Abuse Liability of Reduced Nicotine Content Cigarettes in the Context of Concurrent E-Cigarette Use

Study Overview
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Brief Summary
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Three hundred-twenty (320) adult smokers of menthol or non-menthol combustible cigarettes will be recruited and randomly assigned to one of five groups (n=64/group), who will be asked to switch for 12 weeks to ad libitum use of combustible cigarettes (matched to subjects' menthol preference) containing either 0.4, 1.4, 2.5, 5.6 or 16.9 mg nicotine (standardized nicotine yields ranging from 0.02-0.80 mg/cigarette), respectively. Each group will include 32 heavy (≥ 20 cigarettes/day), and 32 light smokers (≤10 cigarettes/day), who are hypothesized to be more sensitive to nicotine's reinforcing effects. Participants will also have free access to nicotine-containing e-cigarettes (JUUL) throughout the 12-week period. Abuse liability of combustible cigarettes will be assessed by behavioral (cigarettes/day, time to first cigarettes), self-report (rewarding effects, withdrawal symptoms) and biochemical indices (expired air carbon monoxide, cotinine blood sampling). In laboratory sessions, we will measure nicotine thresholds for detecting and recognizing the addictive, rewarding effects of smoking. This study is designed to help the FDA identify a target nicotine threshold that will not attract young people to smoking or induce relapse in former smokers. Additionally, we will determine the level of cigarette nicotine reduction that will be tolerated without inducing dissatisfaction in smokers, information that is relevant to the FDA for designing a stepwise nicotine reduction policy that can be implemented without widespread objections. The knowledge gained from this project will greatly increase our knowledge of nicotine addiction and will help frame an FDA policy relating to the regulation of the nicotine content of tobacco. Ultimately, a well-designed nicotine reduction policy has the potential to greatly reduce the enormous toll of death and disease caused by cigarette smoking.

Official Title
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Abuse Liability of Reduced Nicotine Content Cigarettes in the Context of Concurrent E-Cigarette Use

Conditions
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Nicotine Addiction, Cigarette Smoking

Intervention / Treatment
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* Drug: Smoking research cigarettes with e-cigarette
* Drug: Nicotine discrimination thresholds


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject is healthy as judged by the Investigator based on all available assessments from the Screening Period (e.g., safety laboratory, vital signs, physical examination, ECG, concomitant medications and medical history). Subject smokes on average four days a week for the last 12 months. Subject has no intention of quitting smoking within the next 90 days. Owns a smart phone with text message and data capabilities. Willingness to use and ability to operate e-cigarettes. Willingness to smoke Research Cigarettes. Exclusion Criteria: Any medical or psychiatric condition (or associated symptoms or medications) determined by a medical professional to be severe enough to be disruptive to the study. Severe or uncontrolled psychiatric disease with the exception of anxiety disorders, obsessive-compulsive disorder (OCD) and attention deficit hyperactivity disorder (ADHD); Pregnant or nursing (by self-report) or positive pregnancy test; Daily use of: Experimental (investigational) drugs that are unknown to subject; Smokeless tobacco (chewing tobacco, snuff), cigars, pipes and hookah; e-cigarettes; Use in the past 30 days of nicotine replacement therapy or other smoking cessation product Positive drug screen for cocaine

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 65 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 0.40mg Nicotine Cigarette w/ e-Cigarette<br>Participants will be assigned to smoke 0.40mg nicotine Spectrum cigarettes for 12 weeks with unlimited access to JUUL e-cigarettes. Smoking research cigarettes with e-cigarette | Drug: Smoking research cigarettes with e-cigarette<br>* Smoking research cigarettes with varying levels of nicotine with unlimited access to 15 mg/ml nicotine-containing e-cigarettes.<br>* Other names: JUUL e-Cigarette;|
| Active Comparator: 1.40mg Nicotine Cigarette w/ e-Cigarette<br>Participants will be assigned to smoke 1.40mg nicotine Spectrum cigarettes for 12 weeks with unlimited access to JUUL e-cigarettes. Smoking research cigarettes with e-cigarette | Drug: Smoking research cigarettes with e-cigarette<br>* Smoking research cigarettes with varying levels of nicotine with unlimited access to 15 mg/ml nicotine-containing e-cigarettes.<br>* Other names: JUUL e-Cigarette;|
| Active Comparator: 2.50mg Nicotine Cigarette w/ e-Cigarette<br>Participants will be assigned to smoke 2.50mg nicotine Spectrum cigarettes for 12 weeks with unlimited access to JUUL e-cigarettes. Smoking research cigarettes with e-cigarette | Drug: Smoking research cigarettes with e-cigarette<br>* Smoking research cigarettes with varying levels of nicotine with unlimited access to 15 mg/ml nicotine-containing e-cigarettes.<br>* Other names: JUUL e-Cigarette;|
| Active Comparator: 5.60mg Nicotine Cigarette w/ e-Cigarette<br>Participants will be assigned to smoke 5.60mg nicotine Spectrum cigarettes for 12 weeks with unlimited access to JUUL e-cigarettes. Smoking research cigarettes with e-cigarette | Drug: Smoking research cigarettes with e-cigarette<br>* Smoking research cigarettes with varying levels of nicotine with unlimited access to 15 mg/ml nicotine-containing e-cigarettes.<br>* Other names: JUUL e-Cigarette;|
| Active Comparator: 16.9mg Nicotine Cigarette w/ e-Cigarette<br>Participants will be assigned to smoke 16.9mg nicotine Spectrum cigarettes for 12 weeks with unlimited access to JUUL e-cigarettes. Smoking research cigarettes with e-cigarette | Drug: Smoking research cigarettes with e-cigarette<br>* Smoking research cigarettes with varying levels of nicotine with unlimited access to 15 mg/ml nicotine-containing e-cigarettes.<br>* Other names: JUUL e-Cigarette;|
| Experimental: Halo G6 & Tribeca e-liquid<br>Difference detection assessments. Nicotine discrimination thresholds | Drug: Nicotine discrimination thresholds<br>* Measure of nicotine thresholds for detecting and recognizing the addictive, rewarding effects of smoking.<br>* Other names: Halo G6 with Tribeca e-liquid;|
| Experimental: Spectrum Research Cigarette<br>Difference detection assessments. Nicotine discrimination thresholds | Drug: Nicotine discrimination thresholds<br>* Measure of nicotine thresholds for detecting and recognizing the addictive, rewarding effects of smoking.<br>* Other names: Halo G6 with Tribeca e-liquid;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Expired air CO Measurement | To determine the effects of cigarette nicotine content manipulations on abuse liability as measured by exhaled breath CO. | 12 Weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nicotine discrimination tests to determine nicotine detection thresholds | Results of the laboratory discrimination tests will be analyzed descriptively to determine nicotine detection thresholds. Thresholds will be calculated based on both group-averaged data as well as by using the best estimates of individual thresholds calculated from each smoker's data. Group averaged data will be determined by graphically plotting the overall percent correct against nicotine concentration. | Weeks 1, 2,8,10,12 and 14 | 
| Nicotine discrimination tests to determine nicotine recognition thresholds | Results of the laboratory discrimination tests will be analyzed descriptively to determine nicotine recognition thresholds. Thresholds will be calculated based on both group-averaged data as well as by using the best estimates of individual thresholds calculated from each smoker's data. Group averaged data will be determined by graphically plotting the overall percent correct against nicotine concentration. | Weeks 1, 2,8,10,12 and 14 | 
| Extent of e-cigarette use based on self-report | To determine whether the abuse liability of combustible cigarettes is related to the nicotine intake from e-cigarettes or to total nicotine intake, regression analyses will be conducted to correlate indices of abuse liability to levels of cotinine as well as to the estimated intake of nicotine from cigarettes and e-cigarettes based on self-reported values. | 12 Weeks | 
| Extent of e-cigarette use based on self-report cotinine levels | To determine whether the abuse liability of combustible cigarettes is related to the nicotine intake from e-cigarettes or to total nicotine intake, regression analyses will be conducted to correlate indices of abuse liability to levels of cotinine as well as to the estimated intake of nicotine from cigarettes and e-cigarettes. | 12 Weeks | 
| Mean number of research cigarettes smoked per day as primary index of abuse liability | To assess the effects of cigarette nicotine content on abuse liability among smokers who also use e-cigarettes. The primary index of abuse liability will be mean number of research cigarettes smoked per day. Secondary outcome measures comprise expired air carbon monoxide (CO), Fagerström Test for Nicotine Dependence (FTND) score, withdrawal symptoms and cognitive performance. | 12 Weeks |