Brain Imaging in Tobacco Smokers During a Quit Attempt

Study Overview
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Brief Summary
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The proposed study will help fill gaps in existing research by determining if nicotine-dependent cigarette smokers show changes in α7 nicotinic acetylcholine receptor (nAChR) availability when compared to matched historical controls using positron emission tomography (PET) imaging and the radioactive ligand [18F]-ASEM (3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6 [18F]fluorodibenzo[b,d]thiophene 5,5-dioxide), an α7 nAChR antagonist. The study will also explore whether α7 nAChR availability influences clinically relevant measures of tobacco abstinence (e.g., withdrawal and craving, cognitive impairment), self-reported cigarettes per day, and time to relapse during an 8-day quit attempt during which smokers can receive escalating payments contingent upon providing objective evidence (breath CO and urinary cotinine) of smoking abstinence.

Detailed Description
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The primary objective of this basic clinical research study is to examine the role of the alpha7-nicotinic acetylcholine receptors (nAChRs) in tobacco use disorder. nAChRs are the primary site of action for nicotine (the main psychoactive component of tobacco). The most common types of nAChRs are heteromeric nAChRs containing beta2 subunits and homomeric nAChRs, which contain only alpha7 subunits. It is currently unknown if or how chronic tobacco use affects alpha7 nAChR in humans. The investigators' working hypothesis is brain alpha7 nAChR density associated with chronic nicotine exposure and the development of tobacco use disorder may be influence severity of tobacco craving and withdrawal during early smoking abstinence. Proposed group sample sizes are 18 tobacco smokers (accrual) and 18 nonsmokers (drawn from historical and contemporary controls in ongoing studies). Media-recruited male and female heavy smokers will be assessed for study inclusion/exclusion criteria using a structured diagnostic interview and a standard battery of instruments, as well as a medical exam to determine general health. Study candidates also provide breath and urine samples to determine biomarkers of tobacco use (breath carbon oxide and urinary cotinine levels), other drug use (breath alcohol and urine toxicology) and for females a pregnancy test. To ensure there are a sufficient number of subjects, 60 subjects will be screened for study eligibility and assessed for matching criteria (age, race and sex). Groups (smokers vs. non-smokers) will include equal numbers of males and females. In addition, male and female smokers will be matched for tobacco use disorder severity using symptom counts (DSM 5). Eligible subjects will be enrolled in an outpatient protocol completed at the Behavioral Pharmacology Research Unit (BPRU) at the Johns Hopkins Bayview Medical Center, and at the Johns Hopkins Hospital (JHH) PET imaging Center. Abstinent smokers (as verified by CO and cotinine, see below) will complete an magnetic resonance imaging (MRI) scan and a PET scan with the alpha-7 nAChR radiotracer [18F]-ASEM. Matched historical controls will have completed the MRI and PET scans previously. Tobacco users will receive contingency management incentive payments for verified smoking abstinence (Intervention 2, behavioral counseling). Smokers will continue in the study after the PET scan and complete an 8-day practice quit attempt. To evaluate smoking abstinence and lapse behavior, smokers will be asked to complete study six visits with a practice quit attempt. Smoker will receive the incentive intervention for smoking abstinence. At each visit, smokers will provide carbon monoxide (CO) and urine samples, and complete assessment instruments to self-report on daily symptoms of nicotine withdrawal and craving, and number of cigarettes smoked. The incentive intervention is a validated, established intervention for smoking cessation. At each visit, smokers will receive escalating incentive payments contingent upon provision of samples that meet study defined abstinence criteria. The incentive earning schedule starts at $9 on day 1 of abstinence and increases by $1.50 for each day of verified abstinence to $19.50 on day 8. To boost the incentive for abstinence, provision of samples that meet bonus abstinence (cotinine <100 ng/ml day 8) results additional $10 or $20 bonus payments. The incentive earnings schedule includes allowance for a slip, and a reset contingency to allow smokers to retry the quit attempt and complete the study. This incentive earnings schedule with resets is of high magnitude to reinforce abstinence, and increase participant retainment. The number of days in the quit attempt (8) yields a sufficient sample to examine both withdrawal and biomarkers (CO and cotinine) to quantify number of days in which use of any nicotine occurred vs. days participants were compliant in maintaining abstinence. These data will be utilized to explore the relationship of alpha7-nAChR availability to these clinically meaningful measures of tobacco use and abstinence.

Official Title
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Brain Imaging of Nicotinic Acetylcholine Receptors in Tobacco Users and Nonusers

Conditions
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Tobacco Use Disorder, Tobacco Smoking

Intervention / Treatment
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* Drug: [F18]-ASEM (3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-[18F]fluorodibenzo[b,d]thiophene 5,5-dioxide)
* Behavioral: Contingency Management


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must be healthy volunteers Regular tobacco smokers for a period of 2 or more years Positive breath carbon monoxide (CO) Cotinine positive urine test Meet DSM-V criteria for tobacco use disorder. Exclusion Criteria: Meets DSM-5 criteria for alcohol use disorder or substance use disorder (excluding tobacco use disorder) Meets DSM-5 Psychiatric Disorder; in or in need of treatment History of seizures, seizure disorder or closed head trauma HIV positive Weight > 350 lbs < 5th grade reading level Recent use of smoking cessation products If female: pregnant, lactating, planning pregnancy; positive urine pregnancy screen Any condition which would preclude MRI Radiation exposure in the last year that when combined with the study protocol would exceed the annual limits.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: [F18]-ASEM + Contingency Management<br>PET radiopharmaceutical 3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6 [18F]fluorodibenzo[b,d]thiophene 5,5-dioxide with incentive payments. | Drug: [F18]-ASEM (3-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-6-[18F]fluorodibenzo[b,d]thiophene 5,5-dioxide)<br>* Brain imaging of alpha-7 nicotinic acetylcholine receptors<br>* Other names: [F18]-ASEM;Behavioral: Contingency Management<br>* Incentive payments contingent upon provision of samples that meet criterion levels of exhaled carbon oxide and urinary cotinine at study visits<br>* Other names: Incentive payments;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Distribution volume (VT) as determined by [18F]-ASEM PET scan | Distribution volume (VT) in volumes of interest (VOI) in tobacco smokers, compared to VT in same volumes of interest from historical healthy control nonsmokers. VOI are cingulate, hippocampus, frontal cortex, amygdala, and ventral striatum. VOI are defined via each individual subject's Magnetic Resonance Imaging for anatomical identification of the VOI for alignment with PET images. | 1 day | 
| Total withdrawal score on the Minnesota Nicotine Withdrawal Scale (MNWS) | Self-report form has a 15-item list of symptoms where subjects rate subjects' symptoms severity on a scale of 0-4. Validated symptoms for tobacco withdrawal in smokers will be used for the study to quantify total withdrawal symptoms at baseline (smoking as usual), when compared to symptoms over Visits 1-6 during the quit period. Maximum score for validated symptoms is 36. | 2 weeks | 
| Craving/Urge to smoke as determined via the Questionnaire of Subjective Urges (QSU) | The QSU is a 10-item questionnaire to measure craving/urges to smoke. For each item, subjects rate how strongly the subject feel right now on a Likert scale ranging from 1 (strongly disagree) to 7 (strongly agree). Items are summed to yield two factor scores, Factor 1 Intention/desire to smoke (maximum score =35), and Factor 2: Relief of negative affect and Urgent desire to smoke (maximum score=35). QSU is collected at baseline (smoking as usual) and Visits 1-6 during the quit period. | 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Cigarettes smoked per day | Self-reported number of cigarettes smoked daily using a calendar-based time line method for past 90-days (i.e., time line follow back method) when smoking as usual. Average cigarettes per day from the 90-days will be compared to cigarettes reported for visits 1-6 during the quit attempt. | 3 months | 
| Number of days of smoking abstinence | Number of days abstinent will be determined from counting number of CO-and cotinine-verified abstinence days. Abstinence will be defined as negative breath carbon oxide (CO)6ppm or lower AND urinary cotinine decreased by 25 percent from prior sample or <100 ng/ml. | 2 weeks | 
| Negative mood as determined by the Positive and negative affect scale (PANAS) | Consists of two 10-item mood scales to provide independent measures of positive and negative affect. Maximum score for negative affect subscale = 10. Scores for negative affect subscale when smoking as usual, will be compared to days of CO and/or cotinine verified abstinence. | 2 weeks | 
| Attention as assessed by Connors continuous performance task | In this computerized task, a stimuli are presented, and subjects are instructed to respond as fast as possible to a specific target stimuli (X) and refrain from responding to more rarely occurring non-target stimuli (non-X). Inattention is indicated by high numbers of omissions and long reaction times. Omissions result from the failure to respond to target letters (i.e., non-Xs); omissions and reaction times when smoking as usual will be compared to those on visits 1-6 during the quit attempt abstinence days. | 2 weeks | 
| Performance on the Paced Serial Addition Task (PASAT) | The number of correct responses for each trial of the Paced Serial Addition Task (PASAT); Involves presenting a series of single digit numbers where the two most recent digits must be summed. The participant must respond prior to the presentation of the next digit for a response to be scored as correct. The number of correct responses for each trial (maximum = 60). | 2 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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smoking cessation, neuroimaging, nicotinic acetylcholine receptors, abstinence