Clinical trial NCT02975297
Conditions: Smoking Cessation
Keywords: smoking pre-diabetes overweight exenatide Glucagon-like peptide-1 (GLP-1) agonists
Sponsor: The University of Texas Health Science Center, Houston
Start date: 2016-07-01; Completion date: 2020-01-03
Enrollment: 84 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to identify a potential new treatment for smoking cessation.

Detailed description:

Arms: arm 1: Once weekly exenatide Injectable Product, Nicotine Replacement Therapy (NRT) Patch, smoking cessation counseling arm 2: Once weekly placebo, Nicotine Replacement Therapy (NRT) Patch, smoking cessation counseling
Interventions: intervention 1: Exenatide intervention 2: NRT intervention 3: Counseling intervention 4: Placebo
Intervention descriptions: intervention 1: Exenatide Injectable Product will be administered at a dose of 2 mg subcutaneously once a week for 6 weeks. intervention 2: Nicotine Patch (21mg) / 24 hours. intervention 3: Brief individual behavioral smoking cessation counseling. intervention 4: Normal saline.

Protocol documents:
Prot_SAP_000.pdf: 
IRB APPROVAL DATE: 10/20/2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exenatide Once Weekly for Smoking Cessation: A Randomized Clinical Trial 
 
NCT02975297 
 
Version Date: 10/20/2017 
 
 


IRB APPROVAL DATE: 10/20/2017 
 
 
Project Plans 
 
Exenatide Once Weekly for Smoking Cessation: A Randomized Clinical Trial 
Abstract 
Background: Cigarette smoking is the greatest preventable cause of morbidity and premature mortality 
in the US. Approved pharmacological treatments for smoking cessation are marginally effective, underscoring 
the need for improved pharmacotherapies. Glucagon-like peptide-1 (GLP-1) is produced in the intestinal L-cells 
and in the hindbrain. The peptide maintains glucose homeostasis and reduces food intake. Several GLP-1 
agonists are used clinically for the treatment of type 2 diabetes and obesity. In addition to reducing food intake, 
GLP-1 agonists have recently been shown in preclinical studies to attenuate appetite for drugs and alcohol. 
Aims: Our primary aims are: 1) to examine the impact of treatment with weekly extended-release 
injectable exenatide on smoking abstinence and 2) to assess whether exenatide treatment is associated with 
the reduction in craving and withdrawal symptoms in the study sample. Our secondary aims are: 1) to examine 
the effect of extended-release exenatide on cue-induced craving for cigarettes, 2) to evaluate the effect of 
exenatide treatment on continued abstinence from smoking and craving for cigarettes at 1- and 4- weeks post- 
treatment, and 3) to collect DNA samples from the study participants for the examination of the GLP-1 receptor 
variability and smoking outcomes. 
Methods: We will enroll pre-diabetic and/or overweight smokers (n=90) who desire to quit smoking. 
Participants will be randomized 1:1 to receive once weekly exenatide or placebo for a total of 6 weeks. All 
participants will receive transdermal nicotine replacement therapy (NRT) and behavioral counseling. 
Abstinence from smoking, craving, and withdrawal symptoms will be assessed during and at 6 weeks of 
treatment, as well as at 1- and 4-week post-treatment. 
Expected Outcomes: We hypothesize that: 1) exenatide treatment will increase the number of 
participants able to achieve complete smoking abstinence above that achieved via standard NRT and 2) 
exenatide will reduce craving and withdrawal symptoms, as well as cue-induced craving. Craving and 
withdrawal symptoms predict long-term efficacy, which could be examined in a follow-up study. 
 
A. Background 
Cigarette smoking is the leading cause of preventable mortality in the U.S., producing over 400,000 
deaths annually1. Additional 50,000 deaths occur each year among nonsmokers who are exposed to 
secondhand smoke. Over 16 million Americans suffer from chronic diseases caused by smoking. Annually, 
these diseases cost the U.S. $170 billion in direct medical care and over $156 billion in lost productivity [1]. 
These data illustrate the significance of cigarette smoking on individuals and our society at large and 
underscore the importance of identifying therapeutic approaches to assist smoking cessation. 
The first line pharmacological therapies for smoking cessation include nicotine replacement therapy 
(NRT), bupropion hydrochloride, and varenicline tartrate. Nearly 50 million of Americans smoke cigarettes, and 
although many report wanting to quit, the 12-month abstinence rates with the use of these therapies range 
from 22% to 33% [1]. These relatively modest long-term improvements in abstinence rates underscore the 
importance of developing improved therapeutic approaches to assist smoking cessation [2, 3]. 
Glucagon-like peptide-1 (GLP-1) is produced endogenously in the intestinal L-cells and in the hindbrain 
nucleus tractus solitaries [4-7] in response to nutrient ingestion. Acting primarily via GLP-1 receptors (GLP-1R) 
in the hypothalamus and brain stem, GLP-1 regulates glucose homeostasis via increasing the secretion of 
insulin [8] and suppressing the secretion of glucagon [9, 10]. GLP-1 also reduces food intake [11, 12] in part by 
reducing appetite [13-15]. The proposed study medication, exenatide, a GLP-1 receptor agonist (GLP-1RA), is 
currently used clinically for the treatment of type 2 diabetes mellitus (DM), and a related GLP-1RA (liraglutide) 
was recently FDA-approved for the treatment of obesity in patients with or without DM, suggesting that 
exenatide may have similar effects. 
GLP-1Rs are expressed in many brain regions. In addition to hypothalamus and brain stem, GLP-1Rs 
are expressed throughout the mesolimbic dopamine system [16], and GLP-1 containing neurons extend 
directly into the ventral tegmental area and nucleus accumbens [17] - areas that are intimately associated with 
the regulation of reward. These data suggest that the role of GLP-1 extends beyond the glucoregulatory effects 
to reward regulation and that the GLP-1 system represents a target for pharmacological treatment of addictive 
behaviors [11, 12]. Consistent with this, recent and novel findings from animal studies have indicated that 
treatment with GLP-1RAs attenuates reward induced by alcohol [18, 19], cocaine [20, 21], amphetamine [20, 
22], and most relevant here, nicotine [23]. In mice, treatment with a GLP-1RA at a dIoRsBeNwUitMhBnEoRo: tHhSeCr -MS-17-0802 


IRB NUMBER: HSC-MS-17-0802 
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behavioral effects attenuated nicotine-induced locomotor stimulation, accumbal dopamine release, and 
reduced the expression of nicotine conditioned place preference [23]. 
Of additional relevance to the present application, a number of recent studies aimed to evaluate the 
effects of GLP-1RAs on weight loss using the pharmacogenetic approach [24-26]. The objective of these 
studies was to examine whether GLP-1R variability moderates the effect of GLP-1RA treatment on weight loss. 
The studies showed that GLP-1R variability is indeed associated with weight loss in GLP-1RA-treated 
participants. Several GLP-1R polymorphisms, with the most commonly cited rs6923761, predicted weight 
response to GLP-1RA treatment [24-26]. Given the overlap among food and drugs of abuse as it relates to 
engaging the reward circuitry [27, 28], the findings of these studies suggest that GLP-1R variability may 
moderate the effect of GLP-1RA treatment on smoking outcomes. 
 
B. Research Aims 
We will evaluate, for the first time, the impact of treatment with extended-release injectable exenatide on 
smoking abstinence among pre-diabetic and/or overweight adults presenting for treatment to the UTHealth 
Center for Neurobehavioral Research on Addiction. In addition, to obtain preliminary evidence for a larger 
follow-up study that will evaluate the mediating effects of craving and withdrawal symptoms on abstinence in 
smokers treated with exenatide, we will assess the impact of exenatide on post-quit craving and withdrawal 
symptoms – proximal factors which covary with and predict future abstinence [29-32]. Lastly, we will collect 
DNA samples from the study participants to examine the relationship between GLP-1R variability and smoking 
outcomes. 
 
Primary Aims: 
 
Aim 1: to examine the effect of weekly extended-release injectable exenatide treatment on carbon- 
monoxide confirmed self-reported smoking abstinence in pre-diabetic and/or overweight smokers 
following a quit attempt 
Hypothesis 1.a.: Exenatide will increase the rate of complete smoking abstinence measured by seven- 
day point prevalence abstinence (self-reported and biochemically verified via expired carbon-monoxide 
levels) following six weeks of treatment. 
Hypothesis 1.b.: Exenatide-treated participants will show differential change over time in the probability 
of abstinence as measured by seven-day point prevalence during the six week treatment. 
Aim 2: to examine the effect of weekly extended-release injectable exenatide treatment on post-quit 
craving and withdrawal symptoms in the study sample 
Hypothesis 2.a. Exenatide will reduce post-quit craving (as measured by the Questionnaire of Smoking 
Urges score) and withdrawal symptoms (as measured by the Wisconsin Smoking Withdrawal Scale 
score) following six weeks of treatment. 
Hypothesis 2.b.: Exenatide-treated participants will show differential reduction in post-quit craving and 
withdrawal during the six week treatment. 
 
Secondary Aims: 
 
Aim 1: To examine the effect of the 6-week exenatide treatment on 1- and 4- week post-treatment 
abstinence from smoking and craving for cigarettes in the study participants 
Hypothesis: Exenatide will increase the rate of complete smoking abstinence measured by seven-day 
point prevalence abstinence (self-reported and biochemically verified via expired carbon-monoxide 
levels) at 1- and 4-weeks post-treatment. 
Aim 2: To examine the effect of extended-release exenatide on cue-induced craving for cigarettes 
Hypothesis: Exenatide treated participants will display lower craving for cigarettes (as measured by the 
Questionnaire of Smoking Urges score) following virtual reality exposure. 
Aim 3: To collect blood samples from the study participants and genotype for GLP-1R polymorphisms 
and other polymorphisms in the future. 


IRB NUMBER: HSC-MS-17-0802 
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C. Study Design and Methods 
C1. General Study Design and Procedures 
Our aims will be accomplished via a double-blind, placebo-controlled, randomized clinical trial. The 
participants will be 90 adult smokers who have pre-diabetes (Type 2, HbA1C=5.7-6.4%) or are overweight 
(BMI≥25 kg/m2). The participants will be randomized 1:1 to receive exenatide or placebo. All participants will 
receive transdermal NRT and individual behavioral smoking cessation counseling. Quit date will be set 
following 2 weeks of exenatide/placebo treatment because we anticipate that it will take 2 weeks for the effects 
of exenatide to emerge [33, 34]. Smoking abstinence will be evaluated via self-report and confirmed during 
clinic visits via breath carbon monoxide (CO) measurements. 
 
Table 1. Study Procedures 
 
Study Timeline  
 
 
Smoke? 
 
Screen 
Weeks 1-2 
Quit day 
Weeks 3-6 
End of Treatment 
Week 7 
Week 10 
Ad Libitum 
Ad Libitum 
No 
Smoking 
No 
Smoking 
No 
Smoking 
Informed Consent, MINI, 
Demographics, 
Inclusion/Exclusion Criteria, 
Physical Exam, Medical History 
X 
Blood (DNA) sample 
M, Week 1 
Concomitant Meds, AEs, Vitals 
X 
M 
M 
M 
M 
FTND, Pregnancy Test, Safety Labs 
X 
Exenatide or Placebo 
M 
M 
NRT 
M 
Behavioral Therapy 
M 
M 
Number of Cigarettes Smoked 
X 
M 
M, T, W, T, F, S, S 
M 
M 
Breath CO 
X 
M 
M 
M 
M 
WSWS, QSU, PANAS 
X 
M 
M 
M 
M 
Virtual Reality Session 
M, Week 1 
M, Week 3 
 
AEs-Adverse Events; CO-carbon monoxide; FTND-Fagerstrom Test for Nicotine Dependence; M- Monday; 
MINI-MINI Neuropsychiatric interview, NRT – nicotine replacement therapy; PANAS- Positive and Negative 
Affect Schedule; QSU – Questionnaire of Smoking Urges, WSWS – Wisconsin Smoking Withdrawal Scale 
 
Design Rationale. Administration of exenatide 2 mg once weekly results in therapeutic concentrations (>50 
pg/mL) in approximately 2 weeks, whereas steady-state concentrations of approximately 300 pg/mL are 
achieved within approximately 4-6 weeks [33, 34]. Based on these pharmacokinetics, we selected to set the 
quit date following 2 weeks of exenatide treatment and to evaluate the primary outcome (7-day point 
prevalence abstinence) following a total of 6 weeks of treatment. This is the first study to evaluate the effect of 
exenatide treatment on smoking outcomes; therefore, the optimal time-points for quit date and assessment of 
the primary outcome cannot be predicted with certainty. To mitigate this concern, we will evaluate the trajectory 
of quit attempts and abstinence throughout the duration of the study. 
 
C2. Setting and Treatments 
This study will be conducted at the UTHealth Center for Neurobehavioral Research on Addiction. 
Participants will be recruited using various strategies, including flyers, newspaper ads, and referrals. When the 
potential participants call the provided telephone number, the requirements and the procedures of the study 
will be explained, and a brief prescreen to determine initial eligibility will be administered. The pre-screen 
interview will include questions concerning medical and psychiatric history, psychoactive substance use, and 
smoking history. Individuals who appear eligible based on the initial pre-screen will be invited for a face-to-face 
interview. 
During a face-to-face interview with the study PI, participants will be given consent documents that will 
be read to them if needed. Following completion of the informed consent process, each participant will provide 
his or her medical history and have a brief physical exam including assessment of vital signs and collection of 
samples for laboratory testing. Following completion of the initial screening and determination of the study 
eligibility, participants will return to clinic for randomization (1:1) to receive exenatide treatment or placebo. The 


IRB NUMBER: HSC-MS-17-0802 
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first dose of exenatide/placebo will be administered during that visit. Subsequent to that visit, participants will 
return to clinic once a week for 5 more weeks. A total of 6 weekly injections will thus be administered. All 
participants will receive NRT treatment and individual behavioral smoking cessation counseling as is the 
recommended standard for use with pharmacotherapy. Cue-induced craving for cigarettes is assessed during 
visit 1 (baseline) and visit 3 following virtual reality exposure. Participants receive compensation at the end of 
each study visit. 
Upon the completion of the treatment phase of the study, the participants who were abstinent following 
6 weeks of treatment will be contacted via telephone at 1- and 4-weeks post-treatment to ascertain continued 
abstinence from smoking. Those who report being abstinent, will be invited for in-person visit for the 
biochemical verification of abstinence. 
The blood samples for DNA extraction will be collected during the participants’ first study visit, using 
two 5-ml lavender top vacutainers. The samples will be labeled using unique study identifiers and transported 
at room temperature to the Baylor College of Medicine Psychiatric Genetics Laboratory in the Department of 
Psychiatry and Behavioral Sciences for further analysis. 
 
C3. Recruitment, Eligibility, and Randomization 
Recruitment. We will use advertisements in local newspapers, flyers, as well as referrals to recruit 
volunteers. 
Eligibility. The following inclusion criteria must be met for an individual to participate in the study: 
1. Be English-speaking volunteers who desire to quit smoking and are willing to make a quit attempt 
during the course of the study; 
2. Be aged between 18 and 75 years; 
3. Have smoked ≥10 cigarettes a day for at least one year and provide a breath CO ≥10 ppm; 
4. Have a negative pregnancy test, if female of childbearing potential; 
5. Have HbA1C levels between 5.7 and 6.4% and/or body mass index of ≥25 kg/m2. 
6. Not currently using any therapy for glycemic control (either injectable [i.e. insulin] or oral agents); 
7. Have vital signs as follows: resting pulse between 50 and 95 bpm, BP between 90-150 mmHg systolic 
and 45-95 mmHg diastolic; 
8. Have hematology and chemistry laboratory tests that are within reference limits (10%), with the 
following exception: pancreatic tests (lipase and amylase) must be within normal limits; 
9. Have a medical history and brief physical examination demonstrating no clinically significant 
contraindications for study participation, in the judgment of the principal investigator. 
Exclusion Criteria: 
1. Meet criteria for the following psychiatric and/or substance use disorders as assessed by the MINI: 
items C (current manic or hypomanic episode only), I (alcohol abuse - Alcohol Addendum-past 3 
months only; current alcohol dependence), J (substance abuse -Substance Abuse Addendum – past 3 
months only; current substance dependence), K (current psychotic disorder or current mood disorder 
with psychotic features). 
2. Individuals who meet criteria for non-exclusionary psychiatric disorders that are considered clinically 
unstable and/or unsuitable to participate as determined by the Principal Investigator. 
3. Individuals rated as moderate (9-16) to high (17 or greater) on suicidality as assessed by Module B of 
the MINI. 
4. Have personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia 
syndrome type 2; 
5. Have type 1 diabetes mellitus; 
6. Have severe cardiovascular disease (history of myocardial infarction, life-threatening arrhythmia, or 
worsening angina pectoris); 
7. Have active temporomandibular joint disease; 
8. Have severe gastrointestinal disease (i.e. severe gastroparesis); 
9. Have previous history of pancreatitis or are at risk for pancreatitis; 
10. Have CrCl<30; 
11. Have any previous medically adverse reaction to study medications, nicotine, or menthol; 
12. Be pregnant or lactating or unwilling to provide a negative pregnancy test before study entry; 
13. Not using a reliable form of contraception (e.g., abstinence, birth control pills, intrauterine device, 
condoms, or spermicide); 


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14. Have any illness which in the opinion of the primary investigator would preclude safe and/or successful 
completion of the study. 
Criteria for withholding study treatment: Subsequent doses of exenatide will not be administered if 1) any of 
the following occur: hypoglycemia, hypersensitivity reaction, anaphylaxis, nephrotoxicity, pancreatitis, or severe 
injection site reaction or 2) the study PI believes that there may be any reason to withhold exenatide. Criteria for 
participant discontinuation following study initiation. Inability to comply with study procedures; meet 
discontinuation criteria due to side effects/adverse events associated with the study treatment. Stopping criteria. 
We will monitor the frequency of the treatment-related adverse events. If more than 10% of participants entering 
the study experience treatment-related adverse event, we will halt the study if indicated by the pattern and 
severity of adverse events. Drop out. We plan to recruit a total of 90 subjects and anticipate that 74 subjects will 
complete the study (80% retention). Randomization. An independent investigator will randomize participants 1:1 
into exenatide and placebo groups using blocks of four. Sterile saline will serve as the placebo for exenatide. 
Exenatide dosing, accounting and observation. Exenatide will be administered at a dose of 2 mg subcutaneously 
once a week on Mondays. Any unused medication will be accounted for and disposed of. NRT dosing, accounting 
and observation. NRT will be administered as a transdermal patch at a dose of 21 mg. The patches will be 
dispensed on Mondays in the amount sufficient for 1 week of use. Any unused patches with be accounted for 
and disposed of. Payment to Research Participants. Participants will receive compensation for their time and 
effort. Participants will be compensated at the end of the screening visit and at the end of each study visit, 
regardless of whether they remain in the study. The compensation rate will be as follows: 
Screen: $10 
Visit 1: $10 
Visit 2: $15 
Visit 3: $20 
Visit 4: $25 
Visit 5: $30 
Visit 6: $50 
Post-treatment Visit 1: $10 
Post-treatment Visit 2: $10 
Provision of DNA sample: $20 
C4. Data Collection and Measures 
Clinical Assessments 
The MINI Neuropsychiatric Interview will be administered during screening to determine whether subjects 
meet the DSM-5 criteria for nicotine-use disorder and to rule out presence of any exclusionary psychiatric and 
substance abuse disorders [35]. 
Nicotine dependence will be assessed during screening using Fagerstrom Test for Nicotine 
Dependence [36]. FTND is a valid and reliable 6-items questionnaire that evaluates the quantity of cigarette 
consumption, the compulsion to use, and dependence. 
Baseline smoking status will be assessed during screening via self-reported smoking of >10 
cigarettes/day for >1 year and with recent smoking confirmed by an expired air carbon monoxide (CO, Micro+ 
Smokerlyzer®, Williamsburg, VA ) level of ≥10 ppm. 
Abstinence from smoking. Self-report abstinence will be logged by participants and confirmed via time- 
line follow back procedures [37]. Biochemical verification of abstinence (expired CO level of <5 ppm) will be 
performed during clinic visits. 
Withdrawal symptoms will be assessed using Wisconsin Scale of Withdrawal Symptoms (WSWS) [38]. 
WSWS is a valid and reliable questionnaire which includes subscales of anger, anxiety, concentration, craving, 
hunger, sadness, and sleep. 
Craving for smoking will be evaluated using the Questionnaire of Smoking Urges [39], a 32-item scale 
that assesses the intention and desire to smoke and an anticipation of relief from the withdrawal-associated 
negative affect. 
Positive and negative affect will be assessed using the Positive and Negative Affect Schedule [40] 
(PANAS), a 20-item questionnaire that asks participants to rate the extent to which they experience positive 
(i.e. excited, inspired, proud) or negative (i.e. irritable, distressed, upset) emotions. 
Depressive symptoms will be assessed using the Patient Health Questionnaire Depression Scale 
(PHQ-8) [41], an 8-item questionnaire that assesses presence and severity of depressive symptoms over the 
previous two weeks. 


IRB NUMBER: HSC-MS-17-0802 
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Virtual Reality (cue-induced craving for cigarettes). To assess baseline withdrawal symptoms and 
craving for cigarettes participants complete the Wisconsin Scale of Withdrawal Symptoms (WSWS) and the 
Questionnaire of Smoking Urges (QSU). Participants will then take part in a virtual reality (VR) session that is 
viewed using a head-mounted device (NIVS SX-60, NIVS, Reston, VA) with a head tracker (Ic3 inertia cube, 
Intersense) connected to a desktop computer. Participants are exposed to VR neutral cues (nature scenes), 
followed by series of VR smoking-related cues. VR smoking cues are personalized to match each participant’s 
preferred brand of cigarettes. Similarly, the style of music played in the VR party contexts is also adjusted 
based on participant preference. Cue reactivity is assessed within the VR environment immediately after each 
VR scenario with the aid of a gamepad to answer craving-related questions (using a visual analog scale of 0- 
100). VR neutral context consists of a nature video; VR active paraphernalia context consists of proximal 
smoking-related objects (packs of cigarettes, ashtrays, bottles of alcohol) placed on tables around the room; 
and VR party context consists of similar smoking cues and includes interactions with avatars at the party where 
cigarettes are offered, drinks are poured, and conversations are held while people light up cigarettes. Exposure 
to each VR environment (neutral, paraphernalia, party) lasts approximately 3 minutes and follows a timed path 
where at certain points participants are visually directed for a few seconds to pay attention to non-smoking or 
active cues in order to standardize some of the VR exposure within the environment. This VR paradigm was 
used in a previous study that showed that self-reported levels of “craving” (p<0.01) and “thinking about 
cigarettes” (p<0.0001) were significantly greater after exposure to the active cues versus non-smoking cues 
and that there were significant positive correlations between self-reported craving prior to the VR session and 
craving induced by active VR cues (p<0.01) [42]. 
Medical/Pharmacological Assessments 
Medical history and physical exam. Personal and family health profiles and medical history will be 
collected during screening and reviewed with a licensed medical professional. During this time, a physical exam, 
neurological exam, and neuropsychiatric mental status evaluation will also be conducted. 
Clinical laboratory assessment. During screening, blood for hematology studies will be collected in 
anticoagulant-containing vacutainer tubes for analysis of Hemoglobin A1C, CBC, chemistry, liver function tests, 
renal function tests, and amylase and lipase levels. A urine-based pregnancy test for females will measure 
human chorionic gonadotropin. Blood glucose levels will be assessed using finger stick prior to each dose of 
exenatide. 
Blood samples for DNA extraction. The blood samples will be collected during the participants’ first 
study visit, using two 5-ml lavender top vacutainers. The samples will be labeled using unique study identifiers 
and transported at room temperature to the Baylor College of Medicine Psychiatric Genetics Laboratory in the 
Department of Psychiatry and Behavioral Sciences for further analysis. 
C5. Study Medications 
Exenatide. Exenatide will be administered at a dose of 2 mg subcutaneously once a week for 6 weeks. 
Because administration of exenatide 2 mg once weekly results in therapeutic concentrations (>50 pg/mL) after 
2 weeks of treatment, the participants randomized to exenatide treatment will receive 2 weekly doses of 
exenatide prior to quit day. Because steady-state concentrations are achieved within 4-6 weeks, the 
participants will be treated for a total of 6 weeks [33, 34]. As noted above, this is the first study to examine the 
effect of exenatide treatment on smoking outcomes; therefore, the selected time-points for quit date and 
assessment of the primary outcome may not be optimal. To mitigate this uncertainty, we will evaluate the 
trajectory of quit attempts and abstinence throughout the duration of the study. 
Exenatide will be purchased commercially as Bydureon for SC injection. The incidence of 
hypoglycemia with the use exenatide is low because the release of insulin following administration exenatide is 
glucose-mediated. Although there have been questions about the safety of incretins such as exenatide, as 
treatment may be associated with increased rates of pancreatitis, a recent meta-analysis of 60 studies 
(n=353,639), consisting of 55 randomized controlled trials (n=33,350) and five observational studies (three 
retrospective cohort studies, and two case-control studies; n=320,289) has shown that incretin treatment was 
not associated with increased rates of pancreatitis [43]. Ongoing post-marketing monitoring is also underway. 
In addition, data from rodent studies suggest that GLP-1 agonists may be associated with an increased risk of 
thyroid C-cell hyperplasia and C-cell tumors; however, experiments with monkeys did not show proliferation of 
C-cells in thyroid gland after chronic administration of GLP-1 agonists. Longitudinal data from clinical trials 
have not demonstrated a causal association between GLP-1 agonists and thyroid C-cell pathology over a 2- 
year period [44]. 
NRT. NRT patches (21 mg) will be purchased commercially as generic nicotine patches. The patches 
will be dispensed on Mondays in the amount sufficient for 1 week of use [45]. Nicotine patches is an over-the- 


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count product with a proven safety record. The patches are contraindicated in persons with hypersensitivity to 
nicotine or menthol, those with severe cardiovascular disease (i.e. history of myocardial infarction, life- 
threatening arrhythmia, or worsening angina pectoris), and those with temporomandibular joint disease. To 
address these concerns, patients with these conditions will be excluded from participation in this study. 
C6. Behavioral Counseling 
All participants will receive brief individual behavioral smoking cessation counseling as is the 
recommended standard for use with pharmacotherapy [46]. The counseling protocol is manual driven, has 
been used in several previous studies [47-49] and will consist of 6 in-person sessions (on the days when the 
participants come to clinic to receive exenatide/placebo treatment) and 2 brief supportive phone calls (one day 
pre-quit and 3 days post-quit), lasting 10-15 minutes each, spanning the 6 week active treatment phase. 
Counseling content will follow the previous study [49] and briefly involves preparation for quitting, identification 
of high risk situations for smoking, development of coping skills and direct support before and after the quit 
date, motivational intervention for keeping or resetting a quit date, management of withdrawal symptoms and 
medication compliance. Counseling will be provided by the study PI, actively practicing Family Nurse 
Practitioner with a Ph.D. degree. The study PI will be trained by experienced Ph.D. or Master’s - level smoking 
cessation clinicians from Dr. Cinciripini’s team. The team has extensive experience from the previous trials in 
training and monitoring the integrity of the counseling protocol including recording time and content of each 
session. At the conclusion of active treatment, participants will be offered referral for ongoing cessation 
counseling (quitline). 
C7. Safety Assurances and Adverse Events 
Medical Monitoring. Vital signs will be assessed at each visit. Blood glucose levels will be assessed prior to 
each dose of exenatide. The PI will halt exenatide administration if stopping criteria are met. The dose of 
exenatide that we will use is the standard dose that is currently used clinically; therefore, we expect no medical 
issues to arise. Should a participant become unable to cooperate with study procedures he or she will be 
replaced. 
Adverse event assessment and management. Participants’ well-being will be assessed at each visit. 
Participants will be asked if they are experiencing any discomfort indicating potential side effects. 
Spontaneously reported symptoms or complaints will be recorded and reported as required if events are 
classified as serious. 
D. Data Analysis Plan 
Data Management. Initially, data stripped of all personal identifiers will be collected using paper-and- 
pen or direct computer entry. The database will then be backed up and a copy will be securely e-mailed to the 
PI and statistical consultant for analysis. A research assistant trained in quality assurance procedures will 
thoroughly check data from clinical charts against source documents. Twenty percent of the outcome data will 
be double-entered. In the event of major discrepancies, outcome data will receive 100% source document 
verification. We will construct a relational data-base in Microsoft Access that will maintain data integrity by 
limiting entry codes for respective variables and by preventing orphan records. 
Sample Size Justification. We will enroll 90 subjects in this study. Our intention is to conduct the largest 
study possible, given the budget. In the statistical methods outlined below we describe the data analysis 
strategy that will be used in order to optimize the information provided by the anticipated sample. Furthermore, 
data obtained in this study will serve as the preliminary evidence for a larger follow-up study. 
Statistical Methods. Whether GLP-1RAs confer benefit in treating nicotine dependence has not been 
tested in clinical trials. Frequentist statistics that are based on dichotomous null hypothesis-testing (i.e. 
estimating the probability of observing the data, or data more extreme, given that the null hypothesis is true) 
would be less informative in the context of this early-phase project. We, therefore, select a Bayesian approach 
to data analysis. Bayesian probability estimates incorporate prior information about plausible parameter values 
with the observed data, forming the posterior distribution and thereby, allow estimates of the probability that the 
true value of the parameter falls in some range. The Bayesian approach will thus allow us to bet on the 
alternative hypothesis and ascertain the probability that the treatment confers some level of benefit, given the 
observed data [50]. According to the FDA, Bayesian statistics offer improved methodological efficiency for 
early-phase projects aimed to “repurpose” existing therapies for new indications [51-53]. Decision-making 
based on an initial trial of a compound for a new indication is assisted by estimates of the probability of an 
effect of some specified magnitude, even with small sample sizes [54, 55]. 
Statistical analysis. An intent-to-treat approach will impute those who drop out of the study being 
counted as continuing to smoke. Demographic and baseline characteristics of the study participants by group 
that show correlations with both treatment group and outcomes may be potential confounders and result in 


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analyses including and excluding the salient demographic or baseline characteristic to ascertain the degree to 
which this is the case. Evidence of confounding will result in reporting both adjusted and unadjusted estimates 
of treatment effect. For retention, group differences in the time to drop-out t over the 6-week study period as a 
function of treatment will use Cox Proportional Hazards survival analysis. Data analyses will use generalized 
linear and multilevel models. For Primary Aim 1 and Secondary Aim 1, logistic regression models (with a log- 
link to permit estimates of relative risks) will be used to assess the effect of treatment on 7-day point 
prevalence abstinence following 6 weeks of treatment (Primary Aim 1), as well as at 1- and 4-weeks post- 
treatment (Secondary Aim 1). For Primary Aim 2 and Secondary Aim 2, mixed models and multilevel models 
will be used to assess the effect of treatment on craving (QSU score), withdrawal symptoms (WSWS score), 
and cue-induced craving for cigarettes (QSU score following virtual reality exposure). Lastly, multilevel models 
will the used to examine the trajectory of abstinence throughout the course of the study. Vague, neutral priors 
provide a basis for initially evaluating the trial results: for linear Cox proportional hazards and logistic 
regression, priors for coefficients will take the form ~Normal (μ = 0, σ2 = 1 x 106) in the linear, log-hazard and 
log-relative risk scales. Priors for error or dispersion terms will use ~Gamma(a = 0.001, b = 0.001) and 
~Uniform(1,1000) for level one and two effects respectively. Working with Dr. Charles Green, we will 
investigate the robustness of the resulting posterior distributions using a variety of neutral and pessimistic 
priors representing vague, weakly-informative, and skeptical informative perspectives. Informative priors will 
use extant information (e.g. meta-analytic findings [56] for smoking outcomes). Evaluation of posterior 
distributions will permit statements regarding the probability that effects of varying magnitudes exist, given the 
data. For the genetic analyses (Secondary Aim 3), the primary phenotype to be used as the measure to 
treatment response will be assessment of smoking over the 6-week evaluation period, as measured by self- 
report and corroborated by weekly breath CO measurements. This will match the parent exenatide study 
endpoints. Variants of the GLP-1R will be genotyped and examined for association with treatment response. 
For continuous traits (breath CO levels) we will perform one-way ANOVA with the continuous trait as the 
response variable and genotype as the predictor variable. This will test the null hypothesis that the mean level 
of the trait is the same for all genotypes. We will use linear regression to adjust for any confounding variables 
before performing one-way ANOVA. For dichotomous traits (smoking abstinence), chi-square analysis will test 
the null hypothesis that the trait is independent of genotype. For confounding variables, we will use logistic 
regressed before chi-square analysis. To correct for the multiple testing we will use Bonferroni adjustment. 
 
E. Potential Difficulties and Solutions 
Safety of exenatide. Exenatide does not act like insulin to directly lower blood glucose; therefore, the 
medication is relatively safe and rarely causes hypoglycemia. There have been concerns that GLP-1 may 
cause pancreatitis; however, a recent meta-analysis suggests this is not so [43]. There are also data from 
rodent studies suggesting that GLP-1 agonists are associated with an increased risk of thyroid C-cell 
hyperplasia and C-cell tumors; however, data from clinical trials have not demonstrated a causal association 
between GLP-1 agonists and thyroid C-cell pathology [44]. To address the concerns regarding the risk 
pancreatitis and/or thyroid cancer associated with GLP-1 agonists, potential participants with abnormal levels 
of pancreatic enzymes, those at risk for pancreatitis, and those with personal and/or family history of thyroid C- 
cell tumor will be excluded from participation in this study. It is also possible that exenatide may not be 
tolerated well by the study population. This is unlikely, given that the exenatide is generally well tolerated. If a 
participant does not tolerate exenatide, subsequent dose of exenatide will not be administered and the 
participant will be replaced. 
Recruitment. Critical to any clinical study is recruitment of sufficient numbers of participants. We anticipate no 
difficulty recruiting the required sample size. As noted in the Background section, cigarette smoking is a 
common problem. Retention. Should dropout be a problem we will increase subject payment which will 
increase retention. 
 
F. Interpretation and Potential Importance of Findings 
The objective of this early-phase project is to estimate the probability that the proposed treatment 
(exenatide) confers a clinically relevant level of benefit in treating nicotine dependence. If our hypotheses are 
confirmed, the results of this early-phase project would provide strong preliminary data in support of a definitive 
follow-up study. In a follow-up study we would assign subjects to placebo and exenatide with quit dates at 2 
and 6 weeks of treatment to determine the onset of clinical effects. We would then increase the study duration 
to at least 12 weeks. This would enable us to clarify the length of time needed to achieve the therapeutic levels 
and would provide a clearer test of efficacy. We will also examine the mediating effects of craving and 


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withdrawal symptoms on abstinence, which would elucidate the mechanisms by which GLP-1 agonists 
enhance smoking abstinence. 
Overall, there are at least three aspects of this study that are highly important: 
1) This is the first clinical study to evaluate exenatide as potential treatment for nicotine dependence. If this 
treatment is effective, it could represent a new approach to assist smoking cessation. In addition, because 
exenatide is unrelated to other smoking cessation therapies, it could be combined with other treatments, 
such as NRT or varenicline, to create an effective “quit package”. 
2) If exenatide is effective as treatment for nicotine dependence, smokers with or at risk for DM would require 
only one treatment modality for glucose control and smoking cessation. 
3) Given that fear of weight gain is a frequent reason for smokers’ reluctance to quit [57] treatment with 
exenatide may represent an integrated approach to smoking cessation and post-cessation weight gain in 
overweight smokers. 


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