Clinical Pharmacology of Electronic Cigarettes

Study Overview
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Brief Summary
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The purpose of this study is to learn more about nicotine exposure and the safety of electronic cigarettes (EC). It will focus on the areas that are thought to most closely relate to the addictive potential of EC, namely: (1) EC as nicotine delivery devices, covering issues of nicotine intake and pharmacokinetics, temporal patterns of use and titration of nicotine; and (2) subjective effects of EC use, including relationship of use to reward, withdrawal and craving.

Detailed Description
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Electronic cigarettes (EC) are nicotine delivery devices that generate a nicotine-containing aerosol which is inhaled by the user. EC are perceived by users to be useful in helping quitting smoking of conventional tobacco cigarettes (TC) as well as having a presumed lower risk of adverse health effects compared to TC, the potential for use in public places, reduced cost, and lack of the noxious clinging odors associated with TC use. Many believe that electronic cigarette (EC) function as nicotine delivery devices in the same way as tobacco cigarettes (TC), and that EC will prove to be just as addictive as TC, but this may not be the case because of fundamental differences in the design and method of use of these products. Investigators hypothesize that systemic nicotine exposure will be lower with EC compared to TC; that despite lower nicotine intake EC users will experience similar reward and no greater withdrawal symptoms or craving compared to TC; and that dual EC/ TC users will not titrate their daily intake of nicotine in the same way that TC smokers of high- vs low-yield nicotine TC do. Investigators specifically focus on the areas that are thought to most closely relate to the addictive potential of EC, namely: (1) EC as nicotine delivery devices, covering issues of nicotine intake and pharmacokinetics, temporal patterns of use and titration of nicotine; and (2) subjective effects of EC use, including relationship of use to reward, withdrawal and craving. The investigators will also examine aspects of safety of EC use (by assessment of cardiovascular and hormonal effects of use and of biomarkers of exposure to potentially toxic constituents) and explore the identification and validation of biomarkers that may be useful in distinguishing EC from TC use. Study subjects will be dual users of TC and EC so that the investigators may compare both modalities of use in experienced users in a within-subject design. The study will consist of two 1-week blocks (EC-only or TC-only conditions) with 4 days of outpatient ad libitum product use followed by 3 days in a clinical research ward to include a single-use pharmacokinetic study, monitoring of product use, subjective assessments, blood and urine collections to assess biomarkers, and a 24-hour period of cardiovascular monitoring. Two additional days at the end of the 2nd block will assess similar measurements during a period of nicotine-product abstention.

Official Title
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Clinical Pharmacology of Electronic Cigarettes

Conditions
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Nicotine Dependence

Intervention / Treatment
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* Device: Tobacco Cigarette
* Device: Electronic Cigarette


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy on the basis of medical history and limited physical examination as described below: Heart rate < 105 BPM* Systolic Blood Pressure < 160 and > 90* Diastolic Blood Pressure < 100 and > 50* Body Mass Index ≤ 38.0 *Considered out of range if both machine and manual readings are above/below these thresholds. Current regular dual user of both EC and conventional TC EC device is one of the most popular 1st, 2nd or 3rd generation brands (with the exception of rebuildable atomizers) as determined at time of study commencement Carbon monoxide ≥ 5 ppm or per discretion of Principal Investigator Saliva cotinine ≥50 ng/ml or urine cotinine Age: ≥ 21 years Exclusion Criteria: Current regular use of selected psychiatric medications Current regular use of cardiovascular medications for cardiovascular conditions including hypertension (Example: beta and alpha-blockers) Current regular use of medications inducers of nicotine metabolizing enzymes CYP2A6 (Example: rifampicin, dexamethasone, phenobarbital, and other anticonvulsant drugs). Use of other tobacco products Pregnancy or breastfeeding (by history and pregnancy test) Concurrent use of nicotine-containing medications Drug/Alcohol Dependence Positive toxicology test at the screening visit (THC okay) Concurrent participation in another clinical trial Inability to communicate in English Planning to quit smoking within the next 60 days

Ages Eligible for Study
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Minimum Age: 21 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: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: EC Block1/TC Block 2<br>Participants will be randomized into one of two groups. In this group, participants will be assigned to Electronic Cigarettes only for Study Block #1, then crossover to Tobacco Cigarettes only for Study Block #2. | Device: Tobacco Cigarette<br>* Usual brand tobacco cigarette smoked by study participant.<br>* Other names: TC, Cigarette;Device: Electronic Cigarette<br>* Usual brand electronic cigarettes smoked by study participant.<br>* Other names: EC, E-cig, E-cigarette;|
| Active Comparator: TC Block 1/EC Block 2<br>Participants will be randomized into one of two groups. In this group, participants will be assigned to Tobacco Cigarettes only for Study Block #1, then crossover to Electronic Cigarettes only for Study Block #2. | Device: Tobacco Cigarette<br>* Usual brand tobacco cigarette smoked by study participant.<br>* Other names: TC, Cigarette;Device: Electronic Cigarette<br>* Usual brand electronic cigarettes smoked by study participant.<br>* Other names: EC, E-cig, E-cigarette;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Standardized Session: Mean CMax | Maximum Plasma Nicotine Concentration (Cmax) (ng/mL) | Inpatient Day 1, Up to 4 Hours post Nicotine Administration | 
| Standardized Session: Mean TMax | Time (min) when Max Plasma Nicotine Concentration was achieved | Inpatient Day 1, Up to 4 Hours post Session | 
| Standardized Session: AUC 0-240 | Plasma Nicotine area-under-the curve from 0 to 4 Hours (min*ng/ml) | Inpatient Day 1, Up to 4 Hours post Session | 
| PK-estimated Nicotine Dose | Estimated in dose received (in milligrams) during the Standardized Session. | Inpatient Day 1, Up to 4 Hours post Session | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Standardized Session: QSU Factor 1 (Vaping) | Questionnaire for Smoking Urges Brief modified for e-cigarettes to measure urge to vape.Two factor scores and a total score were derived. Factor 1 represents the desire and intention to smoke with smoking perceived as rewarding, while Factor 2 represents an anticipation of relief from negative effect with an urgent desire to smoke.Scores range from 5 to 35 with higher scores indicating a higher level of craving. | Inpatient Day 1, Up to 4 Hours post Session | 
| Standardized Session: Positive and Negative Affect Score (Negative Affect) | The PANAS Scale or Positive and Negative Affect Schedule (PANAS) is a self-report questionnaire. PANAS, (Sandín et al., 1999; Watson, Clark & Tellegen, 1988).This instrument is composed of 20 items: 10 items measuring positive affective states and 10 items measuring negative affect states.This subscale measures a person's negative emotions. Scores range from 10- 50 with higher scores indicating stronger negative feelings. | Inpatient Day 1, Up to 4 Hours post Session | 
| Standardized Session: Minnesota Nicotine Withdrawal Scale | Minnesota Nicotine Withdrawal Scale (MNWS) is a Self-Report Scale for measuring the severity of nicotine withdrawal symptoms.The possible range of scores for the 12-Item MNWS is between 0 and 48 with higher scores indicated greater withdrawal symptom severity. | Inpatient Day 1, Up to 4 Hours post Session | 
| Standardized Session: QSU Factor 2 (Vaping) | Questionnaire for Smoking Urges Brief modified for e-cigarettes to measure urge to vape.Two factor scores and a total score were derived. Factor 1 represents the desire and intention to smoke with smoking perceived as rewarding, while Factor 2 represents an anticipation of relief from negative effect with an urgent desire to smoke. Scores range from 5 to 35 with higher scores indicating a higher level of craving. | Inpatient Day 1, Up to 4 Hours post Session | 
| Standardized Session: QSU Factor 1 (Smoking) | Questionnaire for Smoking Urges Brief measures urge to smoke.Two factor scores and a total score were derived. Factor 1 represents the desire and intention to smoke with smoking perceived as rewarding, while Factor 2 represents an anticipation of relief from negative effect with an urgent desire to smoke. Scores range from 5 to 35 with higher scores indicating a higher level of craving. | Inpatient Day 1, Up to 4 Hours post Session | 
| Standardized Session: QSU Factor 2 (Smoking) | Questionnaire for Smoking Urges Brief measures urge to smoke.Two factor scores and a total score were derived. Factor 1 represents the desire and intention to smoke with smoking perceived as rewarding, while Factor 2 represents an anticipation of relief from negative effect with an urgent desire to smoke. Scores range from 5 to 35 with higher scores indicating a higher level of craving. | Inpatient Day 1, Up to 4 Hours post Session |