Conditions: Tobacco Use Disorder Nicotine Addiction
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 24
Healthy volunteers: yes

Brief summary:
Tobacco use remains the foremost cause of preventable deaths in the U.S. and worldwide. Advancing new smoking cessation therapies, including those targeting novel biological mechanisms, is a critical public health priority. Accumulating evidence from preclinical studies suggests that glucagon-like peptide-1 (GLP-1) receptor agonists reduce intake and/or reinstatement of addictive drugs, including nicotine. However, translational work is necessary to establish whether GLP-1 receptor agonists alter aspects of nicotine response and smoking behavior in smokers. Human laboratory studies play a pivotal role in drug development by providing a time- and cost-efficient means of validating preclinical findings, also providing an ideal platform for studying mechanisms of medication effects. This is an experimental investigation to examine the effects of an approved GLP-1 receptor agonist on nicotine intake and reinstatement. Dependent smokers will be enrolled in a double-blind, parallel-arm trial with laboratory endpoints. Laboratory procedures will include a validated procedure for measuring smoking lapse/reinstatement after overnight abstinence. This study will provide initial laboratory evidence for the potential efficacy of GLP-1 receptor agonists as adjunctive treatments for smoking cessation.

Detailed description:

Arms:
arm 1: Participants will receive semaglutide via subcutaneous injections at escalating doses (0.25mg to 1.0mg) over 9 weeks. arm 2: Participants will receive sham subcutaneous injections over 9 weeks.

Interventions: intervention 1: Semaglutide intervention 2: Sham/placebo
Intervention descriptions: intervention 1: Semaglutide (subcutaneous) intervention 2: Sham subcutaneous injection

Protocol document:
ICF_000.pdf: 
Cover Page
Study Name: Effects of Semaglutide on Nicotine Intake
NCT 05530577
Informed consent form, dated 08/22/2022


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University of North Carolina at Chapel Hill 
Consent to Participate in a Research Study 
Adult Participants 
Consent Form Version Date: 08/22/2022 (v4) 
IRB Study # 21-1548 
Title of Study: Effects of Semaglutide on Nicotine Intake and Smoking Lapse 
Principal Investigator: Christian Hendershot 
Principal Investigator Department: Psychiatry - General 
Principal Investigator Phone number: (919) 962-5565 
Principal Investigator Email Address: christian_hendershot@med.unc.edu 
Funding Source and/or Sponsor: NIH National Institute on Drug Abuse (NIDA) 
Study Contact telephone number: 919-962-3069 
Concise Summary 
This study is being done to evaluate how the medication semaglutide affects smoking behavior 
and responses nicotine in regular smokers. Semaglutide is a medication that aids in reducing 
blood sugar and body weight, and is approved for the treatment of Type II diabetes. This study 
will help to answer the question of whether semaglutide could be helpful as a treatment for 
people who are trying to quit smoking.  
You are being asked to participate because you report smoking cigarettes regularly, but that you 
are not trying to quit smoking right now. If you agree to participate, your participation will last 
up to approximately 16 weeks, including all scheduled follow ups. During this time you will be 
asked to complete several study components, including weekly clinic visits, questionnaires, brief 
daily surveys, and additional visits that involve smoking. Examples of potential risks of 
participation include medication side effects (such as nausea), discomfort from study procedures 
(e.g., blood draws), and risks related to laboratory smoking procedures (e.g., temporary 
discomfort while abstaining from smoking). The information contained in this consent form is to 
help you decide whether you want to take part in the study. Please take the time to read all the 
information carefully. This consent form is only part of the process of informed consent. If you 
would like additional details about something mentioned here, or information not included here, 
please ask at any time. 
What are some general things you should know about research studies? 
You are being asked to take part in a research study.  To join the study is voluntary. 
You may choose not to participate, or you may withdraw your consent to be in the study, for any 
reason, without penalty. 
Research studies are designed to obtain new knowledge. This new information may help people 
in the future. You may not receive any direct benefit from being in the research study. There also 
may be risks to being in research studies. Deciding not to be in the study or leaving the study 
before it is done will not affect your relationship with the researcher, your health care provider, 


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or the University of North Carolina-Chapel Hill. If you are a patient with an illness, you do not 
have to be in the research study in order to receive health care. 
 
Details about this study are discussed below. It is important that you understand this information 
so that you can make an informed choice about being in this research study.  
 
You will be given a copy of this consent form.  You should ask the researchers named above, or 
staff members who may assist them, any questions you have about this study at any time. 
 
What is the purpose of this study? 
 
The purpose of this study is to evaluate how the medication semaglutide affects smoking 
behavior and responses to nicotine in participants who smoke cigarettes. Semaglutide is 
approved by the U.S. Food and Drug Administration (FDA) to treat Type II diabetes. The 
medication is routinely prescribed to help people control blood sugar and body weight. Research 
with animals has shown that this medication may influence responses to certain commonly used 
drugs, including nicotine. Because you are not being prescribed the study medication for diabetes 
or weight management, this study involves “off-label” use of the medication.  
You are being asked to be in the study because you reported current regular cigarette smoking. 
You also reported that you might be interested in quitting in the future, but not right now. Please 
note that this is not a treatment study to help people quit smoking. 
Are there any reasons you should not be in this study? 
Because this is not a treatment study, you should not be in this study if you are 1) currently 
seeking or receiving treatment for smoking cessation or other substance use, or 2) actively trying 
to smoking, or 3) anticipating trying to make a serious quit attempt in the next three months. 
 
How many people will take part in this study? 
The study will aim to recruit 36 people who complete all study procedures. It is possible that 
more than 36 people will take part overall, although the exact number is undetermined. This 
study is only taking place at UNC-Chapel Hill. 
How long will your part in this study last? 
Participation in this study will take place over approximately 16 weeks. The reason for this time 
period is that the medication dosage will be increased slowly over 9 weeks. In addition to the visit 
today, which will take up to 3-4 hours, you will be asked to attend 10 scheduled weekly follow-up 
visits for study medication and check-ins (up to one hour each), as well as 2 lab visits that involve 
cigarette smoking, which will last up to 4 hours. You will also be asked to complete a brief 
questionnaire (1-2 minutes) each day during the study (which can be completed via mobile phone), 
and to complete several brief phone calls (approximately 5 minutes each) to monitor side effects at 
various points in the study. Overall, we expect your participation in this study to last up to 25-35 
hours over up to 16 weeks, including baseline and screening. 


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If you think you might be unable to commit to the timeframe of the study (16 weeks), or if you 
plan to travel out of town during this period, please let us know now. This may affect your 
availability to attend study visits and complete the study. 
What will happen if you take part in the study? 
I. Screening Visit and Baseline Questionnaires (Week 0 visit) 
To determine your eligibility, a study team member will conduct a conduct an interview about 
your substance use, medical history, and other exclusion/inclusion. This interview will typically 
take place remotely (e.g., by Zoom), but may be completed in person. If eligible, we will ask you 
to complete an in-person visit at UNC that includes a limited physical exam, additional 
questions, an assessment of vitals (heart rate, blood pressure, weight/height), and a blood draw 
via needlestick. You will also be asked to provide an expired carbon monoxide (CO) test (a 
breath test that can detect recent smoking), and a urine sample to test for the presence of several 
drugs. You will be able to collect the sample in a bathroom without anyone watching you. 
Women in this study will also be asked to complete a pregnancy test. These procedures are 
intended primarily to rule out any factors that would make it unsafe for you to take the study 
medication. Your urine sample will also be saved and analyzed to assess levels of nicotine and 
nicotine metabolites. If you test positive for drugs (other than marijuana) or pregnancy (either 
today or later in the study), you will not be eligible for the study.  
If any lab or physical results are abnormal, or suggest things that may be unsafe for you to take 
the medication (e.g., very low blood sugar), the medical staff will notify you of the findings and 
you may be withdrawn from the study. Part of your blood sample will be stored to examine 
additional questions, such as whether certain genetic factors, including factors that influence 
nicotine metabolism, might relate to the study outcmoes. Your blood sample will be labeled only 
with a special number (code), which will remain linked to your identity (the process is outlined 
in a separate consent form).  
Assuming you are eligible, you will be asked to complete questionnaires (about personality, 
substance use, and related factors) on paper. You are free to decline to answer any question. 
Overall, the screening and baseline visit is expected to last up to 3-4 hours in total. If any study 
components cannot be completed today (e.g., depending on your availability and availability of 
study staff), you may be asked to split the screening procedures into two visits. In addition, the 
study physician may ask to meet with you (via telephone or videoconference) to clarify questions 
about medical history or medications. You may also request a conversation with medical staff.  
II. Medication procedures and visits 
The study medication, semaglutide, is a medication for the management of type II diabetes. This 
medication has been shown to reduce blood glucose levels and promote weight loss. Semaglutide 
is one of several medications called “GLP-1 agonists”. GLP-1 is a hormone that is naturally 
produced by the body, and is stimulated by eating meals. Semaglutide (and other GLP-1 
agonists) are designed to mimic some of the actions of the GLP-1 hormone. 
The medication is taken once per week using a “subcutaneous” method, which means depositing 
a small medication dose under the skin. Specifically, the medication is delivered using a micro-


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needle (about the width of 2 human hairs), which is relatively easy and painless to administer. 
The amount of medication administered by the needle is extremely small (almost unmeasurable). 
People who are prescribed semaglutide usually take the medication themselves at home. For 
purposes of this study, we will ask that you attend lab visits to receive the study medication and 
complete side effects questionnaires. The medication dose will be increased gradually over the 
course of the study, in order to limit side effects. Side effects of the medication are described 
under the “potential risks” section below.  
This study also involves “placebo” medication doses. A placebo is an inactive version of the 
medication. Some participants will receive doses of semaglutide that increase gradually over the 
course of the study, and some participants will receive placebo doses. Which medication 
condition you receive will be determined randomly (like flipping a coin). You will be asked to 
wear a blindfold while the medication or placebo is being administered. The study investigators 
and research team will not be aware of your condition. However, if there is a reason to suspect a 
safety concern, the investigators will be able to determine your study condition at any time. 
While participating you will be required to keep your assigned medication at home and bring it 
in with you to study visits. Medication will be provided in a sealed, tamper-resistant bag. It is 
important not to open the bag at any point during the study as this could disqualify you from 
further participation. A UNC medical staff member or pharmacist will be the only person 
responsible for opening and resealing bags. In addition, it is important to store the medication in 
a safe location in your possession at home, and to store the medication at room temperature. 
Please see attached medication instructions for more information. Finally, it is important to bring 
your medication bag to every medication visit. Failure to bring your medication bag will result in 
rescheduling the visit. If medication is lost, this could disqualify you from further participation. 
III. Phone call and questionnaire assessments 
In between visits to UNC you will be asked to complete brief phone calls (four scheduled 5-10 
minute calls) to check in about potential side effects. You will also be asked to complete daily 
surveys (estimated 2-3 minutes per survey). We will provide a booklet for you to complete the 
daily surveys. With your permission, we will also send a reminder text message about the survey 
each day.  
IV. Follow-up Visits 
Weekly Follow-Ups (Weeks 1-10 Visits). There will be weekly follow-up visits at the UNC 
Medical Center or UNC Medical Office Building (Eastowne) during the study. The purpose of 
these visits is to give you the next dose of medication or placebo and to conduct a brief 
assessment (e.g., weight, blood pressure, side effects). At some visits we will ask to take a blood 
sample, which is done using a finger-prick test or blood draw (depending on the study visit day). 
These blood draws will be taken because it is important to monitor your blood sugar levels 
regularly during the study. You will also complete follow-up questions and questionnaires with 
the study staff or a member of the medical team, which will focus on topics related to smoking 
and food intake, and related behaviors. If the study medical staff have any reason to believe that 
continuing in the study would not be safe, you may be withdrawn from the study.  


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Possible reasons for discontinuation might include abnormally low blood sugar, severe side 
effects, or testing positive for drugs other than cannabis during the study. At the final study visit 
(Week 10, discharge visit) you will not be given medication. You will be asked to complete a 
final blood draw and questionnaires and receive your final compensation at this visit. The team 
will try to schedule you for the same weekly time for each of your study visits. If it is not 
possible to attend at your regular time in each week, the team will work with you to find an 
alternate time that works with your schedule. 
Lab Visits. Two of the scheduled visits will be lab visits involving a smoking procedure. The 
purposes of these sessions is to examine responses to nicotine and smoking behavior. For these 
visits we will ask that you abstain from smoking for 12 hours (i.e., overnight) before arriving. It 
is important not to smoke the morning of the lab sessions. We will verify recent smoking using a 
breath carbon monoxide (CO) test to confirm abstinence that morning. We will ask you to bring 
an unopened pack of your preferred cigarettes to these sessions. This is to ensure that you are 
able to smoke your preferred brand.  
At the beginning of the session, you will be asked to fill out questionnaires while attending to 
smoking cues. You will then have the opportunity to smoke cigarettes over approximately two 
hours. We will also ask you to complete questionnaires at various points during the session. We 
will also collect a small urine sample at these visits to measure nicotine metabolites, and take 
another breath CO reading after the session. The smoking visits will last up to 4 hours. If you 
need to drive to these visits, we will provide you with reimbursement for parking at the UNC 
hospital. 
What are the possible benefits from being in this study? 
Research is designed to benefit society by gaining new knowledge. This research study could 
help to develop new treatments for people who have concerns about their smoking. Your 
participation in this study could therefore benefit others in the future. However, you are not 
expected to benefit personally from being in this research study. 
  
What are the possible risks or discomforts involved from being in this study? 
Medication. Semaglutide is a commonly used medication. You will receive an informational 
handout today that describes the study medication. Most medications have certain risks/side 
effects. The most common side effects are gastrointestinal side effects (i.e., stomach or digestive 
discomfort). In studies where semaglutide was taken for a long period of time (at least one year), 
the most commonly reported side effects (i.e., greater than 5% of participants and more common 
than placebo) included: 
• 
nausea 
• 
diarrhea 
• 
vomiting 
• 
constipation 
• 
abdominal pain 
 
Additionally, the rarer reported side effects (greater than 1% but less than 5%) included: 


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• hypoglycemia (low blood sugar) 
• indigestion (dyspepsia) 
• eructation (burping) 
• 
cholelithiasis (gallstones) 
• gastroesophageal reflux 
 
In this study, semaglutide will be taken for approximately 9 weeks. Side effects are most 
common after a dosage increase and are expected to normally go away quickly. We encourage 
you to tell us about any potential side effects you experience, or side effects that don’t go away 
on their own. We will check for side effects at every visit, as well as during scheduled telephone 
calls. The study staff may choose to stop the medication if you are showing signs of serious side 
effects.  
One potential side effect of the medication is low blood sugar. Therefore, it is important that we 
take measurements for blood sugar at each visit. This will require a finger prick test at some 
visits, or a blood draw at selected visits. The study staff will also explain symptoms of low blood 
sugar that you may experience. If you experience low blood sugar, please alert the study team. If 
you visit a physician or are prescribed any medications while enrolled in this study, you should 
inform your physician that you will be taking semaglutide while participating. In addition, please 
inform us if you start a new medication while participating in this study. For women in this 
study, it is important to not participant if you expect to become pregnant within the next 6 
months, because the medication should not be taken while pregnant, or within two months before 
becoming pregnant. You will be asked to confirm that you are able to use a reliable method of 
birth control during the study, and for the two months after stopping the medication. We will also 
ask women to provide a urine pregnancy screen at study visits. 
Blood Samples. Drawing blood may cause temporary pain and discomfort from the needle stick, 
occasional bruising, sweating, feeling faint or lightheaded, and in rare cases, infection or nerve 
pain. 
Smoking. It is possible that you could experience dizziness or nausea while smoking, or boredom 
or discomfort during the smoking sessions. 
Interview and Questionnaire Responses. It is possible you could experience emotional stress, 
inconvenience or an invasion of privacy when answering questions in this study. However, you 
may refuse to answer any questions or perform any test that you do not wish to answer or do. 
Every effort will be made to protect the information you give us. Participation in this study may 
produce emotional stress (such as distress while answering personal questions), inconvenience or 
an invasion of privacy.  
Genetic Analyses. The main aim of this analysis will be to examine genetic markers related to 
nicotine metabolism, such as CYP2A6. These analyses may also focus on genetic factors 
potentially associated with drug use or related behaviors, such as alcohol metabolism or 
impulsivity. DNA samples will be labeled with a number only (not your name) and will be stored 
and analyzed separately from any of your identifying information. The sample will not be used 
for diagnostic purposes or genomic sequencing. DNA samples may be stored indefinitely to 
allow for future analyses. You are free to ask the study team to destroy your genetic sample at 


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any point. Please note that if your sample has been de-linked from your name (e.g., after the 
completion of the study), it may not be possible to identify and destroy the sample, so it may be 
unlikely that this request can be granted. 
Unforeseeable risks. The most likely risks of participation have been outlined above. The study 
procedures could involve risks to the participant (or to the embryo or fetus, if the participant 
becomes pregnant) that are currently unforeseeable. Additionally, there may also be side effects 
or risks to study participation that are unexpected and not known at this time. Every effort will be 
made to protect the information you give us. However, there is a small risk of loss of 
confidentiality that may result in stigmatization or hardship. Procedures we will use to protect 
the information you give us are described above. 
Safety Precautions: Several safety precautions will be in place while you participate. We will 
monitor for side effects regularly, as described above. You will receive regular assessments and 
tests at medication visits to identify any negative reactions to the medication. 
Pregnancy Test (for women only): As a safety precaution, women will be asked to complete a 
pregnancy test at the beginning of the study, and at scheduled study visits. Participants will not 
be charged for the pregnancy tests. If you are planning to become pregnant during the next 6 
months, or if you are sexually active and not using a reliable birth control method, you should 
notify the study physician or nurse, and you will not be eligible to participate. There are no risks 
associated with the pregnancy tests. However, if your pregnancy test is positive, you will no 
longer be eligible to participate in the study. The results of your pregnancy test will remain 
confidential; no one else will receive the results of your pregnancy test. 
What if we learn about new findings or information during the study?  
You will also be informed of any significant new findings that become available during the 
study, such as changes in the risks or benefits resulting from participating in the research or new 
alternatives to participation that might change your mind about participating. If, for example, we 
find out that there are newly reported serious side effects of the study medication, we would 
inform you of these side effects so that you could decide whether you wanted to continue 
participating.  
Will I receive any other clinical results?  
The study physician may choose to communicate clinical results to you if relevant to your safety. 
For instance, if we receive lab tests that indicate you have low blood sugar, these results may be 
communicated to you for safety reasons. 
 
How will information about you be protected? 
We will take measures to protect your privacy and the security of all your personal information. 
Your name and other identifying information will be maintained in locked files and/or restricted 
databases, available only to authorized members of the research team for the duration of the 
study. All of the information we collect about you will be coded with a unique research subject 
identifier and will be kept on password-protected computers, and stored securely in restricted and 
protected databases according to local information security policies. De-identified data (meaning 
data that does not contain information that can directly identify you) from this study may be 
presented at meetings, published in journals/books, used in classrooms for training/teaching 


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purposes, and may be used and shared with other researchers for future research purposes, which 
includes scientists at other universities and institutions. However, all participants’ data will be 
merged together for such purposes, and your name and other identifying information will not be 
used in any published reports about this study. Participants will not be identified in any report or 
publication about this study.  
The blood samples collected at study visits will be labeled with your subject number and date of 
study visit and stored in a secure space. These samples will be stored for up to 24 months after 
we complete all analyses. A portion of the blood samples may be sent to an outside laboratory 
for analysis, but your identifying information will never be shared outside of the research team. 
We may use de-identified data and/or specimens from this study in future research without 
additional consent. Your specimens will not be used for commercial profit.   
Although every effort will be made to keep research records private, there may be times when 
federal or state law requires the disclosure of such records, including personal 
information. Examples of these special circumstances would be if the researcher or other 
members of the research team have reasonable grounds to believe that disclosing information is 
necessary to eliminate or reduce a significant risk of bodily harm to yourself or others, or where 
there is a court order to release records. This is very unlikely, but if disclosure is ever required, 
UNC-Chapel Hill will take steps allowable by law to protect the privacy of personal 
information.  In some cases, your information in this research study could be reviewed by 
representatives of the University, research sponsors, or government agencies (for example, the 
FDA) for purposes such as quality control or safety. 
 
Will my genetic information be shared? 
Your blood and tissue samples contain genes that are made of DNA unique to you. To do more 
powerful research, it is helpful for researchers to share information they get from studying 
human samples. They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies. Researchers can then study the combined 
information to learn even more about health and disease. If you agree to take part in this study, 
some of your genetic and health information might be placed into one or more scientific 
databases. There are many different kinds of scientific databases; some are maintained by this 
institution, some are maintained by the federal government, and some are maintained by private 
companies. For example, the National Institutes of Health (an agency of the federal government) 
maintains a database called “dbGaP.” A researcher who wants to study the information must 
apply to the database. Different databases may have different ways of reviewing such requests. 
Researchers with an approved study may be able to see and use your information, along with 
information from many other people. Your name and other information that could directly 
identify you (such as address or social security number) will never be placed into a scientific 
database. However, because your genetic information is unique to you, there is a small chance 
that someone could trace it back to you. The risk of this happening is very small but may grow in 
the future as technology advances. Researchers will always have a duty to protect your privacy 
and to keep your information confidential. 


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Federal law called the Genetic Information Nondiscrimination Act (GINA) generally makes it 
illegal for health insurance companies, group health plans, and most employers to discriminate 
against you based on your genetic information. GINA does not protect you against genetic 
discrimination by companies that sell life insurance, disability insurance, or long-term care 
insurance. GINA also does not protect you against discrimination based on an already-diagnosed 
genetic condition or disease 
What is a Certificate of Confidentiality?  
This research is covered by a Certificate of Confidentiality. With this Certificate, the researchers 
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 proceedings in the 
United States, for example, if there is a court subpoena, unless you have consented for this use. 
 
The Certificate cannot be used to refuse a request for information from personnel of a federal or 
state agency that is sponsoring the study for auditing or evaluation purposes or for information 
that must be disclosed in order to meet the requirements of the federal Food and Drug 
Administration (FDA). 
 
The Certificate of Confidentiality will not be used to prevent disclosure as required by federal, 
state, or local law, such as mandatory reporting requirements for child abuse or neglect, disabled 
adult abuse or neglect, communicable diseases, injuries caused by suspected criminal violence, 
cancer diagnosis or benign brain or central nervous system tumors or other mandatory reporting 
requirement under applicable law. The Certificate of Confidentiality will not be used if 
disclosure is for other scientific research, as allowed by federal regulations protecting research 
subjects or for any purpose you have consented to in this informed consent document. 
 
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 an 
insurer, employer, or other person obtains your written consent to receive research information, 
then the researchers may not use the Certificate to withhold that information. 
 
By signing this informed consent document, you agree that some of the information generated by 
participating in this study and/or a copy of the consent form may be included in your UNC 
medical record and that this information may be viewed by other physicians or caregivers who 
provide healthcare services to you. This will allow the doctors caring for you to know what study 
medications or tests you may be receiving as a part of the study and know how to take care of 
you if you have other health problems or needs during the study. Additionally, the information 
may be shared with your medical insurance plan if the research services provided are billed to 
your insurance. If you do not have a UNC medical record, the medical staff assisting with this 
study will create a medical record for purposes of research participation. 
What will happen if you are injured by this research? 
All research involves a chance that something bad might happen to you.  If you are hurt, become 
sick, or develop a reaction from something that was done as part of this study, the researcher will 
help you get medical care, but the University of North Carolina at Chapel Hill has not set aside 


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funds to pay you for any such injuries, illnesses or reactions, or for the related medical care. Any 
costs for medical expenses will be billed to you or your insurance company.  You may be 
responsible for any co-payments and your insurance may not cover the costs of study related 
injuries. 
If you think you have been injured from taking part in this study, call the Principal Investigator at 
the phone number provided on this consent form.  They will let you know what you should do.  
By signing this form, you do not give up your right to seek payment or other rights if you are 
harmed as a result of being in this study. 
What if you want to stop before your part in the study is complete? 
You can withdraw from this study at any time, without penalty.  The investigators also have the 
right to stop your participation at any time. This could be because you have had an unexpected 
reaction, or have failed to follow instructions, or because the entire study has been stopped. 
If you withdraw or are withdrawn from this study all data collected up until the point of 
withdrawal will be retained, however no additional information will be collected unless you 
provide additional written permission for further data collection at the time of your withdrawal. 
Will you receive anything for being in this study? 
To compensate you for your time when participating in this study, you will be paid in cash. The 
total possible compensation for completing all study components is $850. Different components 
of the study will have different compensation amounts. The compensation breakdown is 
described below.  
You will receive the following compensation for the in-person study visits: 
• 
$50 for completing the consent/screening/baseline sequence (Week 0) 
• 
$100 for smoking session 1 (To be scheduled between Weeks 0-1) 
o Includes $75 for attendance, plus a $25 payment after confirming overnight abstinence. 
• 
$100 for smoking session 2 (To be scheduled between Weeks 8-9) 
o Includes $75 for attendance, plus a $25 payment after confirming overnight abstinence. 
• 
$30 per visit for each follow-up/medication administration visit during Weeks 1-10 (10 visits 
x$30 per visit = $300) 
• 
Up to $150 for completing and returning daily questionnaires over the study period ($15 per 
weekly set of surveys x 10 weekly visits), which includes the week following the 1.0mg dose, to 
be paid at weekly medication visits) 
• 
A $50 bonus for completing at least 9 of 10 weekly assessments  
If you complete the study, you will receive a final bonus of $100 for completing the study through Week 
10 (to be paid at the final discharge visit). 
The exact compensation amount will depend on the study visits/components you complete, as 
described above. In the event you are not able to complete the full study, you will be 
compensated based on the components completed to that point. In the event you are not able to 
complete a full study session (e.g., the full lab session), you will be compensated at a pro-rated 


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amount of $20 per hour. In the event you are not able to pick up your final cash payment in 
person, we can send the final payment via electronic gift card to your email address. 
Any payment provided for participation in this study may be subject to applicable tax 
withholding obligations. 
Your name, address, and U.S. tax payer identification number (SSN or ITIN) are required to process 
payments and/or to report taxable income to the IRS. You must complete a W-9 (for U.S. persons) or 
W-8BEN and the Foreign Vendor Withholding Assessment with supporting documents (for non-
resident aliens) in order to receive payment for participation. U.S. person participants must complete 
Form W-9 in order to receive payment for participation. If payment by UNC equals or exceeds $600 
per calendar year for U.S. persons, UNC will report the amount to the Internal Revenue Service on 
Form 1099. Nonresident alien participants must complete Form W-8BEN and the Foreign Vendor 
Withholding Assessment with supporting documents in order to receive payment for participation. 
Payments to nonresident alien participants may be subject to tax withholding and are generally 
reported to the Internal Revenue Service on Form 1042-S. This information will not be linked to any 
of the study data and will only be used for payment purposes. If you do not provide your SSN or 
ITIN, or complete the appropriate documentation noted above, we cannot issue you a payment for 
participation. However, you may still choose to participate in this study. 
 
Will it cost you anything to be in this study? 
If you enroll in this study, you may have costs of participating which include transportation and 
parking fees. We will reimburse you for parking at the UNC hospital for the in-person study 
visits. Please speak with the research coordinator about parking reimbursement. You will not be 
responsible for paying for lab tests or medication associated with this study. 
Who is sponsoring this study? 
 
This research is funded by the National Institutes of Health. 
What if you have questions about this study? 
You have the right to ask, and have answered, any questions you may have about this research. If 
you have questions about the study (including payments), complaints, concerns, or if a research-
related injury occurs, you should contact the researchers listed on the first page of this form. 
 
A description of this clinical trial will be available on 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. 
Interest in future studies. 
There may be opportunities for you to participate in additional studies in the principal 
investigator’s lab. If you are interested in being notified of future research opportunities, you can 
opt in to being contacted about future studies. If you opt in, we will retain your contact 


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information indefinitely, and may contact you to ask if you’d like to come back for another study 
in the future. Your information will remain strictly confidential; we will never share your contact 
information with other researchers or organizations. If you agree to be contacted you are in no 
way obligated to participate in future studies and you may ask for your name to be removed from 
our follow-up contact list at any time (in which case your contact info will be deleted). If you 
agree participate in any future studies, we will ask for your consent for participation at that time, 
and will explain the study and any compensation at that time. 
_____ Yes, please keep my contact information to hear about future research opportunities. 
_____ No, please do not save my contact information after this study is complete. 
 
What if you have questions about your rights as a research participant? 
All research on human volunteers is reviewed by a committee that works to protect your rights 
and welfare.  If you have questions or concerns about your rights as a research subject, or if you 
would like to obtain information or offer input, you may contact the Institutional Review Board 
at 919-966-3113 or by email to IRB_subjects@unc.edu. 
 
 
Participant’s Agreement: 
 
I have read the information provided above.  I have asked all the questions I have at this time.  I 
voluntarily agree to participate in this research study. 
 
______________________________________________________ 
Signature of Research Participant 
____________________ 
Date 
______________________________________________________ 
Printed Name of Research Participant  
 
______________________________________________________ 
Signature of Research Team Member Obtaining Consent 
____________________ 
Date 
______________________________________________________ 
Printed Name of Research Team Member Obtaining Consent   
 
______________________________________________________ 
Signature of Witness if applicable; e.g. literacy issues, 
visually impaired, physically unable to sign, witness/interpreter for 
non-English speaking participants using the short form) 


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____________________ 
Date 
______________________________________________________ 
Printed Name of Witness  
  
  
 

Prot_SAP_002.pdf: 
NIH-FDA Phase 2 and 3 IND/IDE Clinical Trial Protocol Template   
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
 


Effects of Semaglutide on Nicotine Intake and Smoking 
Lapse 
Protocol Number: 21-1548 
National Clinical Trial (NCT) Identified Number: NCT05530577 
Investigators: 
Dr. Christian Hendershot (Principal Investigator) 
Dr. Robyn Jordan (Co-Investigator) 
Dr. Amanda Tow (Co-Investigator) 
Dr. Sarah Dermody (Co-Investigator, Biostatistician) 
Dr. Eric Claus (Co-Investigator) 
Dr. Klara Klein (Co-Investigator)  
Dr. Paul Fletcher (Other Significant Contributor) 
Funded by: NIDA 
Version Number:  v1.7 
20 February 2023 
 
 
Summary of Changes from Previous Version: 
Affected 
Section(s) 
Summary of Revisions Made 
Rationale 
5.2 
 
 
Increased BMI range for eligible 
participants from 25-35 to 23+, and 
removed eligibility criterion related 
to TSH values (thyroid disease will 
still be exclusionary). 
Adjustments are intended to make eligibility 
less restrictive, and were made in 
consultation with the study physician. 


  
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
 
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................ 1 
1 
PROTOCOL SUMMARY .............................................................................................................................. 1 
1.1 
Synopsis ............................................................................................................................................... 1 
1.2 
Schema ................................................................................................................................................ 3 
1.3 
Schedule of Activities (SoA) .............................................................................................................. 4 
2 
INTRODUCTION ........................................................................................................................................... 6 
2.1 
Study Rationale ................................................................................................................................... 6 
2.2 
Background .......................................................................................................................................... 7 
2.3 
Risk/Benefit Assessment ................................................................................................................... 8 
2.3.1 
Known Potential Risks .................................................................................................... 8 
2.3.2 
Known Potential Benefits ............................................................................................. 10 
2.3.3 
Assessment of Potential Risks and Benefits ............................................................. 10 
3 
OBJECTIVES AND ENDPOINTS ............................................................................................................. 11 
4 
STUDY DESIGN .......................................................................................................................................... 12 
4.1 
Overall Design ................................................................................................................................... 12 
4.2 
Scientific Rationale for Study Design ............................................................................................. 20 
4.3 
Justification for Dose ........................................................................................................................ 20 
4.4 
End of Study Definition ..................................................................................................................... 21 
5 
STUDY POPULATION ............................................................................................................................... 21 
5.1 
Inclusion Criteria ............................................................................................................................... 21 
5.2 
Exclusion Criteria .............................................................................................................................. 21 
5.3 
Lifestyle Considerations ................................................................................................................... 23 
5.4 
Screen Failures ................................................................................................................................. 23 
5.5 
Strategies for Recruitment and Retention ..................................................................................... 23 
6 
STUDY INTERVENTION ........................................................................................................................... 24 
6.1 
Study Intervention(s) Administration .............................................................................................. 25 
6.1.1 
Study Intervention Description .................................................................................... 25 
6.1.2 
Dosing and Administration ........................................................................................... 25 
6.2 
Preparation/Handling/Storage/Accountability ............................................................................... 26 
6.2.1 
Acquisition and accountability ..................................................................................... 26 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ............................................... 26 
6.2.3 
Product Storage and Stability ...................................................................................... 26 
6.2.4 
Preparation ..................................................................................................................... 27 
6.3 
Measures to Minimize Bias: Randomization and Blinding .......................................................... 27 
6.4 
Study Intervention Compliance ....................................................................................................... 27 
6.5 
Concomitant Therapy ....................................................................................................................... 28 
6.5.1 
Rescue Medicine ........................................................................................................... 28 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ................................................................................................................... 28 
7.1 
Discontinuation of Study Intervention ............................................................................................ 28 
7.2 
Participant Discontinuation/Withdrawal from the Study .............................................................. 28 
7.3 
Lost to Follow-Up .............................................................................................................................. 29 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 30 
8.1 
Efficacy Assessments ...................................................................................................................... 30 
8.2 
Safety and Other Assessments ...................................................................................................... 30 
8.3 
Adverse Events and Serious Adverse Events .............................................................................. 30 


  
NIH-FDA Clinical Trial Protocol Template – v1.0 7 Apr 2017 
 
8.3.1 
Definition of Adverse Events (AE) .............................................................................. 30 
8.3.2 
Definition of Serious Adverse Events (SAE) ............................................................. 31 
8.3.3 
Classification of an Adverse Event ............................................................................. 31 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ...................... 31 
8.3.5 
Adverse Event Reporting ............................................................................................. 32 
8.3.6 
Serious Adverse Event Reporting ............................................................................... 32 
8.3.7 
Reporting Events to Participants ................................................................................. 33 
8.3.8 
Events of Special Interest ............................................................................................ 33 
8.3.9 
Reporting of Pregnancy ................................................................................................ 33 
8.4 
Unanticipated Problems ................................................................................................................... 34 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................ 34 
8.4.2 
Unanticipated Problem Reporting ............................................................................... 34 
8.4.3 
Reporting Unanticipated Problems to Participants ................................................... 34 
9 
STATISTICAL CONSIDERATIONS .......................................................................................................... 34 
9.1 
Statistical Hypotheses ...................................................................................................................... 35 
9.2 
Sample Size Determination ............................................................................................................. 35 
9.3 
Populations for Analyses ................................................................................................................. 35 
9.4 
Statistical Analyses ........................................................................................................................... 36 
9.4.1 
General Approach ......................................................................................................... 36 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................ 36 
9.4.3 
Analysis of the Secondary Endpoint(s) ...................................................................... 36 
9.4.4 
Safety Analyses ............................................................................................................. 37 
9.4.5 
Baseline Descriptive Statistics .................................................................................... 37 
9.4.6 
Planned Interim Analyses ............................................................................................ 37 
9.4.7 
Sub-Group Analyses ..................................................................................................... 37 
9.4.8 
Tabulation of Individual participant Data .................................................................... 37 
9.4.9 
Exploratory Analyses .................................................................................................... 37 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .............................. 37 
10.1 
Regulatory, Ethical, and Study Oversight Considerations .......................................................... 37 
10.1.1 
Informed Consent Process .......................................................................................... 37 
10.1.2 
Study Discontinuation and Closure ............................................................................ 38 
10.1.3 
Confidentiality and Privacy ........................................................................................... 39 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 40 
10.1.5 
Key Roles and Study Governance .............................................................................. 40 
10.1.6 
Clinical Monitoring ......................................................................................................... 40 
10.1.7 
Quality Assurance and Quality Control ...................................................................... 41 
10.1.8 
Data Handling and Record Keeping ........................................................................... 41 
10.1.9 
Protocol Deviations ....................................................................................................... 41 
10.1.10 
Publication and Data Sharing Policy .......................................................................... 41 
10.1.11 
Conflict of Interest Policy .............................................................................................. 42 
10.2 
Additional Considerations ................................................................................................................ 42 
10.3 
Abbreviations ..................................................................................................................................... 42 
10.4 
Protocol Amendment History .......................................................................................................... 44 
11 
REFERENCES ............................................................................................................................................ 46 
 


Effects of semaglutide on nicotine intake and smoking lapse 
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1 
STATEMENT OF COMPLIANCE 
(1) The trial will be carried out in accordance with International Conference on Harmonization Good 
Clinical Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR 
Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the Institutional Review Board (IRB) for review and approval. Approval of both 
the protocol and the consent form must be obtained before any participant is enrolled. Any 
amendment to the protocol will require review and approval by the IRB before the changes are 
implemented to the study. In addition, all changes to the consent form will be IRB-approved; a 
determination will be made regarding whether a new consent needs to be obtained from 
participants who provided consent, using a previously approved consent form. 
 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
Effects of Semaglutide on Nicotine Intake and Smoking Lapse  
  
Study Description: 
This is an early-Phase II human laboratory trial using a randomized, 
placebo-controlled, dose-ranging design to investigate the effects of 
semaglutide (Ozempic®), a GLP-1 receptor agonist, on laboratory nicotine 
responses, reinstatement, self-administration, naturalistic cigarette 
consumption, and weight loss in regular smokers. Participants will attend 
weekly visits while semaglutide dosage is increased to 1.0mg over a period 
of 10 weeks. At scheduled intervals, participants will attend 2 laboratory 
sessions involving a validated smoking lapse procedure to characterize 
medication effects on nicotine reinstatement and laboratory self-
administration. 
  
Objectives: 
 
Primary Objective: To examine effects of semaglutide vs. placebo on 
nicotine reinstatement and self-administration under laboratory 
conditions. 
  
 
Secondary Objectives: To examine medication vs. placebo group 
differences in 1) changes in naturalistic cigarette consumption, and 2) 
changes in body weight over the course of the treatment period.  
 
Tertiary Objectives: To generate preliminary data on medication effects on 
laboratory responses to nicotine, and cue-induced craving among regular 
smokers during treatment with semaglutide. 


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Endpoints: 
Primary Endpoint: Changes in 1) nicotine reinstatement (i.e., minutes of 
resistance to smoking reinstatement), and 2) nicotine self-administration 
(i.e., cigarettes consumed during ad libitum smoking). The comparison of 
interest is the difference between medication and placebo groups in the 
change in laboratory consumption between baseline and the maintenance 
dose of 0.5mg. (i.e., treatment x time interaction). 
 
Secondary Endpoints: Number of cigarettes consumed per day during the 
treatment phase (Weeks 0-10) as measured by a daily diary survey, and 
change in body weight during treatment. Within-subjects changes in these 
outcomes will be compared as a function of medication condition. 
 
Tertiary Endpoints: Laboratory measures of subjective responses to 
cigarette consumption, assessed by the Modified Cigarette Evaluation 
Scale and Drug Effects Questionnaire, and responses to a cue-induced 
craving task.  
 
 
Study Population: 
Participants with at least moderate nicotine dependence (based on 
smoking 5+ cigarettes daily) will be enrolled (N=36). Participants will be 
recruited from the Triangle area (community and hospital settings). 
Participants must be non-treatment-seeking 
 
Phase: 
Phase II  
  
Description of 
Sites/Facilities Enrolling 
Participants: 
This is a single-site study (UNC-Chapel Hill). The project will be based at 
the Bowles Center for Alcohol studies and the Department of Psychiatry, 
with clinical operations taking place at Eastowne Clinical Research Unit 
and CTRC. 
  
Description of Study 
Intervention: 
Semaglutide (Ozempic®) will be administered according to the FDA-
approved schedule, which begins with a starting dose of 0.25mg once per 
week for four weeks. At week five, dosage is increased to 0.5mg/week for 
a subsequent four weeks (maintenance dose). Following four weeks at the 
maintenance dose, dosage can be increased further (1.0mg) provided the 
patient has tolerated the medication. Semaglutide is administered 
subcutaneously via the Ozempic® pen, a cartridge-based device that 
calibrates medication delivery. The placebo condition will consist of 
weekly sham doses, which will involve a brief needle insertion (without an 
injection). 
  
Study Duration: 
Up to 13 months. 
  
Participant Duration: 
25-35 hours (including in-person visits and remote questionnaires) over a 
period of approximately 15 weeks. 
 
 
 


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1.2 
SCHEMA 


Effects of semaglutide on nicotine intake and smoking lapse 
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4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
In-person screening/Baseline visit 
Discharge + Blood draw 
N: 18 Semaglutide 
Randomize 
0.25 mg Semaglutide administration 
Telephone screen 
0.25 mg Semaglutide administration 
0.25 mg Semaglutide administration 
0.25 mg Semaglutide administration + Blood draw 
0.5 mg Semaglutide administration 
0.5 mg Semaglutide administration 
0.5 mg Semaglutide administration 
1 mg Semaglutide administration 
Week 10 
Week 8 
Week 7 
Week 6 
Week 5 
Week 4 
Week 3 
Week 2 
Week 1 
Prior to 
Enrollment 
N: 18 Placebo 
0.5 mg Semaglutide administration + Blood draw 
Smoking session 
Week 9 
Telephone Follow-up 
Week 15 
Smoking session  


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Procedures and Questionnaires 
Telephone Screening 
 
Screening/Baseline 
 
Study Visit 1 - 3  
Target Day 7, 14, 21 
Study Visit 4 
Target Day 28 
Study Visit 5 - 7 
Target Day 35, 42, 49 
Study Visit 8 
Target Day 56  
Study Visit 9 
Target Day 63  
Discharge 
Target Day 70  
Telephone follow-up 
Target Day 77, 105 
Smoking Challenge 
Target Day -10, 58 
Telephone screening 
X 
 
 
 
 
 
 
 
 
 
Administer 0.25 mg Semaglutide or placebo 
 
 
X 
X 
 
 
 
 
 
 
Administer 0.5 mg Semaglutide or placebo 
 
 
 
 
X 
X 
 
 
 
 
Administer 1.0 mg Semaglutide or placebo 
 
 
 
 
 
 
X 
 
 
 
Urine Drug Screen 
 
X 
 
 
 
 
 
 
 
X 
Expired carbon monoxide (CO) 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Locator 
 
X 
 
 
 
 
 
 
 
 
Timeline Follow-Back (TLFB) 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Blood draw 
 
X 
 
X 
 
X 
 
X 
 
 
Blood glucose – finger prick 
 
X 
X 
 
X 
 
X 
 
 
X 
Pregnancy (females only) 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Weight/BMI 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Height 
 
X 
 
 
 
 
 
 
 
 
Vitals (HR, BP) 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Temperature 
 
X 
 
 
 
 
 
 
 
 
Demographics Form 
 
X 
 
 
 
 
 
 
 
 
SCID for DSM-5 (substance use) 
 
X 
 
 
 
 
 
 
 
 
MINI Neuropsychiatric Interview 
 
X 
 
 
 
 
 
 
 
 
Medical and Substance Use History 
Interviews 
 
X 
 
 
 
 
 
 
 
 
Case Report Forms (CRFs) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Alcohol Use Disorder Identification Test 
(AUDIT) 
 
X 
 
 
 
 
 
 
 
 
Alcohol, Cigarette, and Food Purchase Test 
 
X 
 
 
 
 
 
 
 
X 
Self-Report of the Effects of Alcohol 
Questionnaire (SRE) 
 
X 
 
 
 
 
 
 
 
 
Fagerstrom Test for Nicotine Dependence 
(FTND) 
 
X 
 
 
 
 
 
 
 
 
Nicotine Dependence Syndrome Scale 
(NDSS) 
 
X 
 
 
 
 
 
 
 
 
Penn Alcohol Craving Scale (PACS) 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Tiffany Questionnaire of Smoking Urges 
(TQSU) 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Wisconsin Smoking Withdrawal Scale 
(WSWS)  
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Alcohol and Smoking Contemplation  
 
X 
X 
X 
X 
X 
X 
X 
 
 
Three Factor Eating Questionnaire (TFEQ)  
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Monetary Choice Questionnaire (MCQ) 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Cigarette Abstinence Self-Efficacy (CASE) 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Alcohol Abstinence Self-Efficacy (AASE) 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Inventory of Drinking Situations (IDS) 
 
X 
 
 
 
 
 
 
 
 
Impaired Control Scale (ICS)  
 
X 
 
 
 
 
 
 
 
 
Barratt Impulsivity Scale (BIS-11) 
 
X 
 
 
 
 
 
 
 
 
UPPS Impulsive Behavior Scale (UPPS) 
 
X 
 
 
 
 
 
 
 
 
Systematic Assessment for Treatment 
Emergent Effects (SAFTEE) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Reward Based Eating Drive Scale (R-BEDS) 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Simplified Nutritional Appetite Questionnaire 
(SNAQ) 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Control of Eating Questionnaire (CEQ) 
 
X 
X 
X 
X 
X 
X 
X 
 
X 
Wisconsin Inventory of Smoking Dependence 
Motives (WISDM) 
 
X 
 
 
 
 
 
 
 
 
Sweet Taste Preference Test 
 
X 
 
 
 
 
 
 
 
X 


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Center for Epidemiological Studies 
Depression Scale (CES-D) 
 
X 
 
 
 
 
 
 
 
 
Reward Probability Index – Environmental 
Reward Observation Scale (RPI-EROS) 
 
X 
 
 
 
 
 
 
 
 
Toronto Alexithymia Scale (TAS-20) 
 
X 
 
 
 
 
 
 
 
 
Profile of Mood States – Short Form (POMS-
SF) 
 
 
 
 
 
 
 
 
 
X 
Cigarette Evaluation Questionnaire (CEQ) 
 
 
 
 
 
 
 
 
 
X 
Drug Effects Questionnaire (DEQ) 
 
 
 
 
 
 
 
 
 
X 
Peak Provoked Craving (PPC) 
 
 
 
 
 
 
X 
 
 
X 
Obsessive-Compulsive Drinking Scale 
 
X 
 
 
 
 
 
 
 
 
Graded Pain Scale 
 
X 
 
 
 
 
 
 
 
 
 
 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
Despite declines in smoking prevalence in the United States, the likelihood of successfully quitting 
smoking has not improved [1, 2]. Roughly three in four smokers report the desire to quit, and up to half 
report past-year quit attempts [3, 4]. However, only 4-5% of smokers achieve sustained cessation in a 
given year [4], with relapse typically occurring within 5-10 days of a quit attempt [5, 6]. While the 
introduction of varenicline in 2006 was followed by marginally greater rates of pharmacotherapy 
utilization, no appreciable changes in sustained cessation have been observed since [4]. Given only three 
FDA-approved smoking cessation aids (varenicline, bupropion, and nicotine replacement therapy), 
advancing novel smoking cessation therapies is a critical aim [1, 7]. In principle, establishing a repertoire 
of medications will improve options for combination and personalized treatments [8-10]. Because the 
three FDA-approved smoking cessation medications each act on nicotinic receptors, identifying novel 
therapies with alternate pharmacological targets is a key priority [1, 7].  
 
Glucagon-like peptide 1 (GLP-1) is an incretin hormone, produced both peripherally (in the intestines) 
and centrally (e.g., in the hindbrain) [11]. GLP-1 is stimulated following food consumption and stimulates 
satiety and decreases in blood glucose. As a peptide with both hormonal and neurotransmitter 
functions, GLP-1 plays a role in the "gut-brain axis," which has recently been invoked as a target for 
addiction treatment [12]. GLP-1 agonist medications were designed to mimic the function of the 
endogenous GLP-1 peptide, with the benefit of a much longer half-life than endogenous GLP-1. Based on 
their glucose-lowering and appetite-reducing properties, GLP-1 agonists were developed as anti-diabetic 
therapies. Several GLP-1 agonists (e.g., exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide and 
semaglutide,) are now in widespread use as treatments for type II diabetes (T2D). These medications 
have also proven efficacious for weight loss, reducing glycated hemoglobin (HbA1c), and reducing risk 
for some cardiovascular events [11]. Recently, a large-scale, multi-site study of semaglutide 
demonstrated substantial reductions in body weight in adults with overweight or obesity [13]. 
 
Cigarette smoking and obesity are two of the foremost contributors to preventable health burdens 
globally. Moreover, these conditions often co-occur. Among numerous barriers to smoking cessation, a 
commonly cited clinical barrier is patient concerns about weight gain following cessation. Therefore, 
therapies that can simultaneously aid in smoking cessation while promoting weight loss could be 
particularly valuable as adjunctive therapies to standard treatment approaches, such as nicotine 
replacement therapy (NRT). The aim of this project is to conduct an initial Phase II study of semaglutide 
in dependent smokers who are not actively trying to quit smoking. Using a validated smoking lapse 
paradigm, we will investigate the ability of semaglutide to reduce nicotine reinstatement and number of 


Effects of semaglutide on nicotine intake and smoking lapse 
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Protocol 21-1548 
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NIDA Semaglutide Clinical Trial Protocol – v1.7 20 February 2023 
 
7 
cigarettes consumed under laboratory conditions. We will also investigate medication effects on weight 
loss among smokers during treatment with semaglutide over a 10-week treatment period, in order to 
inform future studies in smokers with weight concerns.  
 
Of note, GLP-1 agonists require subcutaneous administration, typically by way of a pre-filled medication 
cartridge with a micro-needle attachment, which allows for easy self-administration in the home without 
assistance from medical staff. Semaglutide is a recently approved (2017) FDA-approved GLP-1 agonist. 
Semaglutide was initially approved in a weekly subcutaneous formulation (Ozempic®) with a maximum 
dose of 1mg/week. A new oral formulation of semaglutide was approved by the FDA in 2019, making 
semaglutide the first drug in its class to be available in both subcutaneous and oral formulations. More 
recently (June 2021), the FDA approved Wegovy.® Similar to Ozempic®, Wegovy® is a weekly 
subcutaneous formulation, but utilizes a higher maximum dose (2.4mg/week) for the indication of 
overweight/obesity. Semaglutide is prescribed at a starting dose of 0.25mg for 4 weeks, followed by 
0.5mg for 4 weeks, followed by further increase up to either 1mg (Ozempic®) or 2.4mg (Wegovy®).  
 
 
2.2 
BACKGROUND  
Accumulating evidence from preclinical studies suggests that GLP-1 agonists reduce intake and/or 
reinstatement of addictive drugs in animal models. In a recent review of 17 preclinical studies [14], all 
studies reported significant effects of GLP-1 agonists on indices of drug motivation and intake [12, 14]. 
Notably, the effects of GLP-1 agonists on drug intake appear to extend to several addictive drugs, 
including nicotine [15]. These findings have led to recent studies aiming to investigate the efficacy of 
GLP-1 agonists as candidate therapies for addiction. Although several human trials are underway in 
various countries, no RCTs have been published to date, and human data on the efficacy of GLP-1 
agonists for reducing drug intake in substance-using populations is needed. 
Although the precise mechanisms mediating the effects of GLP-1 agonists on addiction-related 
behaviors remain to be clarified, it has been suggested that cholinergic-dopaminergic pathways are 
involved in altering the reward value of addictive substances following exposure to GLP-1 agonists [12]. 
Additionally (and relevant to the original goals of this R21 to target the serotonin system using 
lorcaserin), GLP-1 agonists appear to exert their effects in part by way of interactions with the serotonin 
(5-HT) system, including interactions with 5-HT2C receptors. Specifically, GLP-1 agonists appear to 
induce serotonin release, and serotonin signaling appears critical to the efficacy of the medications [16, 
17]. Evidence also suggests that 5-HT2C receptors appear necessary for the efficacy and satiety-inducing 
effects of GLP-1 agonists [18, 19]. 
Of the approved FDA-approved GLP-1 agonists, most preclinical studies of addiction-related phenotypes 
have focused on exenatide, an older GLP-1 agonist first approved in 2005. As noted, semaglutide is the 
newest GLP-1 agonist and the first available in both subcutaneous and oral formulations. Some evidence 
suggests superiority of semaglutide relative to other GLP-1 agonists with respect to efficacy for glycemic 
control [20]. Also, as noted, a recent large-scale trial showed striking reductions in weight during long-
term treatment with higher doses of semaglutide [13]. Given that post-cessation weight gain is a key 
deterrent for many smokers to remain quit, GLP-1 agonists like semaglutide could be an important 
adjunct to traditional smoking cessation therapies.  
 
Human laboratory methods for pharmacotherapy development  


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Human laboratory studies play a pivotal role in drug development by providing an efficient, cost-
effective “bridge” between preclinical studies and full-scale randomized trials [21-28]. By allowing 
efficient cross-validation of both preclinical and Phase III results, human experimental studies serve a 
cornerstone role in translational drug development [7, 21, 22, 29]. An ancillary advantage of these 
studies is the ability to test putative mechanisms of pharmacotherapy effects under controlled 
experimental conditions [26]. As noted, clarifying treatment mechanisms is a critical goal that ultimately 
informs treatment design, and can also inform selection of clinical endpoints for Phase III trials [21]. 
Notably, most candidate SUD medications are tested in Phase III trials without prior or subsequent study 
in human laboratory models [21]. 
 
Importantly, recent reviews have also highlighted areas in which laboratory studies can be improved. 
First, many laboratory studies are limited by a sole focus on self-report outcomes (e.g., craving), which 
lack a direct analogue in animal models [30, 31]. Relative to self-report outcomes, drug self-
administration outcomes appear more sensitive to pharmacotherapy effects, and may improve 
consistency in findings across preclinical and human studies [21]. Additionally, self-reported craving - 
while undoubtedly a clinically important construct - is neither necessary nor sufficient for self-
administration, supporting the need to prioritize objective self-administration outcomes [32]. Another 
limitation of most human lab studies concerns their discordance with Phase III trials in terms of sample 
characteristics. A key limitation, as highlighted in a recent systematic review, is that human laboratory 
studies of smoking pharmacotherapy typically recruit non-motivated smokers, limiting comparisons with 
Phase III trials [29]. Importantly, evidence shows that recruiting non-motivated smokers undermines the 
ability to detect medication effects, whereas recruiting smokers with some motivation to quit (even if 
not engaged in an active quit attempt) improves effect sizes in medication screening trials [24]. 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
Semaglutide (Ozempic®) received FDA approval in 2017 for use as an adjunct to diet and exercise to 
achieve glycemic control in adults with type 2 diabetes mellitus (T2D). Semaglutide received FDA 
approval based on the results of 25 completed trials with the goal of providing results that would be 
applicable to a broad type II diabetes (T2D) population, including the elderly, patients with renal 
impairment, and patients at high cardiovascular risk. These trials involved > 9,300 participants, of whom 
>5,700 were treated with semaglutide. In these trials, treatment with semaglutide alone was efficacious 
for reduction in hemoglobin A1C (HbA1c) below 7% (e.g., 73% of participants had HbA1c <7% at week 
30, compared to 28% of placebo-treated patients). Significant body weight reductions were also 
reported, with the weight loss achieved at end-of-treatment ranging from -1.43 to -4.28 kg 
(corresponding to 2.3−4.9%). Weight reductions were evident after 4 weeks of treatment, and persisted 
up to 104 weeks [75]. The peak plasma concentration of semaglutide is reached 1-3 days post-dose. 
Steady-state exposure is achieved following 4-5 weeks of once-weekly administration, and elimination 
half-life is approximately 1 week. 
Risks related to medication. The most commonly reported side effects/adverse events (AEs) are 
gastrointestinal, with nausea being the most frequently reported symptom. The majority of reports of 
nausea (0.5 mg dose vs placebo; 15.3 vs. 6.1%), vomiting (5.0 vs 2.3%), and/or diarrhea (8.5 vs 1.9%) 
occur shortly following a dose escalation. Abdominal pain (7.3 vs 4.6%) and constipation (5.0 vs 1.5%) 


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were also reported [76]. In studies ranging from 30-56 weeks in duration, the discontinuation rate due 
to these gastrointestinal AEs was ranged from 5-13%, with this number increasing during longer 
treatment durations [77].  
Rarer AEs (occurring at a frequency of <5%) included symptomatic hypoglycemia (≤70 mg/dL glucose 
threshold), which occurred in 1.6% of semaglutide-treated participants versus 0% placebo participants; 
dyspepsia (3.5 vs 1.9%); eructation (2.7 vs 0%); and gastroesophageal reflux disease (1.9 vs 0%). In 
placebo-controlled trials, injection site reactions (e.g., discomfort, erythema) were reported in only 0.2% 
of semaglutide-treated patients, suggesting good tolerability of subcutaneous administration. Patients 
exposed to semaglutide had a mean increase from baseline in amylase of 13% and lipase of 22%. 
Cholelithiasis was reported in 1.5% of treated patients. The 0.5 mg dose resulted in a mean increase in 
heart rate of 2 to 3 beats per minute, while there was a mean decrease in heart rate of 0.3 beats per 
minute in placebo-treated patients. Hypersensitivity reactions (e.g., anaphylaxis, angioedema) have 
been reported with GLP-1 receptor agonists. [76]. Other adverse reactions with a frequency of >0.4% 
associated with semaglutide include fatigue, dysgeusia and dizziness [76].  
Rodent studies have shown an increase in the incidence of thyroid C-cell tumors after lifetime exposure 
of semaglutide at clinically relevant plasma levels. However, several studies in T2D patients taking GLP-
1R agonists have shown no increase in neoplasm risk, even after several years of use [78]. Nevertheless, 
a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia 2A or 2B is 
considered a potential risk factor for taking the medication, and will be an exclusionary criterion.  
In a 2-year trial, acute pancreatitis was observed in 8 semaglutide-treated patients (0.27 cases per 100 
patient years) and 10 placebo-treated patients (0.33 cases per 100 patient years). One case of chronic 
pancreatitis was confirmed in a semaglutide-treated patient. History of pancreatitis will be an exclusion 
factor, and study participants receiving semaglutide will be observed for signs and symptoms of 
pancreatitis (via blood monitoring of serum amylase and lipase). If pancreatitis is suspected, semaglutide 
will be discontinued, and appropriate management recommended.  
Other rare events include postmarketing reports of acute kidney injury and worsening of chronic renal 
failure, which may sometimes require hemodialysis, in patients receiving long-term treatment with GLP-
1 receptor agonists. Some of these events have been reported in patients without known underlying 
renal disease. Most of these events occurred in patients who had experienced nausea, vomiting, 
diarrhea, or dehydration. Therefore, we will monitor renal function when initiating or escalating doses 
of semaglutide in patients reporting severe adverse gastrointestinal reactions.  
Although most safety data on semaglutide comes from trials with T2D participants, there are now a 
number of randomized trials underway examining GLP-1 receptor agonists in participants with 
substance use disorder, including trials on tobacco, cocaine, alcohol, cannabis, and opioids. A full list of 
registered randomized trials can be found by searching for “GLP-1” at ClinicalTrials.gov. The use of a 
short-term medication screening protocol (lasting roughly 10 weeks) will provide an opportunity to 
demonstrate tolerability and generate data on side effect profiles in this population while minimizing 
any risks associated with longer-term medication exposure. 
Risks Related to Questionnaire and Interview Assessments. There may be potential risks associated with 
assessment procedures. Participants may find the battery of psychiatric and psychological assessments 
tedious or intrusive. Participants may experience discomfort resulting from questions about personal 
histories or substance use patterns.  


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Participation in Smoking Sessions. Other potential risks include typical risks related to participation in 
smoking sessions. For example, it is possible that participants may experience dizziness/nausea from 
smoking. However, given our focus on dependent smokers, these risks are likely low. Our group has 
considerable experience with human laboratory studies involving drug administration and self- 
administration procedures [80-84], and the safety precautions required in these studies. Additionally, by 
focusing on non-treatment seekers we will minimize ethical concerns about smoking in the laboratory 
setting. 
Risks Related to DNA Collection. The purpose of collecting saliva for DNA in this study is to allow 
secondary analyses to examine whether medication effects might be different according to certain 
genetic factors. These analyses may also focus on genetic factors potentially associated with drug use or 
related behaviors, such as nicotine and alcohol metabolism, dopaminergic function, or impulsivity. 
Potential risks associated with DNA collection involve potential identification, and there may be risks 
with genetic (DNA) tests that are as yet unknown. Genes may be shown at some point in the future to 
be related to mental illnesses or tendency to addiction. Samples will be labeled with participant ID only, 
and analyzed at an outside laboratory. Samples will be de-identified and links with participant identifiers 
will be broken upon completion of the analyses. We will not conduct any whole genome sequencing of 
the DNA samples. Additionally, the consent form will state that participants have the option to opt out 
of DNA collection, and to request that their samples are destroyed at any time during the study. 
Participants will not receive any feedback from any of the genetic tests from study staff. 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
The participants in this study are not expected to benefit directly from their participation. However, the 
knowledge gained from this study could lead to a better understanding of a medication with potential to 
treat nicotine addiction, and potentially other substance use disorders.  
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
Given the vast health implications of substance use disorder and the currently limited array of effective 
medications, it is imperative to pursue novel pharmacotherapeutic options. A key strategy in this regard 
is to “repurpose” medications that are already approved (and have proven safe) in the context of other 
health conditions. Given the sizable amount of research on GLP-1 receptor agonists in other clinical 
populations, coupled with preclinical evidence that these medications reduce motivation for alcohol, 
nicotine, and other drugs, evaluating this medication class in the proposed population is warranted. If 
GLP-1 receptor agonists prove useful for reducing smoking while also reducing weight, they could have 
promise a therapeutic option for smokers with obesity, smokers with concerns about weight gain during 
smoking cessation. From this standpoint, the risk/benefit profile for testing semaglutide in a population 
of non-diabetic participants is favorable.  
Although we anticipate the risk of adverse events to be low based on the safety profile of the 
medication, gradual dose escalation, and relatively short duration of treatment, several steps will be 
taken to track and report medication- related side effects. As described further in later sections of this 
application, participants will be monitored regularly by virtue of attending weekly lab visits for 
medication delivery, at which side effects will be assessed and clinical lab results monitored. Participants 
will be given a contact number for study medical staff in case of serious emergent side effects, (and 


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instructed to seek medical attention in the event of any serious side effects), and participants will be 
contacted by phone shortly after dose escalations to monitor symptoms. We expect some participants 
to experience nausea shortly following dose escalations, but that these symptoms will usually be 
transient.  
Given the focus on a non-diabetic population, we will be particularly vigilant in monitoring changes in 
body weight and blood glucose, and will exclude participants at the outset with body weight or blood 
glucose levels below normal range, based on physician judgement. We will carefully monitor 
participants with glucose tests and weight measurements at regularly study visits (see schedule of 
activities table), and will instruct participants to be vigilant for potential symptoms of hypoglycemia. 
Periodic blood tests to measure fasting glucose, fasting insulin, serum lipase and amylase, and serum 
calcitonin will occur at baseline and regularly thereafter (i.e., at visits prior to dose escalations). All 
adverse events will be documented and reported in accordance with relevant policies, and the 
regulations of NIH. We have enlisted the TraCS DSMB to assist with safety monitoring of the study. The 
board will convene at the beginning of the study and at scheduled points to review study progress and 
safety data, and to review any SAEs and considerations related to stopping rules (described further 
below). 
Considering the use of an FDA approved medication that has been deemed safe in the context of chronic 
administration for glycemic control, the risks related to medication use in this short-term screening trial 
are acceptable in comparison to the potential benefits of the proposed research (i.e., demonstrating 
potential efficacy of a new medication for smoking cessation). 
Risks Related to Smoking Sessions. As noted, participants could experience transient nausea or dizziness 
while smoking. However, our recruitment of dependent smokers likely minimizes these risks. 
Participants may experience boredom or fatigue during the 2-hour smoking sessions. Our recruitment of 
non-treatment-seeking, dependent smokers is designed to minimize risks and ethical concerns  
associated with the laboratory smoking procedure. 
3 
OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
Primary 
 
 
To examine effects of semaglutide vs. 
placebo on nicotine reinstatement and 
self-administration under laboratory 
conditions.  
 
 
 
 
 
The primary outcomes for the 
human laboratory sessions 
consist of 1) nicotine 
reinstatement (i.e., minutes of 
resistance to smoking 
reinstatement), and 2) 
nicotine self-administration 
(i.e., cigarettes consumed 
during ad libitum smoking). 
The comparison of interest is 
the difference between 
medication and placebo 
groups in the change in 
laboratory outcomes between 
baseline and the maintenance 
dose of 0.5mg. 
Primary: This simulated smoking 
lapse procedure was developed by 
McKee, who is a consultant on this 
project. The McKee paradigm is the 
only validated laboratory procedure 
that models smoking reinstatement 
and self-administration concurrently. 
These primary outcomes are 
selected because they reflect 
objectively defined behaviors 
analogous to those reported in 
preclinical studies. Laboratory assays 
of nicotine reinstatement and self-
administration have been used in 
prior human laboratory studies to 
screen candidate medications, 


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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
 
 
allowing comparisons with effect 
sizes for other medications.  
Secondary 
 
 
To examine group differences in 1) 
naturalistic smoking behaviors over the 
course, and 2) weight loss over the 
course of the 10-week treatment 
period. 
Number of cigarettes 
consumed per day during the 
treatment phase (Weeks 0-
10), as measured by a daily 
diary report. 
 
 
 
 
 
Changes in body weight, 
assessed weekly over the 
treatment period. 
 
 
Measures of cigarettes per day are 
selected to afford greater power for 
modeling change in consumption 
over the treatment period. Note that 
these outcomes are considered 
secondary because this Phase II trial 
involves non-treatment-seeking 
participants who are not attempting 
to reduce cigarette smoking. 
 
GLP-1 receptor agonists lower 
HbA1c and body weight in indicated 
populations (e.g., Type II diabetes). 
Given high co-occurrence of obesity 
and tobacco use disorder, reporting 
whether medication is associated 
with these reductions in the present 
sample is clinically relevant.  
Tertiary/Exploratory  
 
 
To examine group differences in 
subjective responses to cigarette 
smoking and cue exposure.  
Laboratory measures of 
subjective response, assessed 
by the Modified Cigarette 
Evaluation Scale and Drug 
Effects Questionnaire. The 
Positive and Negative Affect 
Scale will also assess change 
in mood.  
 
Cue-elicited craving assessed 
using self-report measures of 
craving during a cue induction 
procedure, peak provoked 
craving (PPC). 
 
Similar to the primary 
outcome, secondary outcome 
analyses will examine 
medication vs. placebo group 
differences in within-subjects 
changes in these outcomes 
over time (0mg to 0.5mg). 
Laboratory measures of cigarette 
subjective response are clinically 
valid indicators of drug motivation, 
and are demonstrated to be 
sensitive to medication effects. 
Investigating these outcomes under 
controlled conditions will allow us to 
test for a medication “signal” on 
measures of nicotine reward. 
Human studies of the effects of GLP-
1 receptor agonists on cue-elicited 
drug craving have not been 
reported. As an exploratory aim, we 
will also utilize an established cue 
reactivity task to assess peak 
provoked craving (PPC). This 
procedure, which involves assessing 
craving during a cue exposure task 
(lighting a cigarette and attending to 
cues) while in a period of short-term 
abstinence, has been demonstrated 
to reliably induce acute craving.  
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
 
Overview of Study Design. 


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The aim of this proposal is to translate preclinical findings on the therapeutic potential of GLP-1 agonists 
by conducting an early-Phase II investigation of semaglutide in dependent smokers. The project will 
include a focus on human laboratory outcomes, including a validated human laboratory analogue of 
smoking lapse and self-administration. Daily measurements of naturalistic smoking, and weight 
reduction during the trial, will be examined as secondary outcomes. Overall, this study aims to generate 
initial data on the efficacy of semaglutide in a sample of smokers who are not actively engaged in a quit 
attempt.  
 
This is a single-site, Phase II, two-arm, double-blind (participants, outcome assessors), randomized, 
placebo-controlled, dose-ranging study. Following a baseline assessment, eligible participants will be 
randomized to medication or placebo conditions by the IDS staff at a 1:1 ratio. The treatment period will 
be approximately 10 weeks, taking into account the dose escalation necessary for this medication. 
Those randomized to semaglutide will receive 0.25mg/week for 4 weeks (Weeks 1-4), 0.5mg/week for 4 
weeks (Weeks 5-8). Provided that participants have tolerated the medication adequately, participants 
will receive a final, single dose of 1.0mg (Week 9), and will return for a discharge lab visit with repeat lab 
tests at Week 10, followed by a final monitoring assessment by phone scheduled approximately 6 weeks 
after the last medication dose (Week 15). Those in the placebo condition will receive sham placebo 
administration at each visit (described in further detail in later sections). Participants will attend weekly 
visits at Eastowne CRU or CTRC to receive medication or placebo doses. 
 
In addition to the medication visits, participants will be asked to attend two laboratory visits involving 
cigarette smoking (one prior to the first medication visit and one during the 0.5mg treatment phase). 
These sessions are designed to assess changes in nicotine reinstatement and ad libitum smoking over 
the course of the treatment period. Laboratory sessions are described in further detail below. 
Measurements of naturalistic cigarette use will also be recorded throughout the treatment period. 
These assessments will be captured using a daily diary that will be provided to participants. Participants 
will receive an automated text message daily via Phone.com as a reminder to complete the diary. 
Additional self-report measures of substance use will be collected at study visits. 
 
As summarized above, the primary objectives are to examine whether treatment with semaglutide 
alters nicotine self-administration and reinstatement (primary outcomes), as well as body weight and 
laboratory measures of nicotine responses (secondary outcomes). We hypothesize that semaglutide 
treatment (versus placebo) will be associated with reductions in nicotine self-administration and 
reinstatement during a laboratory session conducted at the Ozempic® maintenance dose of 0.5mg 
(relative to a session conducted at baseline). Each dosage increase will be contingent on the participant 
tolerating the current dose without significant side effects. 
 
The primary outcomes for this trial will be assessed during exposure to the standard Ozempic® 
maintenance dose (.5mg). While an extended treatment phase at the 1.0mg dose is beyond the scope of 
this small-scale trial, the inclusion of a brief (1-week) phase at 1.0mg is designed to provide initial data 
on tolerability and any changes on selected secondary outcomes (i.e., cigarettes per day). Capturing 
these data will help to support feasibility and pilot data for subsequent funding proposals. 
 
Secondary objectives include examining changes in naturalistic cigarette smoking during the treatment 
period and body weight during the trial. Although participants will not be attempting to reduce smoking 
in this trial, it is hypothesized that treatment with semaglutide will result in reductions in nicotine 
consumption (cigarettes per day) over the course of the treatment period. Tertiary/exploratory 


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outcomes include examining group differences in changes in subjective responses to cigarette smoking 
and cue-elicited craving from placebo to 0.5mg phases. 
 
In total, participation in this study is estimated to take roughly 25-35 hours of combined time over a 
period of approximately 16 weeks. This includes a screening and baseline visit (up to 4 hours), up to 9 
subsequent laboratory visits for medication administration and side effects monitoring (up to 1 hour 
each), and a final discharge visit (Week 10), and final telephone check-in (Week 15). If necessary for 
safety reasons, (e.g., based on lab results), participants may be asked to attend (unplanned) visit(s) for 
follow-up labs at the discretion of the study physician.  Participants will also complete two visits 
involving nicotine self-administration over the course of Weeks 0-10; these sessions may last up to 3-4 
hours each. Participants also will receive calls from staff on Day 2 or 3 of each medication titration phase 
(placebo, 0.25mg, 0.5mg, 1.0mg) to check in on side effects (10 minutes per call), and will be asked to 
complete brief daily questionnaires via a daily diary with reminders sent via daily text message prompt 
(1-2 minutes per day). 
 
 
A detailed summary of study procedures is provided below. 
 
Detailed Study Procedures. 
 
Following initial recruitment (described in section 5.5), participants will be asked to complete the 
following procedures: 
a) Telephone screen 
Initial screening will be conducted by telephone by trained research staff and will assess 
participant’s cigarette use, other drug use, medications, and basic medical inclusion/exclusion 
factors. Potential participants will be given a brief description of the study. The initial telephone 
screen is estimated to take roughly 15-30 minutes. Contact information will be collected from 
interested callers who pass the initial screen. Following the initial screen, participants will proceed 
to be booked for an informed consent and baseline interview session. The informed consent 
procedures will be conducted remotely using a HIPAA-compliant virtual meeting platform (e.g., 
Webex, Zoom) and Docusign. Depending on participant and staff availability, the phone screening 
and informed consent/baseline interview can happen on the same day (after the screening call) or 
at a future date. 
 
b) Screening and Baseline Data Collection Visits 
 
At the informed consent session, a member of the research staff will review the study 
procedures and carry out informed consent procedures (including electronic signature via 
Docusign) prior to proceeding to the baseline interview. Following informed consent, the staff 
member will conduct a semi-structured interview to assess inclusion/exclusion criteria. A 
research assistant will use a structured interview to measure diagnostic and substance use 
screening criteria,; inclusion/exclusion factors related to medical history will also be assessed 
(see criteria listed above). The Structured Clinical Interview for DSM-V [53] will be used to assess 
substance use disorder symptoms. History of other psychiatric diagnoses and medication use 
will be assessed via self-report. The research assistant will also collect information on 
demographic factors, criteria related to current medical status and medications, current alcohol, 
tobacco and other substance use (see “Phone Screen” document), as well as substance use 
disorder symptoms (via select modules from the SCID interview) and symptoms other 


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psychiatric symptoms (using the MINI screening module). Participants who appear eligible will 
be booked for an in-person visit, which will take place at the Eastowne CRU or the laboratory 
site (Medical Wings C), with some procedures (e.g., blood draw) booked at CTRC as necessary. 
The in-person screening/baseline visit will include a brief review of informed consent to answer 
any additional questions, and a brief review of self-report and interview questions from the 
remote screening session. The Timeline Follow-Back (TLFB) [54] will be used to assess alcohol, 
cigarette and other drug use in the 90 days prior.  
 
Participants who remain eligible after the interview will complete vitals and measurements (HR, 
BP, height, weight, temp), and a measure of expired alveolar carbon monoxide (CO). 
Additionally, participants will provide a urine sample and complete a blood draw (up to 70-80 
ml) for a comprehensive metabolic panel (e.g., Na, K, Cl, CO2, BUN, Creatinine, Glucose, 
Calcium, Albumin, Total protein, Total bilirubin, AST, ALT, Alk Phos), baseline measure of HbA1c, 
baseline measure of nicotine metabolites (e.g., 3HC, COT), serum amylase and lipase, and 
complete blood count (e.g., Auto WBC, Corrected WBC, RBC, HGB, HCT, MCV, MCH, MCHC, 
RDW, MPV, Platelet). These procedures will be conducted by the research assistant, and the 
baseline blood draw will be taken by a team member with phlebotomy training. If there is no 
team member with phlebotomy training available that day, the blood draw may also be booked 
at CTRC. If needed, the blood draw and other baseline procedures may be booked as separate 
visits. On the day of the visit that includes the blood draw, participants will be instructed to 
arrive fasting for 12 hours (to allow for assessment of baseline HbA1c and lipids). If participants 
are not able to arrive fasting for the baseline session, the fasting lipids sample may be deferred 
or completed at the next possible visit. Blood samples will be sent to McClendon laboratory for 
testing. A portion of the blood sample (de-identified) will also be stored (Thurston Bowles 
building and Neurosciences Research Building) for subsequent analysis (e.g., nicotine 
metabolites and blood neutrophils, which are affected by cigarette smoking). Neutrophil 
analyses will be conducted by Dr. Robert Tarran’s lab.). The urine sample will be used to test for 
the presence of several drugs (for example, heroin, cocaine, methamphetamines, opiates). (For 
females, the test will include a pregnancy screen.) If a participant tests positive for drugs other 
than cannabis (or if females screen positive for pregnancy), the participant will be excluded from 
the study. 
Participants will complete baseline questionnaires, which will be collected on paper. A 
Demographic Screening Questionnaire will assess basic demographic factors (e.g., age, 
education, income). A Locator form will collect contact information for three individuals who 
can be contacted if a participant is unable to be reached by study staff for follow-up visits. Other 
baseline measures (see Table) will include the Alcohol Use Disorders Identification Test (AUDIT) 
[55], Self-Report of the Effects of Alcohol Questionnaire (SRE) [56, 57], Fagerström Test of 
Nicotine Dependence (FTND) [58], and the Nicotine Dependence Syndrome Scale (NDSS) [59], 
Barratt Impulsivity Scale (BIS-11) [60], UPPS Impulsive Behavior Scale (UPPS) [61], Impaired 
Control Scale (ICS) [62], Center for Epidemiological Studies Depression Scale (CES-D) [63], 
Toronto Alexithymia Scale (TAS-20) [64], the Reward Probability Index (RPI) and the 
Environmental Reward Observation Scale (EROS) [65]. Baseline measures that will be repeated 


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at subsequent visits will include the Timeline Followback (TLFB), the Penn Alcohol Craving Scale 
(PACS) and Tiffany Questionnaire of Smoking Urges (TQSU) [66], and the Wisconsin Smoking 
Withdrawal Scale (WSWS) [67]. To assess potential medication effects on changes in motivation 
and self-efficacy for resisting alcohol/cigarettes, we will use alcohol and smoking Contemplation 
Ladder items, Alcohol and Cigarette Abstinence Self-Efficacy (AASE/CASE) (these scales will be 
repeated at each visit) and the Inventory of Drinking Situations (IDS) scales [68-70]. Appetite and 
eating behavior will be assessed with the Simplified Nutritional Appetite Questionnaire (SNAQ) 
[71], Control of Eating Questionnaire (CEQ) [72], the Three Factor Eating Questionnaire (TFEQ) 
[73] and the Reward-Based Eating Drive Scale (R-BEDS) [74]. During the medication phases, side 
effects will be assessed with the SAFTEE questionnaire [75], a standard tool for alcohol clinical 
trials. Participants will also complete previously validated Purchase Tasks for alcohol, cigarettes, 
and food, and delay discounting will be assessed with the Monetary Choice Questionnaire 
(MCQ) [76-79]. These brief behavioral economic tasks assess perceived value of reinforcers by 
presenting hypothetical scenarios involving choices between the reinforcer (alcohol, cigarette, 
food) and monetary rewards; these measures will be completed at each visit. Finally a previously 
validated sweet taste preference test will be administered at baseline and again on the final 
visit, since this phenotype has been shown to be implicated in both food and alcohol reward, 
and may be modulated by a GLP-1 agonist. This test involves participants tasting solutions of 
sugar water prepared to reach .05, .1, .2, .42, and .83 molar sucrose blinded in pseudo-random 
order, and then rating preference and intensity of the taste. The sweet taste test will be 
overseen by a research assistant using previously published protocols from prior projects at UNC 
[80, Error! Hyperlink reference not valid.]. 
 
The baseline questionnaires and interview assessments are projected to take approximately 3-4 
hours combined. To accommodate potential scheduling/time constraints or delays at the 
baseline visit, some questionnaires that are not time-sensitive (for instance, personality 
questionnaires) may be deferred until a later lab visit as needed, at the discretion of the study 
team. All interview records and paper questionnaires will be stored in study binders in a secure 
location for subsequent entry into an electronic database for analysis. Patients will be given 
breaks as needed. Following the blood draw, participants will be offered a snack and bottled 
water (given the instructions to arrive fasting). If results of the baseline screening/medical 
assessment indicate that the participant is tentatively eligible, they will be given a 
comprehensive orientation to the next phases of study, including the follow-up medication 
visits, the laboratory alcohol administration visits, and the daily surveys. Locator/collateral 
contact information will also be obtained. A Locator form will collect contact information for 
three individuals who can be contacted if a participant is unable to be reached by study staff for 
follow-up visits. Following the completed baseline assessments, the participant’s screening 
summary will be reviewed for eligibility, including review of medical criteria and any 
medications that the participant is taking by the study physician. Lab results will be uploaded to 
the EMR and reviewed by the study physician prior to prescribing the medication. Potential 
interactions with semaglutide will be verified using an established online database such as 
Epocrates or Lexicomp. In the event of any uncertainties about medication interactions, 
participants will be asked to contact their primary care physician to confirm no concerns with 
taking semaglutide.  
 
For eligible participants, the study physician will provide sign-off on all medical criteria (e.g., 
medical history, medications, lab results), and the PI will provide sign-off on other baseline 
criteria. Once participants have been confirmed as eligible, the physician will submit an order to 


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start medication or placebo. Medication and placebo will be dispensed at CTRC (Week 1 visit) at 
a date coordinated with the participant. Participants will be advised to be vigilant for symptoms 
of hypoglycemia at the medical visit, and instructed to contact the study team to review any 
symptoms that emerge (regular glucose tests will also be obtained at follow-up visits, as noted 
in the schedule of assessments). If necessary, the medication review will take place via 
telephone or telemedicine, depending on medical team availability.  
 
Participants’ Week 1 visit will be scheduled with enough lead time to review lab results and 
exclude participants (if needed) prior to administering the study medication. Additionally, if 
clarification of medical criteria is needed at any point during or following the phone or in-person 
screening process, or at any subsequent stage of the study, the study physician may meet with 
the participant via a remote contact method (e.g., phone, Webex/Zoom, or telehealth) to clarify 
medical questions or discuss test results. 
 
c) Daily Assessments.  
Throughout the study, participants will be asked to complete a brief self-report survey each day that 
includes measures of 1) prior-day number of cigarettes smoked; 2) number of drinks consumed on 
the prior day; and 3) prior day peak craving for alcohol and cigarettes. Participants will be provided 
with a paper booklet in which to enter responses and will be asked to bring the booklet to each visit. 
At each visit the research staff will collect the interim daily surveys for retention in the participant’s 
study binder. Participants will be texted an automated text message each day during their 
participation in the study as a reminder to complete the daily survey. If preferred, participants can 
opt to receive an email link. (No daily survey data will be collected from participants via text or 
email.) At each study visit, a staff member will provide compensation for the prior week’s surveys, 
and will review survey adherence and progress towards compensation for good adherence 
(described later), as a means of motivating adherence to self-report assessments. In the event a 
participant completes the daily assessments but forgets to bring the packet to a given visit, they will 
be asked to bring their packet to the following session. Participants will be asked to either a) 
complete the measures in person at the current lab visit, or b) to schedule a brief meeting with a 
research team member via Zoom or Webex in order to complete the questions (depending on 
scheduling and availability). These approaches will be used in specific circumstances if needed (e.g., 
if the participants forgets to complete the daily assessments altogether, or will be unable to bring it 
to the next session). 
 
d) Weekly Laboratory Visits.  
Medication administration visits will occur at either the Eastowne Clinical Research Unit (CRU) or the 
CTRC.  Following the baseline (Week 0) visit, participants will visit CRU or UNC Hospital/CTRC once 
weekly (Weeks 1-9), for subsequent medication or placebo doses, and for a final follow-
up/discharge visit at Week 10. (In addition, the study physician may request an additional follow-up 
lab visit(s) at any point in the study to monitor side effects.) In addition, to accommodate events 
such as missed lab visits or scheduling difficulties, assessment procedures at a given weekly visit 
(e.g., questionnaires, lab tests, smoking sessions) may be conducted within a 7-day window of the 
original target date, as necessary, to avoid unnecessary missing data.  In addition to 
medication/placebo administration, follow-up visits will include 1) vitals, weight measurements, and 
a brief side-effects assessment, 2) a finger-stick glucose test (or fasting blood draw depending on the 


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week, see study flow chart), 3) a brief calendar-based self-report assessment of interim alcohol and 
cigarette use (TLFB), and 4) a repeat CO measurement. These procedures are expected to take 
roughly 30-60 minutes in total, and will be conducted by a trained study team member and/or a 
member of the CRU/CTRC team (e.g., RN). All side effects reports, labs, and other medical test 
results (e.g., glucose tests) will be uploaded in Epic (e.g., lab tests) or sent electronically (e.g., self-
reported medication changes) for review by the study physician. If side effects or lab results suggest 
that further assessment is indicated, a member of the medical team will advise the study team (and 
if necessary, contact the participant) to provide direction. At the Week 4, Week 8, and final 
discharge visits, participants will be asked to arrive fasting to allow for a blood draw for follow-up 
lab assays (identical to those described in the baseline procedures above). As with the baseline 
sample, a portion of each sample will be stored for follow-up analyses (e.g., nicotine metabolites). 
 
e) Smoking Sessions.  
 
All participants will complete laboratory smoking lapse and self-administration sessions at dates 
corresponding with the baseline visit (i.e., between Weeks 0-1) and the end of the .5 mg medication 
phase (e.g., between Weeks 8-9). Sessions will occur during the 0.5mg dose given that some 
participants in the event some participants do not research the maximum 1.0mg dose. During lab 
sessions, participants will report to the lab at approximately 9:00am after receiving instructions to 
abstain from cigarettes (for 12 hours) and alcohol (24 hours). Upon arrival, overnight abstinence will 
be verified based on expired CO of <6ppm (or <50% of the initial screening reading). Upon arrival 
participants will complete measurements of body weight and vitals (HR, BP). Participants will also 
provide a finger-prick blood glucose test for an instant reading on a blood glucose monitor.  
 
Simulated lapse. The simulated smoking lapse procedure was developed by McKee, who is a 
consultant on this project [23, 52]. The McKee paradigm is the only validated laboratory procedure 
that models smoking reinstatement and self-administration in the same procedure [23]. In this 
procedure, a nicotine deprivation period (e.g., overnight abstinence) provides a context to study 
medication effects on reinstatement [23]. Given the requirement of overnight abstinence prior to 
the lapse session, it is important to maximize the likelihood of the participant adhering to these 
instructions. Failure to maintain overnight abstinence could result in having to reschedule the 
session. Therefore, participants will be offered a bonus of $25 for completing the overnight 
abstinence requirement, as additional incentive to adhere to the abstinence instructions. Sessions 
will be conducted in a laboratory space equipped with a fume hood; participants will be seated near 
the hood and will be instructed to direct exhaled smoke into the hood. Research staff will be 
required to don protective equipment (e.g., N95 mask and face shield) when present in the room 
during the time of the task, and will remain outside the room during the procedure, to the extent 
possible. 
 
Upon beginning the task, participants will be presented with a package of their preferred cigarettes 
(participants will be asked to bring one unopened pack in to the session). Participants will be given 
the choice to initiate cigarette smoking, or to delay smoking for up to 50 minutes in exchange for 
monetary reinforcement. Prior studies show that a reinforcement schedule of $1 for every 5 
minutes results in participants resisting, on average, for 25 minutes, providing ideal variability in 
time to reinstatement [23]. If no lapse occurs (i.e., the participant resists for 50 minutes), 
participants will not be forced to smoke a cigarette. Following the initial decision to smoke, 
participants will complete assessments of craving, withdrawal, and subjective effects (described 
below). 


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Next, a 60-minute period of ad libitum smoking will ensue [53]. Participants will be presented with a 
tray containing 8 cigarettes from the package, and will have the opportunity to smoke additional 
cigarettes at their discretion [53]. Again, participants will not be forced to smoke a cigarette. 
Repeated ratings of craving, withdrawal, and subjective effects will be taken at 15-minute intervals 
during the self-administration period. A follow-up measure of expired CO will be taken at the end of 
the session to measure CO “boost”, an additional index of cigarette intake. 
The primary outcomes for the human laboratory sessions consist of 1) nicotine reinstatement (i.e., 
minutes of resistance to smoking reinstatement), and 2) nicotine self-administration (i.e., cigarettes 
consumed during ad libitum smoking). These primary outcomes are selected because they reflect 
objectively defined behaviors analogous to those reported in preclinical studies. Secondary human 
laboratory outcomes will include CO boost and subjective effects during nicotine self-administration, 
e.g., assessed by the Modified Cigarette Evaluation Scale [54] and the Drug Effects Questionnaire 
[55]. The Profile of Mood States Short Form (POMS-SF) will also assess change in mood.  
 
Cue-elicited craving. Human studies of the effects of GLP-1 receptor agonists on cue-elicited drug 
craving have not been reported. As an exploratory aim, we will also utilize an established cue 
reactivity task to assess peak provoked craving (PPC). This procedure, which involves assessing 
craving during a cue exposure task (lighting a cigarette and attending to cues) while in a period of 
short-term abstinence, has been demonstrated to reliably induce acute craving [57]. Given the 
potential for differential medication effects on tonic vs. phasic craving [58], tonic craving will also be 
assessed as a component of the repeated self-report assessments (noted below). The PPC task will 
be administered at week 8, +/- 7 days. 
 
List of Study Assessment Measures (See Section 1.3 for assessment time points) 
1. Demographics form 
2. Timeline Follow-Back (TLFB) 
3. Structured Clinical Interview for DSM-5 Mental Disorders (select modules) 
4. MINI Neuropsychiatric Interview (select modules) 
5. Sweet Taste Preference Test 
6. Alcohol Use Disorder Identification Test (AUDIT) 
7. Self-Report of the Effects of Alcohol Questionnaire (SRE) 
8. Center for Epidemiological Studies Depression Scale (CES-D) 
9. Toronto Alexithymia Scale (TAS-20) 
10. Barratt Impulsivity Scale (BIS-11) 
11. UPPS Impulsive Behavior Scale (UPPS) 
12. Reward Probability Index – Environmental Reward Observation Scale (RPI-EROS) 
13. Impaired Control Scale (ICS) 
14. Fagerstrom Test for Nicotine Dependence (FTND) 
15. Nicotine Dependence Syndrome Scale (NDSS) 
16. Penn Alcohol Craving Scale (PACS) 
17. Tiffany Questionnaire of Smoking Urges (TQSU) 
18. Wisconsin Smoking Withdrawal Scale (WSWS) 
19. Wisconsin Inventory of Smoking Dependence Motives (WISDM) 
20. Alcohol and Smoking Contemplation Ladder 
21. Three Factor Eating Questionnaire (TFEQ) 
22. Reward-Based Eating Drive Scale (R-BEDS) 


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23. Control of Eating Questionnaire (CEQ) 
24. Simplified Nutritional Appetite Questionnaire (SNAQ) 
25. Monetary Choice Questionnaire (MCQ) 
26. Cigarette Abstinence Self-Efficacy (CASE) 
27. Alcohol Abstinence Self-Efficacy (AASE) 
28. Inventory of Drinking Situations (IDS) 
29. Cigarette Evaluation Questionnaire (CEQ) 
30. Drug Effects Questionnaire (DEQ) 
31. Alcohol Purchase Task (APT) 
32. Cigarette Purchase Task (CPT) 
33. Food Purchase Task (FPT) 
34. Profile of Mood States – Short Form (POMS-SF) 
35. Peak Provoked Craving (PPC) 
36. Systematic Assessment for Treatment Emergent Effects (SAFTEE) 
37. Obsessive Compulsive Drinking Scale 
38. Graded Pain Scale 
 
 
Analysis schedule. Analyses of side effect frequency and AE/SAE frequency will be conducted prior to 
scheduled DSMB meetings. Other analyses will be conducted following the completion of the trial, or as 
otherwise required to fulfill DSMB requests or other reporting requirements.  
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
 
This Phase II trial is intended to produce initial data on the effects of semaglutide in dependent smokers, 
with an emphasis on human laboratory outcomes. The dose escalation schedule is based on the 
standard clinical regimen, which is intended to minimize side effects common to GLP-1 agonists (i.e., 
nausea). Participants in the placebo group will complete an identical sequence while receiving sham 
subcutaneous injections (a small needle stick using a micro-needle of the same size, without an 
injection). This placebo condition is selected due to the absence of an available matching placebo 
cartridge from the manufacturer (see section 4.3). All participants will complete laboratory smoking 
lapse sessions at two time points, corresponding with the baseline and 0.5mg, phases. This design allows 
for within-subjects analyses for laboratory outcomes that are best examined at the within-subject level 
(owing to high inter-individual variability in nicotine pharmacokinetics). 
 
 
4.3 
JUSTIFICATION FOR DOSE 
 
Semaglutide (Ozempic®) will be administered according to the FDA-approved dose escalation schedule, 
which begins with a starting dose of 0.25mg (for titration purposes) once per week for four weeks. At 
week five, dosage is increased to 0.5mg/week (the initial first maintenance dose) for a subsequent four 
weeks, at which point dosage can be increased further (1.0mg) if indicated (and presuming that the 
0.5mg dose has been tolerated). The intent for this initial trial is to mimic the typical clinical scenario 
over the first several weeks of medication titration, concluding with one dose of the maximum 
Ozempic® dosage (1mg). Although the newer semaglutide pens (Wegovy®, approved in June 2021) 
deliver semaglutide at dosages up to 2.4mg, we will not exceed 1mg for this initial study. Although 
primary analyses will focus on the 0.5mg dosage, participants will receive one week of 1.0mg treatment 


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at the conclusion of the 0.5mg phase, in order to collect initial data on side effects and naturalistic 
drinking/cigarette use at this dosage in the current population. Participants will be monitored carefully 
and will not be escalated to the next dose if experiencing persistent side effects indicative of poor 
tolerability.  
 
Given the lack of a true placebo (i.e., no manufacturer-developed placebo Ozempic® pens/cartridges) 
for study, we will use a placebo condition that consists of weekly sham doses. Sham doses will involve a 
brief needle prick using a very small (e.g., 32 gauge) needle, using the either the NovoFine proprietary 
needle (as is used in the Ozempic® and Wegovy® pens) or a micro-needle of a similar gauge (e.g., an 
insulin needle). These procedures are described in more detail later in this protocol. By necessity, 
medical staff administering the medication at the CRU or CTRC cannot be blind to condition. However, 
other experimenters and outcomes assessors will remain blind to condition. Participants will be 
instructed during the informed consent and study orientation that they have a 50/50 chance of being 
randomized to medication and placebo groups.  
 
4.4 
END OF STUDY DEFINITION 
 
A participant is considered to have completed the study if he or she has completed all phases of the 
study including the last study visit or the last scheduled procedure shown in the Schedule of Activities 
(SoA), Section 1.3. The end of the study is defined as completion of the last study visit or procedure 
shown in the SoA in the trial overall. 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet the following criteria: 
• 
Age 21-65  
• 
Smoking 5+ cigarettes per day (on average) over the past year, with no period of 
abstinence > 90 days  
• 
Biochemical verification of smoking status, based on expired CO > 8 at baseline 
• 
Willingness to take study medication and complete study procedures 
• 
Willingness to complete lab sessions involving cigarette smoking 
• 
Ability to communicate in English 
5.2 
EXCLUSION CRITERIA 
 
• 
Regular use of electronic nicotine delivery systems (ENDS/vaping), cigars, chewing tobacco or 
snuff, based on at least weekly use in the past 30 days  
• 
Past 30-day use of nicotine replacement therapies/products  
• 
Reporting past 30-day use of illicit drugs other than cannabis at baseline, or having a positive 
toxicology screen for illicit drugs other than cannabis at baseline 


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• 
Current engagement in alcohol or smoking cessation treatments, or currently engaged in 
intentional efforts to quit alcohol use  
• 
Past 30-day use of: Sincalide, Sulfonylureas, insulin and insulin products or other medications 
that may interact with semaglutide, or weight control medications   
• 
Prior use of semaglutide or other GLP-1 agonists  
• 
Known or suspected hypersensitivity to study medication or related products  
• 
Lifetime diagnosis of severe mental illness (including schizophrenia and bipolar disorder)  
• 
Meeting criteria for current alcohol use disorder (AUD) or other substance use disorder (with 
the exception of tobacco or mild cannabis use disorder) 
• 
History of suicide attempt, or recent (past 30 day) suicidal ideation, or psychiatric hospitalization 
in the last 6 months  
• 
Current significant medical or neurological illness (based on self-report or medical record) 
including severe hepatic impairment or cirrhosis, impaired renal function (eGFR <50ml/min), 
acute or chronic pancreatitis, gastroparesis, gallbladder disease or cholelithiasis, other severe 
gastrointestinal disease, heart failure, coronary artery disease, stroke, seizure disorder, or other 
medical condition that poses a risk for the medication or alcohol administration components of 
the study (as determined by the MD)  
• 
A personal or family history of medullary thyroid cancer or multiple endocrine neoplasia 2A or 
2B  
• 
Calcitonin greater than or equal to 50 ng/L  
• 
Uncontrolled thyroid disease at screening  
• 
History of major surgical procedures involving the stomach potentially affecting absorption of 
trial product (e.g., subtotal and total gastrectomy, sleeve gastrectomy, gastric bypass surgery)  
• 
History of Type 1 or Type 2 diabetes, or HbA1c >6.5% measured at screening  
• 
History of diabetic retinopathy, proliferative retinopathy, or maculopathy  
• 
History of diabetic ketoacidosis  
• 
History or presence of malignant neoplasms within the last 5 years (except basal and squamous 
cell skin cancer and carcinoma in situ)  
• 
Currently nursing, pregnant, anticipating pregnancy in the next 6 months, or not using a highly 
effective contraceptive method as judged by the MD, and defined as:   
a. combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal, transdermal)  
b. progestogen-only hormonal contraception associated with inhibition of ovulation (oral, 
injectable, implantable)  
c. intrauterine device  
d. intrauterine hormone-releasing system  
e. bilateral tubal occlusion  
f. vasectomized partner  
g. sexual abstinence  
• 
Elevation of serum lipase, amylase, direct (conjugated) bilirubin, or alkaline phosphatase (ALP), 
ALT, or AST) more than 3X the upper limit of normal on baseline bloodwork 


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• 
Baseline body mass index (BMI) <23kg/m2 
• 
Uncontrolled hypertension or systolic BP >180 mmHg and/or diastolic BP >105 mmHg, averaged 
from three measurements 
• 
Plans for travel outside of the local area in the upcoming 12 weeks that would interfere with lab 
visits during the study period (or other logistic factors that would make it difficult to commit to 
entire duration of study)  
 
5.3 
LIFESTYLE CONSIDERATIONS 
 
Specific lifestyle instructions will include: 
 
• 
Refrain from alcohol consumption or other drug use for 24 hours prior to smoking sessions  
• 
Refrain from smoking for 12 hours prior to arrival at smoking sessions 
• 
Arrive fasting at sessions scheduled for blood draws as needed (e.g., Weeks 0, 4, 8, and final 
discharge visit)  
• 
Women participating in the study must report being willing to use a reliable birth control 
method during the trial (if sexually active), and must report no plans for pregnancy in the next 6 
months.  
• 
Participants will also understand that they may be excluded if they test positive for drugs other 
than cannabis during the time of scheduled drug screens (repeat drug tests will take place 
during weeks 4 and 8). 
 
5.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants, to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (SAE). 
 
Examples of screen failures would include participants excluded following baseline laboratory work, or 
those excluded based on a change in treatment-seeking status at the time of the baseline assessment. 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of a specifc 
modifiable factor (e.g., upcoming travel) may be rescreened at a later date. Rescreened participants will 
be assigned the same participant number as for the initial screening. Data pertaining to screening 
failures will be tabulated in an anonymized fashion.  
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
Participants will be recruited from the community through advertisements, which may include ads in 
local online or print newspapers, bus advertisements, print flyers placed in community or hospital 
settings, business cards, campus listservs, and online postings (e.g. Craigslist (ads will not be placed in 
employment section)), and social media ads (Facebook, Twitter, Instagram) that direct potential 
participants toward a study website/landing page (hosted on Research for Me). Participants may also be 


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recruited from local medical clinics (e.g., primary care clinics) that grant approval for assisting with 
recruitment (e.g., by placing study advertisements in clinics). Flyers and online advertisements will 
include study contact information and a web link and/or QR code leading to the landing page. 
 
In addition to these “passive” methods of recruitment, we will also include “active” recruitment 
methods. These methods will include members of the study team setting up recruitment booths and 
passing out business cards at public events (e.g., festivals) or public venues. Once initial contact with 
participants is made (e.g., via email or in person), research staff will schedule the participant for a phone 
call to explain the study and conduct a screening interview.  
Participants will receive compensation. The payments will be allocated as follows (please see 1.2 for a 
summary of all scheduled sessions): 
• 
$50 for completing the consent/screening/baseline sequence (Week 0) 
• 
$100 for smoking session 1 (To be scheduled between Weeks 0-1) 
o Includes $75 for attendance, plus a $25 payment after confirming overnight abstinence. 
• 
$100 for smoking session 2 (To be scheduled between Weeks 8-9) 
o Includes $75 for attendance, plus a $25 payment after confirming overnight abstinence. 
• 
$30 per visit for each follow-up/medication administration visit during Weeks 1-10 (10 visits 
x$30 per visit = $300) 
• 
Up to $150 for completing and returning daily questionnaires over the study period ($15 per 
weekly set of surveys x 10 weekly visits), which includes the week following the 1.0mg dose, to 
be paid at weekly medication visits) 
• 
A $50 bonus for completing at least 9 of 10 weekly assessments  
• 
Participants will receive a final bonus of $100 for completing the study through Week 10 (to be 
paid at the final discharge visit). 
Therefore, the total maximum compensation over 10 weeks for study visits is $850 Compensation for 
smoking sessions will occur at the end of each session. The final payment (including bonuses) will be 
paid at the Week 10 discharge visit. Overall, these payments are structured to maximize retention in the 
study (given the long dose escalation period and time-intensive laboratory sessions). Additionally, an 
incentive-based structure that includes weekly incentives is important to reinforce engagement with 
daily surveys and minimize missing data. Participants will be updated at each visit with their progress 
toward the bonus incentives for adherence (e.g., weekly bonus of $10 and progress toward final 
adherence bonuses). In the event participants are not able to pick their final payments in person, we will 
offer the option of issuing the final payment via electronic gift card to the participant’s email address, 
with their permission. 
We anticipate phone screening up to 400 individuals and randomizing up to 48 participants to 
medication or placebo conditions, in order to obtain a final sample of 36 eligible participants who 
complete the full course of the 0.5mg phase (allowing for 25% attrition). If attrition is higher than 
anticipated, we will attempt to enroll additional participants to arrive at a final sample of 36 participants 
who complete study procedures through the end of the 0.5mg dosage phase (i.e., through the end of 
Week 9). 
6 
STUDY INTERVENTION 
 


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6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
Semaglutide is a relatively new (approved as Ozempic® in 2017) GLP-1 receptor agonist. A new oral 
formulation of semaglutide was approved by the FDA in 2019, making semaglutide the first drug in its 
class to be available in both subcutaneous and oral formulations. Most recently, semaglutide was 
approved in a higher-dose formulation for the treatment of overweight/obesity (Wegovy®, June 2021). 
GLP-1 agonist medications were designed to mimic the function of the endogenous GLP-1 peptide, with 
the benefit of a much longer half-life than endogenous GLP-1. Based on their glucose-lowering and 
appetite-reducing properties, GLP-1 agonists were developed as anti-diabetic therapies. Several GLP-1 
agonists (e.g., exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide and semaglutide,) are now in 
widespread use as treatments for type II diabetes (T2D); these medications have also proven efficacious 
for weight loss, reducing glycated hemoglobin (HbA1c), and reducing risk for some cardiovascular events 
[29]. Although the primary indication of GLP-1 agonists is T2D, these therapies are increasingly being 
studied for other indications in non-diabetic patients, including obesity/weight management. In June 
2021, the FDA approved semaglutide at a higher dosage (2.4mg/week) for the indication of weight 
management, under the brand name Wegovy®.  
6.1.2 DOSING AND ADMINISTRATION 
Semaglutide (Ozempic) will be administered according to the FDA-approved schedule, which begins with 
a starting dose of 0.25mg once per week for four weeks. At week five, dosage is increased to 0.5mg for a 
subsequent four weeks (initial maintenance dose), after which point dosage can be increased further (to 
1.0mg), presuming the medication is well tolerated.  
 
Although semaglutide can be self-administered in the home setting, medication and placebo 
administration will be delivered by a research nurse  or other medical team member at Eastowne CRU or 
CTRC in order to execute the placebo manipulation and ensure adherence to medication. This approach 
also allows us to collect safety outcomes on a regular basis, further ensuring that participants will be 
monitored carefully. Semaglutide is administered subcutaneously (in the abdomen, thigh, or upper arm). 
Doses are delivered via the Ozempic® pen, a cartridge-based device that calibrates medication delivery 
based on the desired dose. An extremely small needle (4mm, 32-gauge needle – the size of 2 human hairs) 
is used to deposit the medication subcutaneously. Participants in the medication group will receive 
weekly semaglutide injections at 0.25mg/week for 4 weeks, followed by 0.5mg/week for 4 weeks), 
followed by 1 week at 1.0mg. This schedule results in 9 medication administration sessions. At the week 
9 visit, the 1.0mg dose will be delivered as 2 x 0.5 mg doses given in succession. This is because the 
medication pens being used for this study deliver dosages of 0.25 and 0.5mg, and participants are not 
being maintained on the 1.0mg dose after week 9. This timeframe also allows sufficient time to reach 
steady-state plasma concentration levels (achieved within 4-5 weeks of initiating the starting dose).  
 
At the present time, we do not have access to a manufacturer-developed placebo (the medication relies on 
the proprietary Ozempic® pens for delivery). Therefore, this study will use weekly sham injections for 
the placebo group. Sham doses will involve a brief needle prick using a very small (e.g., 32 gauge) 
needle, identical to the one used in the Ozempic® pens (NovoFine), or a needle of similar gauge (e.g., an 
insulin needle). During medication and placebo administration, participants’ view will be shielded from 
the injection site to prevent unblinding. Medication will be delivered in the upper arm, abdomen, or thigh. 
Given the extremely small volume of the injections, we will not utilize saline or another inert substance 
for the placebo administration; rather, the sham doses will consist of briefly inserting the micro-needle. 


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Due to the nature of the placebo condition, it will not be possible to blind the staff RNs administering the 
medication. However, we will provide training to study staff to minimize the likelihood of contaminating 
the blinding procedures. We will also develop procedures to minimize contact between the RNs and 
outcome assessors. All other staff members (including research assistants and outcomes assessors) will 
remain blind to condition, unless unblinding is necessary (e.g., due to an adverse event). 
 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
The team will collaborate with IDS to source the medication (and NovoFine or insulin needles for the 
placebo condition), which will be sourced and stored at the IDS pharmacy prior to dispensing. 
Participants assigned to medication will be prescribed one Ozempic® pen following randomization. As 
per IDS requirements, in between study visits participants will be given their assigned medication pen 
and asked to bring their pen back to each follow-up visit. In between visits, pens will be placed in a small 
plastic container and then encased opaque, tamper-proof bag in order to prevent unblinding. (For 
participants in the placebo condition, a plastic object of roughly equal size and weight will be placed in 
the plastic container and medication bag.)  Participants will be instructed not to open the bag in 
between visits. A refill pen will be prescribed prior to the Week 7 visit, once the doses from the first pen 
have been allocated. Any unused doses from individual pens (e.g., in the event of participant drop-out) 
will be discarded/destroyed by IDS, as will any pens that expire during the course of the trial. In the 
event a pen expires before a participant completes the study, a replacement pen will be prescribed at 
the discretion of the study physicians. 
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
Ozempic® is manufactured by Novo Nordisk. As described above, the medication is dispensed from a 
proprietary device, the Ozempic® pen. Each pen contains 2mg of medication, requiring that each 
participant is prescribed two pens over the course of the study. A full description and visuals can be 
found at the following site: 
https://www.Ozempic®pro.com/how-to-prescribe/Ozempic®-pen.html 
 
The placebo group will receive sham injections that involve a brief needle-prick without dispensing a 
substance. The needles used for the sham injections will be the NovoFine 32G needle, the same needle 
in the Ozempic® pen (https://www.novoneedles.com/novofine.html) or a comparable needle of a 
similar gauge (e.g., an insulin needle). In no case will any fluid be injected during placebo sessions. 
To mimic the active medication administration, the medical staff member will insert the microneedle 
briefly and then remove it while the participant’s view is shielded.  
 
6.2.3 PRODUCT STORAGE AND STABILITY 
 
Pens will be dispensed from IDS. For drug dispensing visits at CRU (Eastowne), scheduled for Weeks 1 
and 7, pens will be delivered the day of the visit by courier. Ozempic pens will be kept in the 
participant’s possession (sealed in a tamper-proof bag) between visits. According to the manufacturer, 
following the first use, the Ozempic® pen can be stored for up to 56 days at room temperature (59 to 86 
F) or refrigerated at 36 to 46 F. As per our plan developed in collaboration with IDS, participants will be 


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instructed to keep the medication bag at room temperature for simplicity. Each participant’s pen will be 
labeled with the study ID number and pens will not be shared across participants. Placebo needles will 
remain packaged until use, and will be stored at room temperature in a secure location. 
 
 
6.2.4 PREPARATION 
 
Semaglutide does not require advance preparation; cartridges are pre-filled and doses are calibrated 
using the pen device. The RN or medical staff member will select the correct dosage and administer the 
medication as per manufacturer guidelines.  
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
 
Following the baseline assessment, participants will be randomized to medication or placebo conditions 
at a 1:1 ratio by a member of the IDS team using a pre-determined randomization scheme. Medication 
and placebo administration will be carried out by a staff RN at CRU or CTRC. Due to the nature of the 
placebo condition, it will not be possible to blind the RNs to condition. However, all other staff members 
will remain blind to condition, and the staff members administering medication will be trained in 
protecting the blind (e.g., redirecting the conversation if the participant comments about medication 
condition; minimizing contact with experimenters.) To maintain blinding of participants, participants’ 
view will be shielded and they will be asked to face away from the injection site during all placebo and 
medication administrations. Aside from the staff members administering medication, no study team 
members interacting with participants will be aware of participants’ assignments. At the stage of interim 
analyses (e.g., in preparing safety reports for DSMB meetings) and final analyses, the study statistician 
will be provided with the assignment log. None of the study personnel involved in recruitment or 
enrollment will have knowledge of the details of the randomization table that will be used by the IDS 
pharmacy. 
 
At the completion of the trial, participants will be provided with a questionnaire asking about perceived 
medication assignment (to assess the success of maintaining the blind). Due to common side effects of 
semaglutide (in particular nausea), we do not expect blinding to be successful in all cases.  
 
6.4 
STUDY INTERVENTION COMPLIANCE 
 
Medication will be administered by CRU or CTRC staff to assure compliance and reduce potential 
sources of non-adherence. A missed session will constitute a missed medication dose. As per 
manufacturer directions, any missed doses/appointments will be corrected by asking the participant to 
come in for the dose as soon as possible within 5 days of the missed dose. After the 5-day mark has 
passed, the dose will be skipped and the participant will resume with the next scheduled dose. Study 
medication logs will serve as the primary source document for tracking medication and placebo 
administration. Participants will be coded as non-adherent if they miss more than 2 scheduled doses 
between Weeks 1-9. In the event of missed medication doses or missed appointments, the physician will 
have the discretion to adjust the appointment date (within the manufacturer or standard practice 
guidelines), or to prescribe a replacement pen if needed to accommodate the target medication 
schedule. 
 


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6.5 
CONCOMITANT THERAPY 
 
Participants may be taking medications for other conditions (provided those treatments are not 
included in the list of exclusion criteria). For this protocol, a prescription medication is defined as a 
medication that can be prescribed only by a properly authorized/licensed clinician. Medications to be 
reported in the Case Report Form (CRF) are concomitant prescription medications, over-the-counter 
medications and supplements. Changes to medication status or other treatments will be assessed at 
each in-person visit, with any changes reviewed by a study physician. Should a concomitant therapy 
preclude further participation for safety or scientific reasons (for instance, if a participant starts a 
therapy that constitutes an exclusion factor), this issue will be discussed by the study leads and the 
participant will be excused from further participation, if required to ensure safety. By definition, 
participants will not be seeking treatment for smoking cessation. If a participant makes the decision to 
seek treatment for smoking during the study, s/he will be referred to appropriate treatment resources 
and excused from further participation. 
 
 
6.5.1 RESCUE MEDICINE 
 
Not applicable 
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
Study discontinuation: The study may be halted if deemed necessary by the lead investigators, DSMB, or 
IRB. Examples of reasons for study discontinuation include unexpectedly high frequency of serious 
adverse events, or significant increases in alcohol use during treatment, leading to the conclusion that 
the medication is not safe in this population. In addition to the participant discontinuation rules noted 
below, the following study stopping rules will trigger halting the study pending a DSMB evaluation: 1) 
Occurrence of any hospitalization or any SAE rated at Grade 4-5 (CTCAE) in a medication-treated 
participant (and deemed likely to be medication-attributable); 2) Documentation of SAEs in >3 
medication-treated participants that are deemed likely attributable to medication; 3) Removal of >5 
subjects due to adverse events deemed attributable to study-related procedures, inclusive of SAE 
and/or medical stopping rules (e.g., weight, disease progression), as defined in 7.2 below. In order to 
classify events as medication-attributable, the PI will request that IDS breaks the blind and provides a 
file containing condition assignment to the study physician(s). If any of the aforementioned events 
trigger a DSMB meeting, the full randomization table will be provided to a statistician, so that group 
differences can be fully evaluated at the meeting. Given the safety profile of semaglutide for other 
clinical conditions, as well as preclinical evidence that GLP-1 receptor agonists reduce drug intake, these 
scenarios are expected to be unlikely. 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. The 
investigators may discontinue or withdraw a participant from the study if clinically or otherwise 
indicated. Examples of reasons for removing a participant include: 


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• 
Significant study intervention non-compliance  
• 
Any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
that indicates that continued participation in the study would be unsafe  
• 
Pregnancy 
• 
Diagnosis of significant disease or disease progression which requires discontinuation of the 
study intervention 
• 
The participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• 
Participant relocates from the local area, or is otherwise unable to attend visits 
• 
Significant or persistent side effects that pose significant discomfort or preclude escalation to 
the 0.5mg dose (e.g., persistent and severe nausea, or  hypoglycemia, as indicated by 
repeated fasting glucose values below normal 54 mg/dL 
• 
Changes in lab tests or clinical status from baseline that render the participant ineligible 
to continue in the judgement of the physician(s) (e.g., elevated liver enzymes, elevated 
serum amylase or lipase levels, weight loss as defined below) 
• 
Excessive weight loss (defined as loss exceeding 5% of baseline weight or BMI < 20) 
• 
A change in treatment-seeking status (i.e., the participant expresses a desire to enter 
treatment for smoking cessation). 
• 
Any other change in medical status or side effects that is significant enough to warrant 
removal in the judgement of the study physicians. 
 
If a participant exhibits changes in symptoms or clinical status that warrant potential removal, 
the study physicians will confer and render a decision as to whether to withdraw the participant. 
With respect to dosage increase, if a participant’s side effects profile or laboratory tests during 
the initial 4-week phase (.25mg) indicate that s/he is unable to safely proceed to the 0.5mg 
dose, the participant may be removed from the study at the discretion of the physicians. If lab 
tests or side effects during the standard maintenance dose of 0.5mg suggest that a participant is 
unlikely to tolerate a higher dose (1mg), they may be excluded from the 1.0mg dose escalation 
at the discretion of the physicians. In this case, participants will be given the option of one 
additional week at the standard therapeutic dose of 0.5mg (i.e., highest tolerated dose). 
Reasons for participant discontinuation or withdrawal from the study will be recorded on the 
Case Report Form (CRF). Subjects who sign the informed consent form but do not receive the 
study intervention (e.g., fail to attend the Week 1 visit for randomization) may be replaced.  
Participants who sign the informed consent form, and are randomized and receive the study 
intervention, and subsequently withdraw, or are withdrawn or discontinued from the study, 
may be replaced. 
 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for 2 consecutive scheduled 
medication visits and is unable to confirm attendance at the following visit (or is unable to be contacted 
by the study staff). 
 
The following actions will be taken if a participant fails to return to a required study visit: 


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• 
The team will attempt to contact the participant and reschedule the missed visit within one 
week, and counsel the participant on the importance of maintaining the assigned visit schedule 
and ascertain if the participant wishes to and/or should continue in the study. 
• 
The team will attempt to contact the individuals that the participant had listed on the Locator 
Form at baseline (maximum of three attempted contacts per individual). 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, up to 3 telephone messages, up to 
3 email messages, and if necessary, a letter to the participant’s last known mailing address or 
local equivalent methods). These contact attempts will be documented in the participant’s 
medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
 
The efficacy assessments/outcomes are noted in summary form in section 3. The ascertainment of these 
outcomes is described in further detail in section 4 (study design). Briefly, the efficacy endpoints are 
human laboratory measures of nicotine reinstatement and cigarette smoking, self-reported cigarette 
consumption over the course of the trial, subjective responses to smoking in the laboratory, and 
changes in body weight. 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 
 
Safety and assessments are summarized in detail in the study design section (Section 4.1). Briefly, safety 
assessments include a baseline assessment, body weight, bloodwork, vitals signs, and clinical interview 
to assess substance use and psychiatric symptoms. Follow-up medical visits will include repeat 
assessments of bloodwork and scheduled time points, as well as follow-up measurements of body 
weight and vitals signs. Medication side effects will be assessed at each visit, and a study team member 
will contact participants within 2-3 days of each dosage increase to evaluate potential side effects. Other 
assessments (questionnaires, interviews) are noted in Section 4.1. 
 
If an urgent medical situation arises at either medication or smoking visits, a team member will contact 
the physicians on the team to consult, based on a predetermined sequence (e.g., contact physician A, 
followed by physician B, then physician C). Additionally, any participants who express a desire to seek 
treatment during the study will be excused from further participation and provided with smoking 
cessation resources. Co-I Dr. Jordan directs outpatient addiction treatment at UNC-CH. 
 
   
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 


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8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include an adverse reaction 
requiring intensive treatment in an emergency room or at home. 
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s daily 
activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below. In a clinical trial, the 
study product must always be suspect.  
 
• 
Related – The AE is known to occur with the study intervention, there is a reasonable possibility 
that the study intervention caused the AE, or there is a temporal relationship between the study 
intervention and event. Reasonable possibility means that there is evidence to suggest a causal 
relationship between the study intervention and the AE. 
• 
Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study intervention 
and event onset, or an alternate etiology has been established. 
 
8.3.3.3 EXPECTEDNESS  
The study physicians will be responsible for determining whether an adverse event (AE) is expected or 
unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the study intervention. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 


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The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. At weekly medication visits, all participants will review a side effects 
checklist (SAFTEE) with a research assistant, which will then be provided for review by a medical staff 
member at CTRC. The staff member will begin with an open-ended question about side effects or any 
other adverse events, followed by a review of specific side effects using the SAFTEE. Any previously 
reported side effects will be queried to determine any change in status (presence or severity). These 
weekly visits will be a primary method for identifying side effects. Additionally, a research staff member 
will contact participants by phone in the week following the initial dose, as well as the week following 
each dose escalation. Phone calls will be scheduled 2-3 days following these events.  
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate case report form (CRF). Information to be collected includes event description, time of 
onset, clinician’s assessment of severity, relationship to study product (assessed only by those with the 
training and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs 
occurring while on study will be documented appropriately regardless of relationship. All AEs will be 
followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE. 
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
 
Under the direction of the PI, members of the research team will record all reportable events with start 
dates occurring any time after informed consent is obtained until 7 (for non-serious AEs) or 30 days (for 
SAEs) after the last day of study participation. At each study visit, the investigator will inquire about the 
occurrence of AE/SAEs since the last visit. Any such events will be followed for outcome information 
until resolution or stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
All project staff will be trained to identify adverse events (AEs), which must be reported to the PI and 
study physicians within 24 hours. In addition, any unanticipated participant issues will be discussed in 
weekly staff meetings, which will provide another opportunity to identify AEs.  
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
Research staff will be trained to report potential AEs or SAEs to the PI immediately. For any potential 
AEs/SAEs, the study physician will make a determination to distinguish between AEs, SAEs and 
unanticipated problems and provide judgment about attributions. Management and reporting of AEs, 
SAEs, and unanticipated problems will be carried out in accordance with Good Clinical Practice (GCP) 
standards, as outlined by the Food and Drug Administration. AEs will be defined as any negative medical 


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event during the trial (whether or not the event is deemed related to the study medication). SAEs are 
defied as events that are potentially life threatening or result in heath; cause congenital malformation; 
result in persistent/significant disability or incapacity; require inpatient hospitalization or prolongation 
of hospitalization; or reflect an otherwise notable medical event in the judgment of the study physician. 
AEs/SAEs will be monitored regularly by the study research team and medical staff, in particular by 
inquiring about adverse events at each weekly visit. Should AEs or SAEs occur, they will be recorded, 
rated as mild/moderate/severe by the study physician, and reported in accordance with UNC IRB 
requirements and GCP standards. Any AEs will be reported to the IRB in progress reports and at the 
conclusion of the study. SAEs and unanticipated events will be reported to the IRB and DSMB within 48 
hours, and to NIDA if judged as treatment-related. All staff working on this study will be made aware of 
the monitoring and reporting requirements for AEs/SAEs, and will have completed GCP training and 
other trainings required to conduct human subjects research at UNC.  
 
Any AEs, SAEs or unanticipated problems will be followed until resolution by the PIs and/or research 
staff. Participants will be contacted regularly during follow-up and any observations of AEs/SAEs will be 
discussed among the PIs and the study physician at regular meetings (or immediately, in the event of 
SAEs or unanticipated problems). In the event of SAEs or unanticipated problems, the physician and 
study PIs will be notified immediately, and the participant will be referred to or provided with 
appropriate medical support.  
 
Participants will be advised to seek prompt medical attention in the event of an unanticipated medical 
event. In the event of an SAE, a member of the study medical staff will maintain regular contact with the 
participant until the event is resolved and fully documented. A determination of relatedness to 
medication will be made based on symptoms, timing, and other factors. 
 
Monitoring will be the primary responsibility of the PI. In addition, a Data and Safety Monitoring Board 
will be established to maximize safety (the TraCS DSMB has been engaged for this project, and will 
review progress at their scheduled semiannual meetings during the trial). 
 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
If an event is deemed an AE or SAE, participants will receive a phone call from study personnel to inform 
them that the event has been recorded and will be reported as such. Any incidental findings uncovered 
during the baseline medical exam or weekly visits (e.g., via bloodwork or other measurements) will be 
reported to the participant by the study physician, and an appropriate follow-up plan will be 
recommended to the participant.  
 
8.3.8 EVENTS OF SPECIAL INTEREST  
 
Not applicable 
 
8.3.9 REPORTING OF PREGNANCY  
 
Women enrolled in the trial will be asked to confirm that they are able to use a reliable contraception 
method for the duration of the trial and for at least 2 months after receiving the final medication dose. 
At the baseline visit, female subjects will undergo a urine pregnancy test upon arrival to the clinical site. 


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In the case of a positive pregnancy test, the participant will be notified immediately, and study 
participation will be halted. If any follow-up plan is recommended by the study physician, the physician 
or PI will communicate this recommendation to the participant.  
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
Any UPs identified by the study team will be discussed amongst the study leadership team, and 
corrective actions will be identified. If applicable, a protocol amendment will be developed and 
submitted to the IRB. 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB), and if applicable, the DSMB. The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
In the case of a UP that may impact participants’ safety or alter their experience during the trial (e.g., by 
necessitating a change in protocol), participants will be notified by a study team member at the 
subsequent visit. In the event of any UP that may have an imminent impact on participant safety, a team 
member will contact the participant by phone to inform them of the problem.   
 
9 
STATISTICAL CONSIDERATIONS  


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9.1 
STATISTICAL HYPOTHESES 
 
• 
Primary Efficacy Endpoint(s):  
 
o Nicotine reinstatement (i.e., minutes of resistance to smoking reinstatement), and nicotine 
self-administration (i.e., cigarettes consumed during ad libitum smoking) during laboratory 
smoking procedures (co-primary endpoints). The effect of interest is the interaction 
between medication group (semaglutide vs. placebo) and time/dosage (baseline vs. 0.5mg). 
The baseline session will take place between Weeks 0 and 1, and the 0.5mg session will take 
place between weeks 8 and 9. 
 
• 
Secondary Efficacy Endpoint(s): 
 
o Changes in subjective responses to nicotine during laboratory smoking procedures (drug 
effects and mood). The effect of interest is the interaction between medication group 
(semaglutide vs. placebo) and time/dosage (baseline vs. 0.5mg). The baseline session will 
take place between Weeks 0 and 1, and the 0.5mg session will take place between weeks 8 
and 9. 
o Changes in cigarette consumption over the course of the trial, as assessed via daily cell 
phone surveys. The effect of interest is the interaction between medication group 
(semaglutide vs. placebo) and time (Week 1 to Week 10). 
 
All primary analyses are superiority analyses. Additional details are provided in 9.4.2. 
 
9.2 
SAMPLE SIZE DETERMINATION 
 
Because no human data on semaglutide’s effects on smoking-related outcomes is available, there is no a 
priori effect size estimate to facilitate power calculations on these particular outcomes. We will seek a 
final sample size of 36 participants. Our analyses suggest that this allows sufficient power (.80) to detect 
a medium effect size (f = .25) for an interaction between group (medication vs. placebo) and dosage 
(baseline, 0.25mg, 0.5mg). This estimate assumes an alpha level of .05 and a within-person correlation 
(r) of 0.5 across time points. Further, because our mixed multilevel model (MLM) analyses will involve 
more time points for certain analyses (e.g., daily assessments), this approach will increase power 
further, which is advantageous in the event that medication effects are in the small range. Assuming a 
25% attrition rate, we anticipate needing to randomize up to 48 participants to arrive at a final sample 
of 36. 
 
9.3 
POPULATIONS FOR ANALYSES 
 
Primary analyses will include all participants who were randomized and received a medication or 
placebo dose following the week 0 visit (randomization will occur after the Week 0 visit, just prior to the 
Week 1 visit). MLM analyses can accommodate missing data, allowing inclusion of participants without 
complete data (e.g., missed visits or missed daily survey responses). 
 
A supplementary per-protocol analyses will be conducted using all participants who received 1) at least 
7 of the 9 scheduled doses, and 2) those participants who receive the final (1.0mg) dose. This planned 


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analysis will be conducted irrespective of the number of participants in these groups. If the sample 
permits, an exploratory subgroup analysis will examine participants as a function of weight 
(overweight/obese vs. not overweight or obese). 
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
 
Primary analyses will rely on multilevel models (MLM), which are well suited to examining within-person 
changes over time, while also accommodating missing data and unequal group sizes, and allowing the 
evaluation of between-subjects moderators (e.g., overweight/obesity status) if necessary. MLM with 
maximum likelihood estimation can accommodate missing data under the assumption that the data are 
missing at random. Secondary, sensitivity analyses will be conducted to test the robustness of study 
findings for violations of the assumption that data is missing at random. Specifically, we will examine if 
baseline variables are associated with data missingness (for instance, age, sex, level of substance use) 
using t-tests and chi-square analyses (for continuous and dichotomous variables, respectively). Baseline 
variables that are associated with data missingness will be included as covariates in additional adjusted 
models (that adjust for the baseline variables related to missingness). Assumptions for the statistical 
methods being used will be tested. Should there be evidence of violations of these assumptions (e.g., 
presence of outlying and influential cases, distributional concerns for residuals, and so on), appropriate 
corrective actions will be taken. Sensitivity analyses will be used to determine the extent to which the 
main study results are influenced by these violations. We will focus our interpretations on small p-values 
(p < .05) that indicate evidence against the null hypothesis. We will report the number of decimal places 
of the p-value in line with the journal’s guidelines and APA recommendations (usually 2 or 3 decimal 
places). For specific outcomes, the units of measurement and expected ranges of values (or example 
ranges, if the full range is unknown) are noted in the subsequent analysis sections 9.4.2 and 9.4.3. Any 
extreme outliers (defined as >3.0 standard deviations from the mean) will be recoded to one unit 
greater than the next most extreme value, in order to reduce undue influence of extreme outliers. For 
all statistical tests, confidence intervals will be evaluated in combination with tests of statistical 
significance. Assumptions for the statistical methods being used will be tested. Should there be evidence 
of violations of these assumptions (e.g., presence of outlying and influential cases, distributional 
concerns for residuals, and so on), appropriate corrective actions will be taken. Sensitivity analyses will 
be used to determine the extent to which the main study results are influenced by these violations. 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
Smoking sessions: MLM will be used to examine changes in nicotine reinstatement and number of 
cigarettes consumed (co-primary outcomes) as a function of medication phase (baseline; 0.5mg). These 
analyses will use medication phase as the within-subjects factor and condition (semaglutide vs. placebo) 
as the between-person factor.  
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
Daily self-report data: We will use MLM to estimate within-person changes in primary outcomes (e.g., 
daily cigarette use over the trial period), using study week as the within-subjects factor and condition 
(semaglutide, placebo) as the between-person factor. A similar analysis will be applied to examine 
changes in body weight over the course of the trial. 


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Smoking sessions: MLM will also be used to examine changes in self-reported drug and mood effects 
during laboratory smoking as a function of medication phase (within-person) and drug condition 
(between person). These analyses will focus on the subjective questionnaires administered immediately 
after the first cigarette smoked during the 2-hour smoking lapse/self-administration session.  
 
 
9.4.4 SAFETY ANALYSES 
 
Total side effects reported (e.g., 0-15), and number of severe side effects reported during each 
medication phase will be assessed using MLM with medication phase (baseline, 0.25mg, 0.5mg, 1.0mg) 
as the within-subject factor and condition (semaglutide, placebo) as the between-person factor. These 
count variables will be analyzed using a negative binomial MLM, however, this assumption will be tested 
and the modeling approach will revised as needed to properly account for the nature of the outcome 
variable (e.g., zero-inflated negative binomial regression).  
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
 
Descriptive statistics will be used to report relevant demographics such as age, sex, and education.  
 
9.4.6 PLANNED INTERIM ANALYSES  
 
No interim analyses of efficacy will be planned. 
 
9.4.7 SUB-GROUP ANALYSES 
 
Not applicable 
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Not applicable 
 
9.4.9 EXPLORATORY ANALYSES 
 
Sex will be examined as an exploratory moderator in all analyses. 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
 
10.1.1 INFORMED CONSENT PROCESS 
 
In obtaining and documenting informed consent, the team will comply with applicable regulatory 
requirements (e.g., 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56) and adhere to ICH GCP. Consent will 


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be obtained by a study team member or other qualified staff member (e.g., RCMU) in person at the 
outset of the baseline session. Additional procedures are noted below. 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
In obtaining and documenting informed consent, the team will comply with applicable regulatory 
requirements (e.g., 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56) and adhere to ICH GCP. Consent will 
be obtained remotely (via web teleconference and Docusign, as described previously) by a qualified 
study staff member in person at the outset of the baseline session. Additional procedures are noted 
below. 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. The 
initial consent process will be conducted remotely using a HIPAA-compliant web platform (e.g., WebEx, 
Zoom, Teams) and Part 11-compliant Docusign to maintain optimal safety. A copy of the consent form 
will be provided to the participant in advance of the scheduled videoconference. A qualified team 
member will explain the research study to the participant and answer any questions that may arise. A 
verbal explanation will be provided in terms suited to the participant’s comprehension of the purposes, 
procedures, and potential risks of the study and of their rights as research participants.  Participants will 
have the opportunity to carefully review the consent form and ask questions prior to signing. The 
participants should have the opportunity to discuss the study with their family or surrogates or think 
about it prior to agreeing to participate. The participant will electronically sign the informed consent 
document prior to any procedures being done specifically for the study. Participants must be informed 
that participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. A copy of the signed informed consent document will be given to the participants for their 
records. The informed consent process will be conducted and documented in the source document 
(including the date), and the form signed (via Docusign), before the participant undergoes any study-
specific procedures. The rights and welfare of the participants will be protected by emphasizing to them 
that the study is voluntary and the quality of their medical care will not be adversely affected if they 
decline to participate. While the initial consent form will be conducted electronically, supplementary 
consent forms (e.g., consent to unencrypted communication, HIPAA authorization, and biospecimen 
consent) may be conducted either remotely (via Docusign) in advance of the baseline visit or in person 
(paper form) at the baseline visit, depending on timing.  
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, investigator, funding agency, and 
regulatory authorities.  If the study is prematurely terminated or suspended, the Principal Investigator 
(PI) will promptly inform study participants, the Institutional Review Board (IRB), and sponsor and will 
provide the reason(s) for the termination or suspension.  Study participants will be contacted, as 
applicable, and be informed of changes to study visit schedule. Circumstances that may warrant 


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termination or suspension include, but are not limited to determination of unexpected, significant, or 
unacceptable risk to participants. Study may resume once concerns about safety, protocol compliance, 
and data quality are addressed, and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any unauthorized 
third party. All research activities will be conducted in as private a setting as possible. 
 
Any computerized data will be password protected and contained on a secure, password-protected 
computer or a secure server. Recruitment data (de-identified) will be stored in a secure, password-
protected file accessible only to the study investigators and personnel. At the end of recruitment, 
eligible subject files will be separated from those failing to meet eligibility criteria, and records of 
ineligible recruitment subjects will be anonymized. Data pertaining to screening failures will be 
tabulated in an anonymized fashion. Data collected in other formats (e.g., medical screening notes) will 
be labeled only by study identifier and stored in binders in secure, locked cabinets while the study is 
taking place. Files will be stored and archived in accordance with Good Clinical Practice (GCP) standards. 
For all questionnaire and interview assessments, participants will be informed that they may decline to 
answer any question if they so choose. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), regulatory agencies or pharmaceutical company supplying study product may 
inspect all documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored during the study for purposes of 
maintain contact with participants, and for communicating any safety information or unanticipated 
problems. At the end of the study, all records will continue to be kept in a secure location for as long a 
period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be stored at UNC in the PI’s laboratory and on secure backup servers with password-protected access. 
This will not include the participant’s contact or identifying information. Rather, individual participants 
and their research data will be identified by a unique study identification number. Electronic data are 
stored on a password protected drive only accessible by the research team.  Data obtained on paper will 
be transferred to an electronic data file (Excel, SPSS, REDCap), stored on a secure server, and identified 
by participants ID.  For non-computer based forms, the data collection sheets are stored in a locked 
cabinet in a separate locked data storage space at the PI’s laboratory. 
 
At the end of the study, all study databases will be de-identified and archived in the PI’s laboratory and 
backed up on a secure server hosted at UNC. De-identified data resulting from this study may also be 


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presented at meetings, published in journals or presentations. In addition, this study will be registered 
at ClinicalTrials.gov, and de-identified information from this study will be submitted to ClinicalTrials.gov. 
 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored at the PI’s laboratory. The study biostatistician 
will be given access to the data necessary for conducting specified analyses, and data will be de-
identified prior to giving access.  
 
De-identified biological samples will be stored at UNC for the duration of the study, until all biological 
tests are completed and the data transferred to electronic format. De-identified DNA samples will be 
stored indefinitely, provided the participant has given consent for DNA storage, in order to examine 
future questions related to phenotypes of interest for this line of research.  
 
During the conduct of the study, an individual participant can choose to withdraw consent to have 
biological specimens stored for future research. However, withdrawal of consent with regard to 
biosample storage may not be possible after the study is completed (after specimens are de-identified). 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
Provide the name and contact information of the Principal Investigator and the Medical Monitor. 
Principal Investigator 
Medical Monitor 
Christian Hendershot, Ph.D., Associate 
Professor 
TBD (The medical monitor and DSMB 
members will be identified and added prior to 
data collection) 
UNC-Chapel Hill  
 
104 Manning Dr. 
 
Christian_Hendershot@med.unc.edu 
 
Christian Hendershot, Ph.D., Associate 
Professor 
 
 
The investigative team is summarized on the face page of this protocol. As noted, a DSMB will be formed 
prior to carrying out the study.  
 
Safety oversight will be under the direction of a Data and Safety Monitoring Board (DSMB). Members of 
the DSMB will be independent from the study conduct and free of conflict of interest. The DSMB will 
dictate the intervals at which they meet to assess safety and efficacy data. At this time, each data 
element that the DSMB needs to assess will be clearly defined. The DSMB will provide its input to the 
IRB and National Institutes of Health as necessary. 
 
10.1.6 CLINICAL MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s). A local study monitor will be appointed to provide on-site monitoring during the course 
of the research study.  


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10.1.7 QUALITY ASSURANCE AND QUALITY CONTROL 
 
The PI will be responsible for addressing quality control issues and correcting errors or protocol 
deviations. The PI will have oversight over training study staff and ensuring that protocol elements are 
carried out with fidelity. Quality control will be ensured by developing SOPs for protocol elements to 
standardize data collection procedures. The investigational site will provide direct access to all trial 
related sites, source data/documents, and reports for the purpose of monitoring and auditing by the 
sponsor, and inspection by local and regulatory authorities. 
 
10.1.8 DATA HANDLING AND RECORD KEEPING  
 
 
10.1.8.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
As a single-site, small-scale trial, the project will not involve coordinated data collection and 
management responsibilities across sites/teams. Data safety and storage precautions are outlined 
elsewhere in the study protocol.  
 
10.1.8.2 STUDY RECORDS RETENTION  
Study records will be retained for a minimum of 7 years following study completion. Paper source 
documents will be archived in accordance with UNC policies. Electronic materials and de-identified 
datasets will be stored securely as outlined above.  
 
10.1.9 PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The PI 
will report deviations within 7 working days of identification of the protocol deviation, or within 7 
working days of the scheduled protocol-required activity.  All deviations must be addressed in study 
source documents, reported to NIAAA Program Official and the IRB. Protocol deviations must be sent to 
the reviewing Institutional Review Board (IRB) per their policies. The site investigator is responsible for 
knowing and adhering to the reviewing IRB requirements. Further details about the handling of protocol 
deviations will be included in the MOP. 
 
10.1.10 
PUBLICATION AND DATA SHARING POLICY 
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
 


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This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals. Data from this study may be requested from other researchers after the completion 
of the primary endpoint by contacting the PI. 
 
 
10.1.11 
CONFLICT OF INTEREST POLICY 
 
Any actual conflict of interest of persons who have a role in the design, conduct, analysis, publication, or 
any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived 
conflict of interest will be required to have such conflicts managed in a way that is appropriate to their 
participation in the design and conduct of this trial. All investigators will make a conflict of interest 
declaration at the outset of the study and at regular intervals thereafter in accordance with UNC 
policies. 
 
10.2 ADDITIONAL CONSIDERATIONS 
Not applicable 
 
10.3 ABBREVIATIONS 
 
AASE 
Alcohol Abstinence Self-Efficacy 
AE 
Adverse Event 
APT 
Alcohol Purchase Task 
AUDIT 
Alcohol Use Disorder Identification Test 
BIS-11 
Barratt Impulsivity Scale 
BMI 
Body Mass Index 
BrAC 
Breath Alcohol Concentration 
CASE 
Cigarette Abstinence Self-Efficacy 
CES-D 
Center for Epidemiological Studies Depression Scale 
CEQ 
Control of Eating Questionnaire 
CFR 
Code of Federal Regulations 
CMP 
Clinical Monitoring Plan 
CO 
Carbon Monoxide 
CPT 
Cigarette Purchase Task 
CRF 
Case Report Form 
CTRC 
Clinical & Translational Research Center 
DEQ 
Drug Effects Questionnaire 
DNA 
Deoxyribonucleic acid 
DSM-5 
Diagnostic and Statistical Manual for Mental Disorders v.5 
DSMB 
Data Safety Monitoring Board 
FDA 
Food and Drug Administration 
FPT 
Food Purchase Task 
FTND 
Fagerstrom test for Nicotine Dependence 
GCP 
Good Clinical Practice 
GLP-1 
Glucagon-Like Peptide 1 
GLP-1R 
Glucagon-Like Peptide 1 Receptor 
HbA1c 
Glycated hemoglobin 
ICH 
International Conference on Harmonisation  


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ICS 
Impaired Control Scale 
IDS 
Inventory of Drinking Situations 
IRB 
Institutional Review Board 
MCQ 
Monetary Choice Questionnaire 
MNWS 
Minnesota Nicotine Withdrawal Scale 
MOP 
Manual of Procedures 
NC Tracs 
North Carolina Translational & Clinical Sciences Institute 
NDSS 
Nicotine Dependence Syndrome Scale 
NIAAA 
National Institute on Alcohol Abuse and Alcoholism 
NIH  
National Institutes of Health 
NRT 
Nicotine Replacement Therapy 
PACS 
Penn Alcohol Craving Scale 
PPC 
Peak Provoked Craving 
PI 
Principal Investigator 
POMS-SF 
Profile Of Mood States Short Form 
QA 
Quality Assurance 
QC 
Quality Control 
RBEDS 
Reward Based Eating Drive Scale 
RPI-EROS 
Reward Probability Index – Environmental Reward Observation Scale 
SAE 
Serious Adverse Event 
SAFTEE 
Systematic Assessment for Treatment Emergent Effects 
SNAQ 
Simplified Nutritional Appetite Questionnaire 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
SRE 
Self-Report of the Effects of Alcohol Questionnaire 
SUD 
Substance Use Disorder 
T2D 
Type II Diabetes 
TAS-20 
Toronto Alexithymia Scale 
TFEQ 
Three Factor Eating Questionnaire 
TLFB 
Timeline Follow-Back Interview 
TQSU 
Tiffany Questionnaire of Smoking Urges 
UP 
Unanticipated Problem 
UPPS-P 
UPPS-P Impulsive Behavior Scale 
WISDM 
Wisconsin Inventory of Smoking Dependence Motives 
WSWS 
Wisconsin Smoking Withdrawal Scale 
5-HT2C 
Serotonin 2C Receptpr 
 
 
 
 


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10.4 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, including a 
description of the change and rationale. A Summary of Changes table for the current amendment is 
located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
1.2 
July 26 2021 
Elaboration on statistical analyses 
and clarification on other procedural 
issues. 
Minor changes requested 
during initial review of the 
protocol. 
1.3 
Feb 28 2021 
Clarification of medication 
dispensing procedures, addition of 
personnel, addition of Docusign 
procedures, other protocol 
modifications. 
Changes addressed issues that 
emerged while preparing for 
recruitment and meeting with 
IDS and study investigators. 
1.4 
June 23 
2022 
Minor revisions to exclusion criteria, 
and clarification of medication 
dosing and DSMB meeting plan 
Refinement of study 
procedures and clarification of 
monitoring schedule as 
requested by DSMB and IDS 
1.5 
August 22 
2022 
Updates to medication storage, use 
of Phone.com for text messaging, 
select questionnaire modifications, 
modifications to alcohol self-
administration session 
Medication storage changes 
requested by IDS; Phone.com 
added as per UNC requirements 
for text messaging; other 
changes intended to streamline 
and improve assessment 
procedures 
1.6 
October 31 
2022 
Adjustments to inclusion criteria; 
added analysis for blood neutrophils; 
added additional recruitment flyers. 
Changes made to facilitate 
recruitment and address an 
exploratory research question. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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