequency with which it will 
be collected. For these participants, the amount drawn may not exceed the lesser of 50 ml or 3 ml 
per kg in an 8-week period and collection may not occur more frequently than 2 times per week. 
  ☐ Category 3 
Prospective collection of biological specimens for research purposes by noninvasive means. 
Examples may include: 
(a) hair and nail clippings in a non-disfiguring manner; 
(b) deciduous teeth at time of exfoliation or if routine patient care indicates a need for extraction; 
(c) permanent teeth if routine patient care indicated a need for extraction; 
(d) excreta and external secretions (including sweat); 
(e) uncannulated saliva collected either in an unstimulated fashion or stimulated by chewing gum 
base or wax or by applying a dilute citric solution to the tongue; 
(f) placenta removal at delivery; 
(g) amniotic fluid obtained at the time of rupture of the membrane prior to or during labor; 
(h) supra- and subgingival dental plaque and calculus, provided the collection procedure is not 
more invasive than routing prophylactic scaling of the teeth and the process is accomplished in 
accordance with accepted prophylactic techniques; 
(i) mucosal and skin cells collected by buccal scraping or swab, skin swab, or mouth washings; 
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(j) sputum collected after saline mist nebulization. 
  ☐ Category 4 
   
Collection of data through noninvasive procedures (not involving general anesthesia or sedation) 
routinely employed in clinical practice, excluding procedures involving x-rays or microwaves. 
Where medical devices are employed, they must be cleared/approved for marketing. (Studies 
intended to evaluate the safety and effectiveness of the medical device are not generally eligible for 
expedited review, including studies of cleared medical devices for new indications.) 
 
Examples may include: 
 (a) physical sensors that are applied either to the surface of the body or at a distance and do not 
involve input of significant amounts of energy into the subject or an invasion of the subject's 
privacy; 
(b) weighing or testing sensory acuity; 
(c) magnetic resonance imaging; 
(d) electrocardiography, electroencephalography, thermography, detection of naturally occurring 
radioactivity, electroretinography, ultrasound, diagnostic infrared imaging, doppler blood flow, and 
echocardiography; 
(e) moderate exercise, muscular strength testing, body composition assessment, and flexibility 
testing where appropriate given the age, weight, and health of the individual. 
 ☐ Category 5 
   
Research involving materials (data, documents, records, or specimens) that have been collected, or 
will be collected solely for non-research purposes (such as medical treatment or diagnosis). NOTE: 
Some research in this category may be Exempt. Review the categories for Exemption before 
selecting this option. 
 ☐ Category 6 
Collection of data from voice, video, digital, or image recordings made for research purposes. 
 ☐ Category 7 
Research on individual or group characteristics or behavior (including, but not limited to, research 
on perception, cognition, motivation, identity, language, communication, cultural beliefs or 
practices, and social behavior) or research employing survey, interview, oral history, focus group, 
program evaluation, human factors evaluation, or quality assurance methodologies. NOTE: Some 
research in this category may be Exempt. Review the categories for Exemption before selecting 
this option. 
 
 
 
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PART III.  RESEARCH DESIGN & METHODS 
1. Introduction and Background in lay language.
Although stress has long been linked to substance use, craving and relapse, there are no available
medications that target stress-induced substance use disorder (SUD). In particular, with the rise in
opioid use, there is still a crucial need for developing effective pharmacological treatments that target
and integrate the complexity of this disease. The long-term goal of this project is to identify the key
neuroendocrine pathways that are responsible for stress-induced craving in individuals with opioid use
disorder (OUD) in order to better understand how they can be effectively treated. To achieve this goal,
we will utilize oxytocin, as a putative pharmacological intervention, because: 1) oxytocin’s
neuroanatomical-neuroendocrine pathways are shared with stress hormones; 2) oxytocin modulates
dopaminergic transmission, lowers stress response and mitigates drug seeking-behaviors; and 3) an
increasing number of studies suggest that the oxytocin neural circuits closely interact with the
endogenous opioid system.
One of the most challenging aspects in designing a human laboratory study is the inclusion of an acute 
stress condition that represents a comprehensive naturalistic environment for OUD individuals. Hence, 
testing pharmacotherapies in stress-induced opioid use models in laboratory paradigms is critical for 
the identification and development of therapeutic interventions to prevent drug use. Pharmacological 
challenges such as yohimbine, an α-2 adrenoceptor antagonist, have been shown to activate central 
stress response in addition to increasing sympathetic nervous system activity, facilitating recall of 
traumatic memories and increasing heroin craving in opioid-dependent individuals. Thus, for this 
proposal we will integrate oxytocin (pharmacological therapy), with a cue-reactivity paradigm (specific 
for opioid cues) and yohimbine (neuroendocrine stress activation) in individuals receiving opioid 
replacement therapy (ORT) with buprenorphine/naloxone or methadone.  
The proposed research is significant because, using pharmacological probes, it will provide a much 
needed insight into the fundamental neurobiological mechanisms underlying stress-induced opioid 
craving with the goal to improve therapeutic outcomes and prevent relapse for this population.  
2. Specific Aims and Study Objectives
With the dramatic rise in opioid use, there is a critical need for effective pharmacological treatments for 
opioid use disorder (OUD). Although stress has long been linked to substance use, craving and relapse, 
no medications for OUD target stress-related pathways involved in the development and maintenance 
of OUD.
The goal of this research is to evaluate whether oxytocin, a hormone with anti-stress properties, 
dampens the effects of stress and opioid-associated cues on opioid craving and thus may be an 
effective adjunctive treatment for OUD.  
The central hypothesis of this research is that oxytocin will reduce stress-induced opioid craving in 
patients with OUD treated with buprenorphine/naloxone or methadone as opioid replacement therapy 
(ORT). This hypothesis is based on the model of addiction (Koob, Neuron 2008) in which chronic 
substance use and stress lead to neurobehavioral counter-adaptations that dysregulate biobehavioral 
response. 
In this double-blind, placebo controlled, randomized trial, individuals with OUD (N=50) who are currently 
receiving treatment with buprenorphine/naloxone or methadone will be randomized to intranasal 
oxytocin (40 international units, IU) and oxytocin-matched placebo, administered twice/day for 7 days 
with a minimum of two days between the opposite condition (oxytocin or placebo). On days 5 and 7, 
and on days 14 and 16, participants will complete two counter-balanced sessions in which they receive 
yohimbine (32.4 mg) or yohimbine-matched placebo, and responses to opioid cues are assessed.  
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Aim 1: assess the effects of oxytocin on cue-induced opioid craving after yohimbine stress-induced. 
We hypothesize that opioid craving will be reduced in the oxytocin condition, compared to the oxytocin-
matched placebo, after yohimbine stress induction.  
Aim 2: assess whether baseline levels of stress affect the effects of oxytocin on cue-induced opioid 
craving after yohimbine-matched placebo. We hypothesize that after yohimbine-matched placebo 
administration, opioid craving will be reduced in the oxytocin condition only among individuals with 
higher levels of stress at baseline. 
Aim 3: to assess the safety and tolerability of oxytocin and yohimbine in OUD individuals receiving 
buprenorphine/naloxone or methadone. Participants will complete a laboratory session that includes a 
battery of medical/physiological/psychological assessments to monitor adverse events. 
Aim 4: 
Exploratory Aims: we will examine the effect of oxytocin, as compared to placebo, on 
neuroendocrine fluctuations of salivary cortisol (three points area under the curve) and blood 
neurotensin, orexin and substance P by comparing hormones concentrations at baseline and 
after study medication and placebo administration (visit 3, 4, 5 and 6).  
This research will be the first to assess the clinical efficacy of repeated oxytocin administration to 
prevent opioid stress-induced relapse. Considering the high comorbidity between OUD, anxiety 
disorder and PTSD, this proposal will pave the avenue for testing oxytocin as an adjunct opioid 
replacement therapy (ORT) for an as needed personalized pharmacotherapy for this population. 
 If your study ONLY involves the use of identifiable secondary data / biospecimens, including 
coded data from which you may be able to ascertain identity, 
skip to PART VI. Otherwise, please continue. 
3. Materials, Methods and Analysis.
This study will use a within subject design with oxytocin vs. oxytocin-matching placebo and 
yohimbine vs. yohimbine-matching placebo. The cue reactivity (CR) (opioid craving induced by 
personalized opioid cues) will follow the physiological symptoms (triggered by yohimbine) to isolate 
the stress signal associated with opioid. Eligible participants will be randomized to use intranasal 
oxytocin or placebo spray under double-blind conditions for 7 days. On days 5 and 7, participants 
will complete a session in which they receive yohimbine and one in which they receive placebo, under 
double-blind conditions, with the order of these conditions randomized across participants. After a 
two-day wash-out period, participants will receive the opposite condition within the oxytocin 
group (oxytocin or placebo, counterbalanced) to be administered for 7 days. On days 14 and 
16, participants will complete an additional 
two 
labs 
where 
they 
will 
receive 
yohimbine 
and yohimbine matched placebo (counterbalanced). In a follow-up visit, we will complete final 
assessments before concluding the study (Figure 1).
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FIGURE 1 – Pharmacological interventions during the study 
Drugs and Doses Participants will receive intranasal oxytocin (40 IU) and oxytocin-matched 
placebo twice a day for 14 days; there will be one week of oxytocin administration and one week 
of placebo administration with two days of washout between the two conditions. They will receive 
two oral doses of yohimbine (32.4 mg) and two oral doses of yohimbine-matched placebo in the 
laboratory sessions. 
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Dr. Haass-Koffler already obtained the Investigational New Drug (IND: 135570) from FDA for this study 
(Appendix A). 
Oxytocin: The oxytocin and oxytocin-matched placebo will be formulated at 5mg/0.1mL (5mg/spray) 
and dispensed as 10-mL nasal spray, twice a day (2 sprays per nostril) for 7 days (total daily dose: 40 
international units, IU). Previous pilot studies have demonstrated that oxytocin administered either as 
single dose (73) or daily for two weeks (72) was well-tolerated in individuals with co-occurring opioid 
and cocaine disorder. The intranasal dose was chosen based on earlier work (102, 103) and previous 
studies (69, 104) have shown that 40 IU is well-tolerated in healthy populations with minimal to no side 
effects or adverse events. The administration period (7 days) is within the confines of an acceptable 
timeframe based on previous studies and ongoing oxytocin clinical trials (NCT: 02407340 and NCT: 
02548728). A study conducted by the PI’s mentor, Dr. Leggio and his team (105), indicated that both 
intranasal and intravenous exogenous (labelled) oxytocin cross the blood brain barrier and reach the 
CSF in rhesus macaques (106). As most of the neurohypophysial hormones, oxytocin has very short 
half-life, however, the pharmacological effect of oxytocin may extend from the transient kinetic effects. 
Intranasal oxytocin has shown to blunt stress effects on hippocampal synaptic plasticity and memory 
in rats via acting on oxytocin receptors and regulating phosphorylated extracellular signal-regulated 
kinases (pERK)(107). As such, oxytocin may induce compensatory mechanisms regulating secretion 
of magnocellular neurons in the hypothalamus which are operant on other hormones (108).   
Yohimbine: Patients will receive a single oral dose of 32.4mg yohimbine or yohimbine-matched placebo 
in the lab, approximately one hour prior to the cue reactivity procedure, which correspond to the 
yohimbine time to reach maximum concentration (tmax=1 h). Yohimbine 32.4mg is based from multi-
dose yohimbine administration to heroin-dependent/buprenorphine stabilized volunteers which 
increased opioid-seeking behaviors (15). The PI has already obtained an IND from the FDA for the use 
of yohimbine in this study and she is currently using this same oral dose in another trial funded via her 
K01 (NCT: 02243709; IND: 121984)]. Further supporting the safety of yohimbine, other prior studies 
have used yohimbine to examine neuroendocrine probes to boost stress signal in human studies (20, 
22, 109). Ample data support the safe use of yohimbine to induce craving in alcohol-dependent 
individuals (22), and the safe induction of stress in PTSD veterans (110) and gamblers (96).  
Telephone prescreening (Attachment J) 
Visit 1 (Screening) Before starting any procedure the participant will sign the Consent document 
(Attachment K). Participants will be assessed on inclusion/exclusion criteria according the CADRE 
psychometric scales, vital signs, ECG, blood, saliva and urine analysis standardized format. Specific 
for this project, we will include an additional blood analysis ensure the presence of buprenorphine and 
absence of opioids. Females will  report their last menses and the use of hormone-based contraceptives 
(111).  
Visit 2 (Randomization) – Day 1 After medical clearance, blood will be collected for clinical 
laboratory tests to assess basal β-endorphin, and other stress hormones (neurotensin, orexins and 
substance P) during five visits (Visit 1, 3, 4, 5 and 6) (one vial). Basal salivary oxytocin and cortisol 
will be collected by passive drooling (one vial). Since oxytocin has shown to decrease cortisol 
release and anxiety in response to social stress (6), samples of salivary cortisol will be collected at 
three time points (stress induction, cue reactivity and end of the experiment) to measure cortisol 
levels as a biomarker of oxytocin’s effect on acute stress. Then, participants will be randomized to 
either oxytocin or oxytocin-matched placebo group that will be dispensed as a nasal spray and the 
session will include a 30 min 
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discussion of the proper administration of the nasal spray, the potential side effects and drug-drug 
interactions.  
Visit 3 (Laboratory Session I) – Day 5 Participants will provide a urine sample (drug toxicology), and 
a one vial blood sample (β-endorphin, hormone levels). Participants will then complete a series of 
assessments (Table 1) and receive a single oral dose of yohimbine or yohimbine-matched placebo. 
Fifteen minutes later, participants will administer a dose of oxytocin or oxytocin-matched placebo (40 
IU, 4 sprays per nostril), after 30 min the first sample of saliva (cortisol and oxytocin) will be collected 
and the cue-reactivity will begin (112). Cue-Reactivity (CR) Task will be administered in a similar 
manner to other published studies (72, 73) for individuals with OUD with cues selected based on 
patients’ drug experience. To measure cue-induced opioid craving, participants will a view images of 
neutral stimuli and then of opioid drug use (24). Participants will rate their craving via drug visual analog 
scale (VAS) and the second sample of saliva cortisol will be collected (45 min later). Vital signs will be 
monitored during the entire procedure. Participants will then complete Post-Cue measures, will have 
their vital signs measured and conduct the last sample of saliva. 
Visit 4 (Laboratory Session II) – Day 7 Participants will come back after two days. The procedure will 
be similar to Visit 3 but they will receive the opposite condition (yohimbine or yohimbine-
matched placebo). 
A two-day washout period will occur followed by initiation of the opposite intranasal medication 
condition (i.e. oxytocin and oxytocin-matched placebo) to be administered for one week starting at 
day 9.  
Visit 5 (Laboratory Session III) – Day 14 Participants will complete the lab procedures as 
described in Visit 3 and 4, however, this time will be administered the opposite oxytocin condition (i.e. 
oxytocin or oxytocin-matched placebo). Participants will also receive yohimbine or yohimbine-
matched placebo (counterbalanced).  
Visit 6 (Laboratory Session IV) – Day 17 Participants will come back after two days. The 
procedures will be completed as described in Visits 3-5, but they will receive the opposite condition 
(yohimbine or yohimbine-matched placebo).  
Visit 7 (follow-up) – Day 20 After three days, participants will come to the lab for the final 
assessments (Table 1).   
For those that have previously completed the study and will be re-enrolled in the opposite 
medication conditions, they will go through an additional two visits for safety criteria and to once 
again confirm eligibility: visit A and Visit B 
Visit A: Participants will review their brief medical history questionnaire with the nurse practitioner, 
and compete assessments about any anxious or depressive symptoms. 
Visit B: Upon completion of visits 5 and 6 where participants were randomized to the 
opposite medication condition, they will once again come to the lab to complete the final 
assessments (Table 1).  
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Medication compliance: To ensure study medication compliance, oxytocin levels will be measured 
at screening (to determine oxytocin baseline values), at Visit 3, 4, 5 and 6. Buprenorphine levels will 
be checked by urine at each visit, in order to ensure ORT compliance and reduce the risk of 
withdrawal after study conclusion.  
Assessments Demographic and baseline characteristics will be assessed according the CADRE 
standardized format (Attachment B). Additionally, specific for this project, we will include (Attachment 
G):  
Opioid craving/withdrawal. a) Clinical Opiate Withdrawal Scale (COWS) (113) an 11-item scale that 
measures the stage or severity of opiate withdrawal and the level of physical dependence, b) Opioid 
Craving Scale (OCS) a 3-item scale adapted from the 3-item Cocaine Craving Scale (114), that 
assesses opioid craving and c) Opioid Timeline Follow-back (115) a calendar-assisted interview that 
will help participants estimate their amount of opioid use over the last 90 days.  
Mood, Anxiety and Trauma Measures, in addition to the CADRE standardized assessments, we 
included anxiety and stress measure: a) Hamilton Anxiety Rating Scale (HAM-A) (116) is a 14-item 
scale that measures anxiety symptoms (psychic anxiety and somatic anxiety), b) Hamilton Rating Scale 
for Depression HAM-D a 21-item scale designed to assess potential depressive symptoms, and c) 
State-Trait Anxiety Inventory (STAI) (117) is 40-item measure that is split into state anxiety (20 items) 
and trait anxiety (20 items).  
The list of the CADRE standardized assessments and measures is attached (Attachment B) and ad 
hoc assessments administer during the study period is described in Table 1 (Attachment G). Other 
potential effects of oxytocin as pharmacotherapy for OUD on relapse, drug-taking or subjective rating 
of drug effect will be monitored throughout the study.  
TABLE 1 – Assessments 
Measure 
Visit 1 
Screening 
Visit 2 
Randomization 
Visit 3, 4, 5 
and 6 
Laboratory 
Visit 7 
Follow-up 
Visit A 
Visit B 
Adverse Events Evaluation (AEE) 
x 
x 
x 
x 
Clinical Opiate Withdrawal Scale 
(COWS) 
x 
x 
x 
x 
x 
x 
Concomitant medications, nicotine and 
marihuana use 
x 
x 
x 
x 
x 
x 
Prior and Concomitant Medications Log 
x 
x 
x 
x 
x 
x 
Hamilton anxiety rating scale (HAM-A) 
x 
x 
x 
x 
x 
x 
Hormone blood collection (blood and 
saliva) 
x 
x 
Opioid Craving Scale (OCS) 
x 
x 
x 
x 
x 
State Anxiety Inventory-State (STAI-
State) 
x 
x 
x 
Trait Anxiety Inventory-Trait (STAI-Trait) 
x 
Study medication accountability 
x 
Buprenorphine urine level 
x 
x 
x 
x 
x 
x 
Menopausal Health Questionnaire 
x 
Hamilton Rating Scale for Depression 
HAMD 
x 
x 
PTSD PCL 5 
x 
Drug Attention Scale (DAS) 
x 
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Desire for Drug Questionnaire (DDQ) 
x 
Obsessive Compulsive Drug Use Scale 
(OCDUS) 
x 
Drug or Treatment Drug Craving 
Questionnaire  
x 
Clinical Laboratory Core (CLC) 
Measures Aim 3 of the CADRE’s Clinical Laboratory Core (CLC) is to build a center-wide database of 
transdiagnostic biological and environmental factors associated with the development and progression 
of SUDs and chronic disease. This database will enable CADRE project and pilot investigators to test 
multi-causal models of the relationships between SUDs and chronic disease. Measures to be included 
in all projects in service of this aim include: the MINI 7.0.2. (brief patient-completed structured clinical 
interview for DSM-5 disorders), measures of stigma, trauma, family history of alcohol/substance use, 
affective dysregulation (anhedonia), behavioral dysregulation (impulsivity), sleep, physical activity, 
health-related quality of life, and blood samples from which DNA will be extracted and biobanked for 
future analysis. All measures are described in the CLC Research Plan. The CLC measures will be 
included in each project’s baseline assessment battery, along with project-specific measures, by the 
CLC’s data management team to ensure uniformity in item wording and response format across 
projects. 
Assessments: The CADRE CLC will provide a core assessment battery to all RPs to measure 
mechanisms underlying chronic disease. As described in the CLC Research Plan, these include 
measures of pain, trauma, family history of AUD/SUD, affect, behavioral dysregulation, physical activity, 
sleep, 
and 
health-related 
quality 
of 
life. Biomarkers collected 
in 
all 
projects 
include: 
enzymes aminotransferase 
and 
alanine 
aminotransferase 
(AST, 
ALT), markers 
of 
liver 
damage; creatinine and blood urea nitrogen, markers of kidney function; salivary cortisol, a marker of 
stress response; soluble CD14 (sCD14), a marker of monocyte activation; tumor necrosis factor alpha 
(TNF-α) and interleukin-6 (IL-6), pro-inflammatory cytokines; kynurenine/tryptophan ratio (Kyn/Tryp), 
implicated in neuropsychiatric symptoms associated with immune activation; and monocyte 
chemoattractant protein 1 (MCP-1), a chemokine that regulates migration and infiltration of 
monocytes/macrophages and is involved in various neuroinflammatory disorders.  
THE BLUE TEXT IN THE FOLLOWING SECTIONS IS A GUIDE TO ENSURE ALL RELEVANT 
INFORMATION IS INCLUDED IN YOUR APPLICATION. YOU MAY DELETE THE BLUE TEXT 
BEFORE SUBMISSION 
4. Participant Population.
One hundred individuals receiving buprenorphine/naloxone as opioid replacement therapy (ORT) 
will be screened randomized. We included individual receiving ORT because we specifically target 
risk of relapse in a treatment-seeking population. No vulnerable population will be included in the 
study.

INCLUSION CRITERIA

~Male or female (50%), 18 to 70 (inclusive) years of age;

Currently meets DSM-5 criteria for OUD;

Currently on a stable dose of buprenorphine/naloxone or methadone for at least 3 
months;

In good health as confirmed by medical history, physical examination and blood 
work (AST/ALT; bilirubin, creatinine clearance within normal limit);

Willing to take medication and adhere to the study procedures;
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
Understand informed consent and questionnaires in English at an 8th grade level;

Clinical Opiate Withdrawal Scale (COWS) = 0 at study screening and prior
laboratory sessions.

EXCLUSION CRITERIA

Women who are breastfeeding, test positive for pregnancy or are unwilling to use
medically-approved birth control;

Liver function within 5x the Upper normal limits (AST/ALT) and renal function within 2x
the Lower Normal Limit (bilirubin, creatine clearance).

Suicide attempts in the last three months;

Current substance disorder other than marijuana, nicotine and caffeine as
assessed by self-report and urine toxicology screen at baseline;

Current use of medications that may interact with study medications;

History of hypersensitivity to study medications;

Clinically significant electrolyte abnormalities, current rhinitis or use of
vasoconstricting medications or prostaglandins.
NOTE: the exclusion criteria are based in reducing participants’ safety. 
Participants need to speak English and be able to understand informed consent and questionnaires in 
English 
which 
will 
be 
written 
exclusively 
at 
an 
8th 
grade 
level. 
One hundred individuals receiving buprenorphine/naloxone or methadone as opioid replacement 
therapy (ORT) will be screened, 80 will be randomized, with 50 expected to complete the study. 
Potentially eligible participants will be invited for an in-person screening, where they will provide written 
informed consent and undergo a physical examination in the NEW Clinical Laboratory Core (CLC).  
The sample size estimate is based on recent findings reporting that baseline levels of stress 
significantly predicted oxytocin effects on cue-induced craving (Mitchell et al., J Addict Med, 2016). 
Effect sizes were calculated based on a between-subjects in oxytocin study with alcohol related 
responses (Pedersn et al., ACER, 2013). The estimate of opioid craving (measured by the OCQ) were 
calculated from the M and the SD of alcohol-related outcomes: oxytocin was superior to placebo in 
reducing alcohol withdrawal (i.e. less lorazepam required to complete detoxification: 3.4 mg±4.7, vs. 
16.5 mg±4.4, p<0.01), lower mean CIWA scores (4.3 mg ±2.3 vs. 11.8 mg ± 0.4, p<0.01). We estimated 
that with a standard threshold, α = 0.05, for med-large effect (f = 0.35), two group independent variable 
and three covariates in ANCOVA, the N is 67 to detect 0.80 power.  With an additional 0.20 to account 
for attrition [N = 50 (completers) + 13 = 80 (enrolled)]. The estimated power at N = 67, with the addition 
of an interaction term (for Aim 2) would be = 0.63. Therefore, the calculated sample size is well powered 
to address the hypothesis of the main medication effect (Aim 1) and of the interaction effect with stress 
and anxiety (Aim 2). 
5. Recruitment Methods
We will recruit equal numbers of men and women in this study since not only stress affects prescription
opioid misuse, but also sex. This target population should be feasible to recruit considering that the
prevalence of prescription opioid use among women is substantial. Participants will respond to the
recruitment materials by telephone or email and will be pre-screened on the telephone for initial
eligibility by the RA. Dr. Josiah Rich, PI of COBRE Opioid grant, will collaborate with Dr. Haass-Koffler
for the recruitment of this project (letter of support to the CADRE PI: Dr. Monti).
Potentially eligible participants will be invited for an in-person screening by the RA and the nurse 
practitioner, where they will provide written informed consent and undergo a physical examination, 
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blood work and electrocardiogram (ECG). After confirmation of eligibility by the study physician (Dr. 
Swift), participants will be enrolled in the study by the PI (Dr. Haass-Koffler) with the support of the RA. 
The biomedical assessments (urine test and ECG) will be performed by a trained RA under the 
supervision of the nurse practitioner and the blood will be collected by a phlebotomist or nurse 
practitioner.  
The RA will receive training in administer the screening assessments by trained research personnel 
(either by the PI or the nurse practitioner). Screening test and procedure to ensure that potential 
participants are eligible to participate. 
TABLE 1 – Assessments at screening, Visit 1 
Measure 
Personnel administering 
the assessment 
Blood test clinical analysis, buprenorphine blood level 
NP, PL 
Clinical Opiate Withdrawal Scale (COWS) 
RA 
Concomitant medications, nicotine and marihuana use 
RA 
Hamilton anxiety rating scale (HAM-A) 
RA 
Hormone collection (blood and saliva) 
Blood (NP), Saliva (RA) 
Opioid Craving Scale (OCS)/Timeline Followback (TLFB) 
RA 
State Anxiety Inventory-State (STAI-State) 
RA 
Trait Anxiety Inventory-Trait (STAI-Trait) 
RA 
Legend - PI: Dr. Haass-Koffler, NP: Nurse Practitioner (TBD), RA: Research Assistant 
(TBD), PL: Phlebotomist (TBD)  
NOTE: The de-identified screening data (study code) will be kept after eligibility is determined 
for research purpose. The document that links the study code with identifiable information will be 
destroyed after conclusion of the trial. The screening consent process is fully described in Part V. 
All screening material will be in English. 
Standard care: opioid replacement therapy (ORT) with buprenorphine/naloxone or methadone. 
Intervention: standard care + oxytocin 40 IU intranasal, twice a day 
6. Compensation / Reimbursement
Compensation schedule and amount is described below:
Visit 1 will take ~ 4 hours and participants will receive $40 for the visit. 
Visit 2 ~1 hour and participants will receive $40 for the visit.  
Visits 3, 4, 5 and 6 will take ~3 hours and participants will receive $100/visit.  
Visit 7 will take ~1 hour and participants will receive $20 + a $50 bonus for completing the study. 
Total possible compensation is $550. Participants will be compensated in cash or Clincard and for 
the sessions that they complete. The amount of compensation is based on the time spent in each 
session and based on other similar study conducted by the PI or Dr. Swift at Brown University. 
Participants will receive parking validation or RIPTA tickets (both ways) as reimbursement for travel 
cost. 
Participants that have previously completed the study and are re-enrolled in the opposite medication 
condition counterbalanced, will receive an extra $20 for Visits A and B both; these visits are 
for safety criteria and to ensure eligibility once again. A sum of $590 compensation is possible for 
these individuals.
v. 08/17/2021
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2) issues associated with undue inducement,
3) issues associated with coercion,
4) side effects or drug interactions with oxytocin,
5) craving for opioids,
6) discomfort from opioid craving during cue reactivity, and
7) discomfort from the neuroendocrine activation produce by
yohimbine.
Participants will be protected against any potential risks and will be closely monitored throughout the 
study.  
1. Participants may experience some discomfort when answering questionnaires items, however we
expect that the risks will be low. Based on past and current research by Drs. Haass-Koffler and
Swift, participants have not had any discomfort or issues that have arisen from questionnaires.
2. The risk of breach of confidentiality is low and strict precautions will be taken to minimize the risk of
breach of confidentiality. A Data Safety Monitoring Plan (DSMP) will be in place that follows Brown’s
IRB guidelines.
3. The risk of undue inducement is low. Monetary compensation for this study is commensurate with
the amount of time and effort that is required for the study.
4. The risk of coercion is low, since we have a well formulated "alternatives to participation" section of
the consent so subjects don't believe enrolling is the only way to get help with OUD.
5. Participants may experience some side effects associated with oxytocin administration and there is
some risk of drug-drug interactions. However, oxytocin will be administered intranasally and will
have reduced first-pass metabolism. Also, based on past research, oxytocin has minimal side
effects and is well-tolerated by participants. A detailed procedure to minimize risk associated with
oxytocin is defined below.
6. Participants may experience some discomfort from opioid withdrawal, but these should be minimal
since the participants are taking ORT. As outlined below, several precautions will be taken to help
minimize any opioid withdrawal symptoms that participants may experience.
7. Participants may experience craving for opioids after being exposed to opioid cues. Past research
by Drs. Swift and Haass-Koffler have shown that participants do not have significant craving or
subsequent drug use after cue exposure.
In this study, yohimbine (32.4 mg), formulated by JB Pharmacy is administered below the 
therapeutic index to a dose considered unsafe (>100 mg). Furthermore, yohimbine will be administered 
only once, during the laboratory session. Dr. Haass-Koffler has already obtained the Investigational 
New Drug (IND:135570) from the FDA that determined that it is safe to proceed to clinical investigation 
using oxytocin and yohimbine in patients receiving buprenorphine/naloxone or methadone therapy 
(Appendix A).  
Finally, Dr. Haass-Koffler has a current and ongoing human laboratory study (PI and IND holder: NCT: 
02243709; IND: 121984) using the same dose of yohimbine within a similar laboratory paradigm 
formulated by the same pharmacy with no adverse events that have been reported to the FDA, NIH or 
IRB. 
As detailed in the Description of Potential Risks, the following will be set forth to protect against risks 
of the study:  
1) discomfort from answering questionnaire items,
7. Potential Research Risks / Discomforts to Participants.
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1. To protect against or minimize discomfort from answering questionnaire items, participants may
refuse to answer questions that they do not feel comfortable answering. Participants with discomfort
may withdraw from the study with no penalty and will be referred to Dr. Swift for a clinical
assessment if distress continues.
2. To protect against a breach of confidentiality, all data acquired during the study will only be
accessible by the research staff and used for research purposes only. All research data will be kept
in a locked filing cabinet or on a password-protected computer database in the study office. Only
participant code numbers will be used to identify participants. Consent forms and logs with
participant’s names and codes will be locked in a separate cabinet in the PI’s office as an extra layer
of security. All biological samples will be guarded in a similar manner. Only participant code numbers
will be labeled on biological samples and will be locked in a laboratory suite. All interviews and
assessments will be conducted in an interview room with a closed door to ensure participant privacy
and confidentiality. The NIH Certificate of Confidentiality will protect against disclosing any
identifying information/characteristics of participants in legal demands such as court orders or
subpoenas. The Certificate will ensure further protection of participants’ confidentiality.
3. To protect against issues associated with undue inducement, participants will be compensated
appropriately for their time and effort. The study involves about a week of participation and given
the considerable time commitment and involvement, compensating participants for their time and
travel costs is appropriate and comparable to other study protocols. Those who drop out of the study
early will be compensated for sessions that they completed.
4. To protect against issues associated with coercion, participants will be informed that participation is
not required to get help treatment help with OUD. Also, we are not enrolling vulnerable populations.
5. To protect against or minimize any risk of side effects associated with oxytocin, yohimbine or any
drug-drug interactions, potential risks will be judiciously outlined to participants and thorough
screening procedures will be in place to minimize recruitment of those that might be at a higher risk
of adverse events. The study physician (Dr. Swift) and the CADRE NP will carefully review all
participant screens and the PI will evaluate the individual medication profile to minimize any risk
association with the medication. The participants will be instructed on the proper administration of
the medication and they will return the spray bottle at the last visit. The safety of oxytocin is
supported by other work with intranasal oxytocin spray (102, 103). No adverse events or side-effects
were reported during the studies. Dr. Swift’s contact information will be provided to participants so
that participants can contact him between visits if necessary.
6. To protect against or minimize any discomfort from opioid withdrawal, participants will be closely
monitored throughout the study. Opioid withdrawal will be assessed before each visit and since
individuals with a COW > 0 will be excluded from the study at screening, we don’t expect withdrawal
from opioids to be severe. Dr. Swift and/or the CADRE NP will be accessible 24/7 during the study
and participants will be instructed to call if they experience any withdrawal symptoms. Emergency
medical services will be immediately called if a serious adverse event arises during the study. Opioid
withdrawal symptoms can be uncomfortable but are not dangerous.
7. To protect against or minimize any discomfort from opioid craving during cue reactivity, participants
will be closely monitored throughout the laboratory session. Buprenorphine/naloxone or methadone
level will be assessed at visit 3 to ensure ORT compliance. Participants’ vital signs (BP, HR and
MAP) and opioid craving with behavioral assessments will be monitored during the entire session.
8. The safety of yohimbine (32.4mg), formulated by Bayview Pharmacy is administered below the
therapeutic index to a dose considered unsafe (>100mg). Furthermore, yohimbine will be
administered only once, during the laboratory session.
.
The protocol involves an intervention proposed as an adjunct therapy to the standard care.  There
are minimal risk for participants in their daily lives, however they may feel discomfort during the
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laboratory procedures (stress-induction).  See below additional consideration to prevent the 
additional risks:  
•
JB Pharmacy will provide the oxytocin (40 IU intranasal) and yohimbine (32.4 mg, oral) that will
be administered at CAAS under team supervision prior to the laboratory session. Risks of
medications will be minimized through careful and detailed screening of participants by the PI,
(Dr. Haass-Koffler) who is a trained pharmacist and pharmacologist and the co-I, and study
physician (Dr. Swift) who is a practicing physician and addiction psychiatrist, to minimize
recruitment of those who might be at higher risk for adverse events, as well as careful and
detailed monitoring of adverse events and participant well-being during the study.
•
Oxytocin. There are usually no side effects in individuals that administer intranasal oxytocin
spray at the dose provided in this proposed project. The half-life of intranasal oxytocin in serum
is 3-17 minutes and therefore side effects should be minimal. Common side effects include:
relaxation, irritability and stomach cramps. Less common side effects that are reported at higher
doses include: mild dizziness, dry mouth, nausea, vomiting, nasal irritation, runny nose, or
tearing of the eyes are common with medication given by nasal spray. Participants will be
instructed on how to properly administer the nasal spray by the CADRE NP, with an empty
sprayer bottle. The participant will administer the first dose while at the CADRE laboratory to
ensure correct administration. Participants will be instructed to stop taking the medication and
to call the PI if any side effects or adverse events as a result of the medication occur. The PI will
then contact Dr. Swift and/or the CADRE NP who will recommend next steps. Participants may
withdraw from the study at any time if they do not feel comfortable administering the medication
and will be compensated for sessions that they have completed. To protect against or minimize
any risk associated with opioid craving after the opioid cue-reactivity task, participants’ vital signs
and opioid craving with behavioral assessments will be monitored. If a clinically significant
increase in craving were to occur, participants may require clinical management. Dr. Swift and/or
the CADRE NP will be immediately called and will evaluate each participant on a case-by-case
scenario.
•
Yohimbine: The oral dose of yohimbine for this study is based on prior studies, in particular from
an ongoing study of Dr. Haass-Koffler’s (PI and IND holder: NCT: 02243709; IND: 121984) in
which yohimbine was administered to examine neuroendocrine probes in human studies. Ample
data supports the safety of yohimbine to induce craving in alcohol-dependent individuals, and
the safe induction of stress in PTSD veterans and gamblers. In this study, yohimbine (32.4mg),
formulated by Bayview Pharmacy is administered below the therapeutic index to a dose
considered unsafe (>100mg). Furthermore, yohimbine will be administered only once, during the
laboratory session and under direct supervision of the study personnel. It will be given at a
safety-tested dose to increase noradrenergic activity already being evaluated in psychiatric
patients with clinically relevant stress conditions such as PTSD, anxiety, and depression. Finally,
yohimbine’s short half-life (t1/2 = 1-2 hour) provides a transient effect. The protocol includes close
monitoring of vital signs (BP, HR and MAP) and cortisol levels. Dr. Swift and/or the CADRE NP
will evaluate any possible adverse effect due to yohimbine administration. In addition, we will
administer the standardized CADRE assessment to determine stress and anxiety at baseline. If
anxiety is higher at the end of the study we will call Dr. Swift and/or the CADRE NP to have him
meet with the patient before being released. The most common side effects reported by the use
of yohimbine are: an allergic reaction, irregular or fast heartbeat, confusion, dizziness, anxiety,
irritability, or nervousness, tremor, headache, skin flushing and we have not encounter these
effect in our ongoing trial (PI and IND holder: NCT: 02243709; IND: 121984).
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•
Drug-drug interactions There are no known drug-drug interactions between buprenorphine or
buprenorphine co-formulated with naloxone and yohimbine and or methadone and yohimbine.
To protect against any risk of additional drug-drug interactions, participants will be thoroughly
screened for any prescriptions or over-the-counter medications that may interact with oxytocin
and yohimbine. Dr. Haass-Koffler will oversee the possible drug-drug interactions that may arise
from the co-administration of existing medications taken by participants with the study
medications. She will evaluate the medication profile for each screening visit and she will prepare
a full pharmacokinetics/ pharmacodynamics (PK/PD) report for the final review of Dr. Swift using
the Clinical Pharmacology database provided by Brown. Participants will be instructed to
immediately call the PI if they start taking new medications. The PI will then contact Dr. Swift
who will recommend next steps. Participants will be asked to avoid any medications that could
interact with oxytocin and yohimbine. To further minimize any risk associated with drug-drug
interactions, participants will receive a wallet card with contact numbers of the PI, study
physician, as well as emergency numbers. Participants will be instructed to carry the card at all
times and to call Dr. Swift 24/7 in case of an emergency
Data and Safety Monitoring Plan (DSMP) is attached to this protocol (Attachment D) 
8. Potential Benefits of the Research. NOTE: Compensation for participation is not a benefit
and should not be included in this section.
•
Potential benefits to human subjects and to others There are no direct benefits to participants in
this study. However, considering the potential benefits and the knowledge to be gained, we
believe that the benefits outweigh the risks. The risk-benefit ratio provides a justification for
conducting this study, which could ultimately lead to more effective treatment options for opioid
use disorder.
•
Importance of the knowledge to be gained With the serious health and economic consequences
associated with opioid use disorder, this study provides a much needed understanding of the
behavioral and biological factors involved with opioid craving and use. This study aims to
examine the potential efficacy of a novel pharmacological treatment for opioid dependent
individuals during stress conditions. If effective, the findings of this study could lay the
groundwork for an effective treatment strategy for opioid use disorder and individuals with other
addictive disorders.
PART IV.  APPENDICES SCREENER 
Please complete & attach the following Appendices to this Application, as applicable. 
Incl.      N/A 
☐
☒
Appendix A. Children as Subjects 
To be attached when minors are included as participants [please be aware of the age of 
majority for your specific research site(s)] 
☐
☒
Appendix B. Prisoners as Subjects 
To be attached when prisoners are included as participants. 
☒
☐
Appendix C. Use of Drugs 
To be attached when the research includes the use of FDA-regulated or unregulated drugs. 
☐
☒
Appendix D. Use of Devices 
To be attached when the research includes the use of FDA-regulated or unregulated devices. 
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☒
☐
Appendix E. Prescription Drug / Medication Management 
To be attached when study procedures include administering prescription medications to 
study participants. 
☐
☒
Appendix F. Mental Health Safety Plan 
To be attached when participants may experience significant emotional distress, or be at risk 
of themselves or others. 
LIST OF ATTACHMENTS 
A.
FDA IND#135570 (Specific for this project)
B.
CADRE CORE Standardized Assessments and Measures
C.
Use of Drugs (oxytocin and yohimbine)
D.
Data and Safety Monitoring Plan (DSMP)
E.
Prescription Drug / Medication Management
F.
Mental Health Safety Plan
F. 2 CADRE Suicidality Mental Health Monitoring
G. Project ad hoc Assessments and Measures
H.
Oxytocin Drug Manual
I.
Yohimbine Drug Manual
J.
Telephone pre-screening
K.
Informed Consent Document
L.
Recruitment material
PART V.  INFORMED CONSENT 
Informed consent is a process, not just a form. The IRB must ensure the informed consent process clearly 
discloses and facilitates the understanding of all information needed to make an informed decision to 
participate while promoting the voluntariness of participation. 
Please review the Consent/assent templates and related guidance on the HRPP Forms & Templates page 
before developing your consent forms. 
1. Describe the informed consent process:
In a private room in Dr. Haass-Koffler’ laboratory, following a breath alcohol content (BrAC) = 0.00,
participants will provide a written informed consent to participate. Participants will be asked to read the
document thoroughly and indicate that they have done as much in order to proceed to the study.
Potential participants have the option of refusing to participate in the study, withdrawing their
participation at any time, and/or refusing to answer any questions that they feel uncomfortable
responding to (Attachment K).
2. Facilitate Understanding
To ensure that participants understand the informed consent, participants will read each page. All
participants will be informed of the study procedures, study rationale and any potential risks and
benefits. The PI or Research Assistant will answer any questions about the informed consent and study
that participants may have.
Being fluent in English is part of the study inclusion criteria and thus participants will not be permitted 
to enroll in the study unless they meet this criterion 
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We will ensure ongoing consent by adding language to remind participants that they have the option 
of refusing to participate in the study, withdrawing their participation at any time, and/or refusing to 
answer any questions that they feel uncomfortable responding to. 
 
3. Documentation 
Participants will be asked to sign a copy of the consent form that the researcher will keep on file in a 
locked storage cabinet. A second copy of the consent form will be provided to study participants to 
keep. 
 
4. Additional Considerations 
All study participants will be consented. This study does not involve minors, any deception, and all 
data including biospeciments will be full de-identified. 
 
Proceed to PART VII. DATA SECURITY ASSESSMENT 
 
 
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PART VI. USE OF SECONDARY DATA / BIOSPECIMENS 
 
1. From what source(s) will you acquire or access the data / biospecimens? 
 
 
2. Do any of the source(s) require a Data Use Agreement (DUA) or other Agreement that requires institutional 
signature to obtain, access or use the data / biospecimens? ☐ Yes   ☐ No 
 
If “yes,” please include a copy of the Agreement(s) with this submission and also follow the Data Use 
Agreement review and signature processes. 
 
3. Describe the type(s) of data and date range(s) of the data you will use and the characteristics of the study 
research population (e.g., age range, sex, and any other pertinent demographic information.) 
 
 
Proceed to PART VII. DATA SECURITY ASSESSMENT 
 
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PART VII. DATA SECURITY ASSESSMENT 
 
1. Do the study data / biospecimens include identifiers? Video and audio recordings are considered 
identifiable. 
☒ Yes   ☐ No* 
If “no,” I affirm that I have read and will abide by the Level 1 Risk Minimum Security 
Standards: ☐ Yes   ☐ No  
Proceed to Part VIII. 
 
If “yes,” answer the following questions. 
 
A. Describe the identifiers associated with the data / biospecimens. 
Biospeciments will be coded by de-identified study numbers immediately after 
collection.  The file connecting the participant ID to their study code will be kept in a 
secured password protected department folder, the destroyed after conclusion of the 
trial.  
 
B. Justify why identifiers are required to conduct the research. 
This is a biomedical study that requires blood and saliva collection for screening 
eligibility, safety measure and to answer research question. 
 
C. Described the proposed research use of the identifiable data / biospecimens. 
The de-identified data will be used for the purpose of this study and the other 
CADRE projects.  
 
D. Self-classify the Risk Level of these data / biospecimens (select the highest level of risk for 
all data / biospecimens being collected). 
     ☒ Level 2 Risk 
     ☐ Level 3 Risk 
2. How will study data / biospecimens be collected? 
   ☐ Brown desktop 
   ☐ Laptop 
   ☒ Departmental server 
   ☐ CIS managed server 
   ☐ Brown Qualtrics 
   ☐ REDCap; Please describe what instance of REDCap is being used (Brown does not have an instance of 
REDCap):  
   ☐ MTurk (AMT) 
   ☐ Text messaging  You must complete the Text messaging section after completing Qs 3 – 5. 
   ☐ Mobile App (on tablet, iPad, Phone)  You must complete the Mobile App section after completing Qs 3-5. 
   ☐ Zoom  
   ☐ Other audio / videoconferencing tool; please describe the tool:  
   ☒ Paper records, including photographs. Please describe, including how you will securely store 
        the paper records:    
Subject’s identifiable information (i.e. screening questionnaires) will be stored separately from 
individual data. Paper records will be maintained in locked file cabinets in locked offices. The file 
connecting the participant ID to their study code will be kept in a secured password protected 
department folder, the destroyed after conclusion of the trial. 
 
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   ☐ Web-based site / survey / other tool not listed above  You must complete the Web-based Other section after 
completing Qs 3 – 5. 
   ☐ Other; please describe:  
 
3. Who will have access to the study data / biospecimens? 
   ☐ A. Brown PI only. How will unauthorized access by others be prevented? 
 
 
   ☒ B. Brown PI and other Brown research team members. How will unauthorized access by others be 
prevented? 
Data will be stored on a Brown University protected drive. Unauthorized access by others will be 
prevented by password protecting the folder that the file is located in, as well as the file itself. All 
computer and biospeciment information will be de-identified and referred to by a subject 
identification number following collection. All electronic records will be maintained on password 
protected fileservers in a locked office, further protected by firewalls and other security procedures 
 
 
   ☐ C. Data will be shared with research collaborators external to Brown. This data sharing intent 
       must be described as part of your consent process / form. Please describe how you will 
       securely share / transfer the data outside of Brown:  
 
 
Note that an Outgoing Data Use Agreement is required when sharing identifiable data external to Brown. 
Please follow the procedures outlined here. You do not need to submit a copy of a DUA to the HRPP. This 
will be linked by the ORI administratively. 
 
4. Where will the study data / biospecimens be stored? 
   ☒ Departmental server 
   ☐ CIS managed server 
   ☐ Stronghold 
   ☐ Campus file storage 
   ☐ REDCap  
   ☐ Other. Please describe:  
 
5. If traveling with your data, describe how your data will be secured. 
NA 
6. For how long will you retain identifiable data / biospecimens? How will you destroy identifiers when no 
longer required? 
We will be deleting the file connecting the participant ID to their study code at the completion of 
the study. 
 
Text Messaging (only complete if instructed above.) 
1. Are you using the current text messaging service available on the device? 
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☐ Yes   ☐ No 
 
If “no,” you must also complete the Mobile App section. 
2. Whose device will be used? ☐ Participant’s personal phone   ☐ Brown-issued phone 
3. Content of messaging: (If brief, insert here; otherwise, please provide as an attachment) 
4. Is the communication one-way or two-way? ☐ One-way   ☐ Two-way 
Mobile App (only complete if instructed above.) 
1. Name of the mobile app:  
2. Has this site / tool been reviewed by CIS IT Security?  
☐ Yes   ☐ No 
If “no,” answer the following: 
a. Who created the site / tool (vendor name or off the-shelf app creator name)? 
b. Where is it hosted?  
c. Is the site / tool scanned for security vulnerabilities? ☐ Yes   ☐ No 
d. What version of software is being used, if applicable: ☐ N/A or  
e. How are the data encrypted?  
3. Whose device will be used? ☐ Participant’s personal phone   ☐ Brown-issued phone 
If Participant’s person phone: 
a. How is the app downloaded to the device?  
b. Is a password or PIN required for the app? ☐ Yes   ☐ No 
4. Will data be stored on the device for any period of time? 
☐ Yes   ☐ No 
 
a. If “yes,” please describe (i.e., queue on phone and then transmitted to server):  
 
 
b. Is the app data encrypted on the device? ☐ Yes   ☐ No 
5. Device features mobile app can access ☐ N/A 
   ☐ Device ID and call information 
   ☐ Identity 
   ☐ Contacts   
   ☐ Camera 
   ☐ SMS or chat 
   ☐ Storage 
   ☐ Device and application history 
   ☐ Phone 
   ☐ Photo / media / files 
   ☐ Microphone 
   ☐ Location 
   ☐ Other; please describe:  
 
6. Will a third-party have access to research data through this app? ☐ Yes   ☐ No 
7. Is data transmitted by the device?  
☐ Yes   ☐ No 
If “yes,” how is it encrypted in transit?  
 
8. Are phone numbers or mobile identification numbers stored with the data? ☐ Yes   ☐ No 
Web-based Other (only complete if instructed above.) 
1. Name of the site / tool:  
2. Has this site / tool been reviewed by CIS IT Security?  
☐ Yes   ☐ No 
If “no,” answer the following: 
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a. Who created the site / tool (vendor name or off the-shelf app creator name)? 
b. Where is it hosted?  
c. Is the site / tool scanned for security vulnerabilities? ☐ Yes   ☐ No 
d. What version of software is being used, if applicable: ☐ N/A or  
e. How are the data encrypted?  
☐ Yes   ☐ No 
If “no,” answer the following: 
a. Who created the site / tool (vendor name)?  
b. Where is it hosted?  
c. Is the site / tool scanned for security vulnerabilities? ☐ Yes   ☐ No 
d. What version of software is being used, if applicable: ☐ N/A or  
e. How are the data encrypted?  
3. Is informed consent being obtained via this site / tool?  
☐ Yes   ☐ No 
If “yes,” how is re-identification prevented?  
 
4. Does the technology allow for the explicit exclusion of the collection of IP address of the participant’s 
connection?  
☐ Yes   ☐ No 
If “yes,” will you use this option to exclude the collection of IP address? 
☐ Yes   ☐ No 
 
Brown Qualtrics: CIS has pre-vetted Brown Qualtrics for collection/storage of up to Risk Level III data. Qualtrics is the preferred 
survey tool for all Brown research data collection. 
 
REDCap: Brown does not currently have its own instance of REDCap. Access to REDCap through a Lifespan collaborator must be 
explicitly identified. 
 
Data collection: The expectation is that data collection devices will only store data during active data collection. Data must then be 
transitioned to more secure long-term storage solutions. 
 
Departmental/CIS managed servers: If data are collected/entered directly onto a Departmental or CIS managed server, you must 
ensure that the server meets the security standards described in the Minimum Security Standards for Servers based on the Risk Level 
of the data identified in 1D. 
 
 
Proceed to PART VIII. INTERNATIONAL RESEARCH 
 
 
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PART VIII. INTERNATIONAL RESEARCH 
 
1.  Does the research involve human subjects activities outside of the United States? 
☐ Yes   ☒ No 
a. If “yes,” please list the countries. If “no,” you are not required to complete this Part of 
the application. Proceed to PART IX. ATTACHMENTS. 
 
 
 
------------------------------------------------------------------------------------------------------------- 
b. What is the status of permissions / approvals from local ethics boards or committees? 
 ☐ Received; please append to this Application. 
 ☐ Pending  
 ☐ N/A. Please explain:  
------------------------------------------------------------------------------------------------------------- 
c. Will this research take place in a non-public setting (including a school, hospital or 
clinic) for which local permission is required? ☐ Yes   ☐ No 
If “yes,” please append a letter(s) of support or permission(s) to this Application.  
 
------------------------------------------------------------------------------------------------------------- 
d. Describe how you have taken into account any social, political, or cultural issues that 
may impact participants.  
 
 
 
 
 ☐ I have reviewed the current version of the International Compilation of Human Research 
Standards and agree to abide by relevant local laws, regulations and guidelines. 
☐ I have reviewed the General Data Protection Regulations guidance and will abide by any 
requirements. 
☐ I have reviewed ORI’s export control guidance on international travel, international 
collaborations, and international shipping (if applicable) 
 
 
 
 
Proceed to PART IX. ATTACHMENTS 
 
 
Brown University IRB Original Approval: 05/16/2019 
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PART IX. ATTACHMENTS 
 
 
Please attach the following materials to this Application for Full Board / Expedited IRB Review, as 
applicable. 
 
Incl.      N/A  
☒ 
☐ 
Informed consent documents / scripts 
☒ 
☐ 
Data collection materials (questionnaires, surveys, interview scripts, etc.) 
☐ 
☒ 
Permissions, approval documents, and/or support letters identified in PART VII. 
☒ 
☐ 
Recruitment materials (emails, flyers, letters, scripts, posters, brochures, etc.) 
☐ 
☒ 
Application for IRB Authorization Agreement 
☐ 
☒ 
Data Use Agreement from data provider(s) 
☒ 
☐ 
Data Safety Monitoring Plan 
☒ 
☐ 
Other: IND 
 
LIST OF ATTACHMENTS 
 
A. FDA IND#135570 (Specific for this project) 
B. CADRE CORE Standardized Assessments and Measures  
C. Use of Drugs (oxytocin and yohimbine) 
D. Data and Safety Monitoring Plan (DSMP)  
E. Prescription Drug / Medication Management 
F. Mental Health Safety Plan  
F. 2 CADRE Suicidality Mental Health Monitoring 
G. Project ad hoc Assessments and Measures  
H. Oxytocin Drug Manual 
I. 
Yohimbine Drug Manual 
J. Telephone pre-screening  
K. Informed Consent Document  
L. Recruitment Material  
 
PART X. CONFLICT OF INTEREST  
 
The Brown University Conflict of Interest Policy for Officers of Instruction and Research (“COI Policy”) 
defines the term “Investigator” as “the project director or principal investigator and any other person, 
regardless of title or position (e.g., full or part-time faculty member, staff member, student, trainee, 
collaborator, or consultant), who is responsible for the design, conduct, or reporting of sponsored 
research.” 
 
Using this definition of “Investigator,” please ensure that all Investigators on this protocol answer questions 
(1) and (2) below. Attach additional sheets for any Investigators who are not the PI; additional sheets are 
available on the HRPP website. 
 
Brown University IRB Original Approval: 05/16/2019 
Brown University IRB Amendment Approval: 11/21/2019 
Brown University IRB Amendment Approval: 09/02/2020 
Brown University IRB Amendment Approval: 10/15/2020
Brown University IRB Amendment Approval: 11/18/21


1. Have you completed a conflict of interest disclosure (i.e. COI Reporting Form) within the past 12 months 
and is it accurate and up-to-date as of the time of this submission, as required by Brown’s COI Policy? (You 
may access the InfoEd system here to confirm.) 
☒ Yes   ☐ No 
If “no,” please do so before submitting this Application 
2. Do you have a significant financial interest (SFI) that is related to this research protocol?   
“Related” could mean the research involves products, technology, intellectual property, or services made, 
owned, or provided by the entity/ies in which you have an SFI. It could also mean that the SFI could be 
affected by the proposed research or its results.     
 
☐ Yes   ☒ No 
If “yes,” please identify the SFI and explain the relatedness:  
☐ Additional COI sheets for Investigators are attached to this Application. 
(Required for Advisors) 
 
PART XI. INVESTIGATOR & FACULTY ADVISOR AGREEMENTS / 
PRINCIPAL INVESTIGATOR RESPONSIBILITIES  
 
 
 A. Conduct of the Research 
1. I accept responsibility for the ethical conduct of this research and protection of participants as set 
forth in the Belmont Report, Common Rule, and Brown University policies. 
2. I accept responsibility for ensuring this research is conducted in accordance with: 
a) Sound research design and methods; 
b) The parameters of the research plan and activities described in this Application; 
c) The applicable terms of the grant, contract, or other signed funding agreements; 
d) Applicable laws and regulations, including those protecting the rights, safety and welfare of 
human subjects. 
3. I certify that I am, or my faculty advisor is, sufficiently qualified by education, training and 
experience to assume responsibility for the proper conduct of this research. I accept 
responsibility for ensuring that all member of the research team have or will complete human 
subjects CITI training before any work with participants or identifiable data / biospecimens 
begins. 
4. I accept responsibility to personally conduct and/or directly supervise this research. I certify that 
I have sufficient time and resources to properly conduct and/or supervise this research. 
 
B. Ensuring and Maintaining Compliance 
1. I will comply with relevant regulatory and institutional reporting requirements, including Brown 
University’s Reportable Events Policy.  
2. I understand that it is my responsibility to ensure that any research personnel, including myself, 
responsible for the design, conduct or reporting of the research declares any conflicts of interest 
related to this research. I will ensure that any changes that impact my or other research 
personnel’s answers to the questions in PART IX. Conflict of Interest, are reported promptly to 
Brown’s HRPP. 
3. I will ensure that prospective agreement and/or informed consent is obtained and a copy is 
provided to participants, when appropriate. 
4. If there are changes to the research described in this Application for Full Board / Expedited IRB 
Review that may impact the study’s classification as Full Board or Exepdited research, I will 
promptly notify the Brown HRPP of such changes. 
Brown University IRB Original Approval: 05/16/2019 
Brown University IRB Amendment Approval: 11/21/2019 
Brown University IRB Amendment Approval: 09/02/2020 
Brown University IRB Amendment Approval: 10/15/2020
Brown University IRB Amendment Approval: 11/18/21


5. I will notify the Brown HRPP when I have completed all activities involving human subjects or 
identifiable participant data or identifiable biospecimens. 
6. I will maintain approval, as applicable, with collaborative parties, including approvals from other 
countries or jurisdictions. 
7. I will cooperate with any post-approval monitoring or auditing of study activities and/or study 
records as requested and/or required by the Brown ORI, the Brown IRB, funding entities, 
sponsors, and/or any federal or state regulatory agencies. 
 
C. Study records, Reports and Documentation 
1. I will maintain all research protocol materials and consent materials for the duration of this 
study. 
2. I will maintain research records for at least three years following the end of this research, or for a 
longer length of time if specified in applicable regulations or sponsor requirements. I will take 
measures to prevent accidental or premature destruction of these records. 
3. I will abide by all terms of any Data Use Agreement (or equivalent agreement) related to this 
study, including those agreed to electronically (through an online attestation). 
4. I will ensure that the data security measures for acquisition, collection, transfer and use of study 
data described in PART VI. of this Application are adhered to by all members of the research 
team.  
 
                
By my signature below, I certify that I have read and agree to uphold all of you and/or Advisor 
Responsibilities in PART XI. 
 
 
 
 
Principal Investigator signature:    
 
 
 
Date:  4/29/2019 
 
 
 
=============================================================================== 
 
An Advisor’s signature is required for all graduate/medical student projects 
 
Advisor certifies the following:  Advisor has read the complete protocol, approves this project, and will remain 
available to advise the student throughout the course of the proposed human subjects research, or will transfer 
responsibilities to another Advisor if unable to advise for the entirety of the project. 
 
Advisor’s name (please print):         
 
Advisor's signature:   
 
 
 
 
 
Date:  Click here to enter a date. 
 
 
 
Brown University IRB Original Approval: 05/16/2019 
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For IRB Use Only 
 
Signature of the IRB:  
 
Date of IRB approval: Click here to enter a date. 
Brown University IRB Original Approval: 05/16/2019 
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Brown University IRB Amendment Approval: 09/02/2020 
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Brown University IRB Amendment Approval: 11/18/21

SAP_001.pdf: 
1 
Oxytocin, Stress, Craving, Opioid Use Disorder (OSCO)
STATISTICAL ANALYSIS PLAN 
Carolina L. Haass-Koffler, PharmD, PhD 
121 South Main Street 
Providence, RI 02903 
Tel: 401-863-6624; Fax: 401-863-6697 
carolina_haass-koffler@brown.edu 
ORIGINAL: 2019 AUGUST 08 
REVISED: 2022 MAY 05
Clinical trial registration: Clinicaltrials.gov; NCT04051619 
IND/FDA: 135570, oxytocin and yohimbine (Holder: Haass-Koffler) 


2 
 
Table of Contents 
Study design, setting and approval .......................................................................................................... 3 
Statistical analysis ......................................................................................................................................... 3 
Missing data reporting .................................................................................................................................. 4 
References ....................................................................................................................................................... 6 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


3 
 
Study design, setting and approval 
 
This was a Phase 1, outpatient, randomized, double-blind, cross-over (2x2 design with oxytocin and yohimbine), 
placebo-controlled, human laboratory study (Figure 1). The trial took place at the Center for Alcohol and 
Addiction Studies, Brown University, Providence, RI, USA from 2019-2023. The clinical protocol was approved 
by the Brown University Institutional Review Board (IRB), received an FDA Investigational New Drug 
(IND135570), and was registered on clinicaltrials.gov (NCT04051619). The study was initiated as a between-
subjects design. However, following the COVID-19 pandemic, in order to speed up recruitment, the study was 
changed to a within-subjects crossover design. This modification in the clinical protocol was executed following 
the FDA Guidance Document on Changes or Modification during conduct of Clinical Investigations 1. After 
receiving approval from the Brown University IRB in November 2021, the FDA was notified in an annual progress 
report and the study design was updated on clinicaltrials.gov in February 2022.  
 
 
Statistical analysis  
 
For all outcomes, we utilized an intention-to-treat (ITT) approach, where participants were examined based on 
their a priori randomized protocol and received at least one dose of the study medication (oxytocin or oxytocin-
matched placebo) 2  
The ITT analysis was suitable for this crossover design 3 as the placebo condition was treated 
identically to the active drug condition (route, administration and laboratory procedures). Distributional 
characteristics of outcome measures were examined to evaluate similarity to the normal distribution, 
detailed descriptive analysis of demographics, substance use, and clinical characteristics. The cortisol 
had a kurtosis in excess of four; consequently, an outlier analysis was performed and a total of 5 outliers 
falling outside of ±3 interquartile range were Winsorized as recommended 4. Comparisons with these 
characteristics, in relation to enrolled versus completer status, were performed using t-tests to analyze 
continuous variables (age) and χ2 for categorical variables (sex, race, medication status). Attrition rates 
between the screening visit and follow-up visit were examined descriptively to assess for potential bias. 
In addition, a logistic regression was performed to test for possible bias due to period (placebo first, 
then oxytocin and oxytocin first, then placebo) or medication carryover (placebo and oxytocin), as done 
in our prior cross-over trial 5. This study tested the feasibility of the combined study design, the safety 
and tolerability of IN oxytocin and yohimbine, and the potential value of testing IN oxytocin as adjunct 
therapy in an appropriately-powered larger RCT. In selecting a target sample size, we balanced power 
considerations and feasibility given the preliminary nature of this trial. Because of the within-subjects 
design, power to test the effects of the study drug was optimized for this modest sample size. For the 
safety and tolerability outcomes (primary) adverse events, difference was detected based on a 


4 
 
judgement concerning the minimal effect, which has clinical relevance in the management of patients. 
In a noninferiority trial, the exact sample size could not be fixed in advance because it depends upon 
the chosen stopping guidelines 6.  
Outcomes: Primary (craving) and secondary (safety and tolerability) outcomes were assessed in real-
time in the laboratory. Seven-day oxytocin administration was compared to the oxytocin-matched placebo 
condition during the CR procedure, in which noradrenergic activation produced by yohimbine or yohimbine-
matched placebo condition (2X2 design) was measured. We used Generalized Linear Model (GLM) with model-
based estimator in the covariance matrix, with medication (oxytocin/placebo) and noradrenergic activation 
(yohimbine/placebo) as within-subject factors. The model was specified to evaluate the effect of drug 
(oxytocin/placebo) by noradrenergic (yohimbine/placebo) interaction, main effect of the drug, and main effect of 
noradrenergic activation. Craving was assessed using the DDQ with time coded as: t0=relaxation, t1=interaction 
with drug paraphernalia/opioid auditory cues and t2=opioid use video. Safety and tolerability were assessed 
using: SBP, DBP, HR (vital signs), HAM-A and STAI (anxiety). The STAI y1 (state) was included as an additional 
safety measure for anxiety to ensure participants were not experiencing acute symptoms of anxiety within the 
laboratory. The STAI y2 (trait) was inserted as a covariate in the model to control for baseline anxiety level, along 
with stress (PSS), HPA (cortisol), and noradrenergic response (α-amylase). Time at laboratory sessions was 
coded as: t0=baseline, t45min=45-min after yohimbine administration, and t90min=post cue-exposure to specifically 
evaluate the contribution of each laboratory procedure (yohimbine and CR). Withdrawal symptoms (COWS) and 
AEs were assessed at specific timepoints: t0=pre-laboratory and t1=post-laboratory procedures.  
Other outcomes (safety and tolerability) were measured retrospectively during the one-week 
outpatient setting and included the: COWS (withdrawal), anxiety (HAM-A and STAI), stress (PSS), 
depression (HAM-D) and AEs. The other outcomes were analyzed using ANOVA test and the number 
of AEs via a χ2 test. For missing data approach, we first categorized missing data as missing completely 
at random (MCAR), missing at random (MAR) or missing not at random (MNAR) 7. Analysis with GLM 
(using all available pairs of data to model missing values with maximum likelihood estimation) was 
deemed suitable for our analyses because no systematic differences existed between participants with 
missing data and those with complete data (MCAR) 8. 
 
Missing data reporting 9 
 
1. Amount of missing data in the dataset:  
a. Oxytocin condition: 10% did not receive either oxytocin or placebo condition (within subject, n=16; 
between subject, n=4) 
b. Yohimbine condition: 11.12% did not receive yohimbine condition (yohimbine, n=14; placebo, 
n=16; no yohimbine, n=4):  


5 
 
2. Reason for missing: 
a. Oxytocin condition: change from between subject to within subject design 
b. Yohimbine condition: safety concerns due to past history of cardiovascular disease and/or current 
hypertension (n=3), stroke (n=1) 
3. Consequences:  
a. Oxytocin condition: no differences between participants with and without missing values except 
there were no subject taking methadone in the subjects with missing values. 
b. Yohimbine condition: no differences between participants with and without missing values except 
there were cardiovascular concerns in the subjects with missing values. 
4. Method: GLM with MNAR using all available pairs of data to model missing values with maximum 
likelihood estimation 
5. Software: IBM SPSS Statistics for Windows, version 29 (IBM Corp., Armonk, NY, USA) 
 
All statistical analyses were performed after participants had completed their follow-up visits and the 
study database had been locked. The results were presented using summary statistics: number of subjects (n); 
mean (M); standard deviation (SD) or frequency distributions (%) and effect size was reported as Cohen’s d.  
All statistical procedures were performed by IBM SPSS Statistics for Windows, version 29 (IBM 
Corp., Armonk, NY, USA), and GraphPad Prism (v.10) was used to generate figures (La Jolla, CA, 
USA). All statistical tests were two-tailed, and statistical significance was accepted if an alpha 
value p<.05 was obtained. 
 
 
 
 


6 
 
 
References 
 
1. 
FDA. Changes or modifications during the conduct of a clinical investigation; final guidance for 
industry and CDRH staff. 20012001. 
2. 
Schulz K, Altman D, Moher D. Consolidated Standards of Reporting Trials Group CONSORT 
2010 Statement: Updated Guidelines for Reporting Parallel Group Randomised Trials. Bmj. 
2010;340:c332. 
3. 
Pearce K, Fisher L, Dixon D, Herson J, Frankowski R, Hearon M. Intention to treat in clinical 
trials, Statistical Issues in Drug Research and Development. Edited by Pearce KE. New York, Marcel 
Dekker; 1990. 
4. 
Tukey JW. The future of data analysis. The annals of mathematical statistics. 1962;33(1):1-67. 
5. 
Haass-Koffler CL, Perciballi R, Magill M, Loche A, Cacciaglia R, Leggio L, Swift RM. An 
inpatient human laboratory study assessing the safety and tolerability, pharmacokinetics, and 
biobehavioral effect of GET 73 when co-administered with alcohol in individuals with alcohol use 
disorder. Psychopharmacology (Berl). 2021. Epub 20211103. doi: 10.1007/s00213-021-06008-1. 
PubMed PMID: 34731268. 
6. 
U.S. Department of Health and Human Services FDA. Guidance for Industry, E9 Statistical 
Principles for Clinical Trials. Center for Drug Evaluation and Research (CDER) CfBEaRC; 1998 1998. 
Report No.: E9. 
7. 
Little RJ, Rubin DB. Statistical analysis with missing data: John Wiley & Sons; 2019. 
8. 
Nakagawa S. Missing data: mechanisms, methods and messages. Ecological statistics: 
Contemporary theory and application. 2015:81-105. 
9. 
Van Buuren S, Groothuis-Oudshoorn K. mice: Multivariate imputation by chained equations in 
R. Journal of statistical software. 2011;45:1-67.