Pharmacokinetics and Pharmacodynamics of Different Nicotine Salt Concentration Vape System Pods and Free-base Nicotine

Study Overview
=================
Brief Summary
-----------------
Comparison of the pharmacokinetics and pharmacodynamics of two different nicotine salt concentrations and free-base nicotine using an open vape pod system

Detailed Description
-----------------
On each study day, one puff will be taken with the assigned product every 30 seconds (total of 10 puffs). Blood samples will be collected to measure nicotine 15 minutes before vaping and 2, 5, 15, 30, 60, 120, and 180 minutes after the last puff. Heart rate and blood pressure will be measured 15 minutes before and 2, 10, 15, 30, 60, 120, and 180 minutes after the last puff. Post-use withdrawal, craving, reward, and satisfaction will be assessed 10 minutes and 1 and 3 hours after the last puff using the modified Minnesota Nicotine Withdrawal Scale (MNWS), the Tiffany Questionnaire on Smoking Urges (QSU), and the Positive and Negative Affect Schedule (PANAS) questionnaires. Respiratory symptoms will be assessed at baseline and 5 minutes after the last puff. Ten minutes post-use, the direct effects of the assigned product (e.g. satisfying, calming, pleasant, vape another one right now) will also be assessed using visual analog scales.

Official Title
-----------------
Randomized Crossover Study Comparing the Pharmacokinetics and Pharmacodynamics of Two Different Nicotine Salt Concentrations and Free-base Nicotine Using an Open Vape Pod System

Conditions
-----------------
Nicotine Dependence

Intervention / Treatment
-----------------
* Other: standardized vaping protocol


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Men or women, age 18 or older at screening, who have used electronic cigarettes and/or smoked at least 5 cigarettes per day in the past 30 days Saliva cotinine of > 50 ng/mL at screening No clinically significant findings on the physical examination at screening Ability to communicate well with the investigator and to understand and comply with the requirements of the study Women of child-bearing age: willingness of using a reliable contraception method during the study Signed informed consent Exclusion Criteria: Known hypersensitivity/allergy to a content of the e-liquid Pregnancy or breast feeding BMI < 18 or > 28 kg/m2 at screening History or clinical evidence of alcoholism or drug abuse within the 3-year period prior to screening Loss of ≥ 250 ml of blood within 3 months prior to screening, including blood donation Treatment with an investigational drug within 30 days prior to screening Treatment with prescribed or over-the-counter (OTC) medications with potential influence on CYP2A6 function within 1 week prior to screening (with the exception of contraception) History or clinical evidence of any disease (e.g. gastrointestinal tract-disease) and/or existence of any surgical or medical condition, which in the opinion of the investigator might interfere with the absorption, distribution, metabolism or excretion of the study drugs, or which might increase the risk for toxicity Legal incapacity or limited legal capacity at screening Any circumstances or conditions, which, in the opinion of the investigator, may affect full participation in the study or compliance with the protocol

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Participants will be switched in a within-subject crossover design among the three product types.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Nicotine salt 20 mg/mL<br>Vaping of nicotine salt e-liquids with a nicotine concentration of 20 mg/mL. | Other: standardized vaping protocol<br>* The following questionnaires will first be completed: Modified Minnesota Nicotine Withdrawal Scale, Tiffany Questionnaire on Smoking Urges-Brief total (global) craving score, Positive and Negative Affect Schedule. The assigned product will then be given to the participant, and one puff will be taken every 30 seconds (total of 10 puffs). Blood samples will be collected 15 minutes before vaping and 2, 5, 15, 30, 60, 120, and 180 minutes after the last puff. Heart rate and blood pressure will be measured 15 minutes before and 2, 10, 15, 30, 60, 120, and 180 minutes after the last puff. Post-use withdrawal, craving, reward, and satisfaction will be assessed 10 minutes and 1 and 3 hours after the last puff. Respiratory Symptoms will be assessed at baseline and 5 minutes after the last puff. Ten minutes post-use, the direct effects will also be assessed.<br>|
| Other: Nicotine salt 40 mg/mL<br>Vaping of nicotine salt e-liquids with a nicotine concentration of 40 mg/mL. | Other: standardized vaping protocol<br>* The following questionnaires will first be completed: Modified Minnesota Nicotine Withdrawal Scale, Tiffany Questionnaire on Smoking Urges-Brief total (global) craving score, Positive and Negative Affect Schedule. The assigned product will then be given to the participant, and one puff will be taken every 30 seconds (total of 10 puffs). Blood samples will be collected 15 minutes before vaping and 2, 5, 15, 30, 60, 120, and 180 minutes after the last puff. Heart rate and blood pressure will be measured 15 minutes before and 2, 10, 15, 30, 60, 120, and 180 minutes after the last puff. Post-use withdrawal, craving, reward, and satisfaction will be assessed 10 minutes and 1 and 3 hours after the last puff. Respiratory Symptoms will be assessed at baseline and 5 minutes after the last puff. Ten minutes post-use, the direct effects will also be assessed.<br>|
| Other: Free-base nicotine 20 mg/mL<br>Vaping of free-base nicotine e-liquids with a nicotine concentration of 20 mg/mL. | Other: standardized vaping protocol<br>* The following questionnaires will first be completed: Modified Minnesota Nicotine Withdrawal Scale, Tiffany Questionnaire on Smoking Urges-Brief total (global) craving score, Positive and Negative Affect Schedule. The assigned product will then be given to the participant, and one puff will be taken every 30 seconds (total of 10 puffs). Blood samples will be collected 15 minutes before vaping and 2, 5, 15, 30, 60, 120, and 180 minutes after the last puff. Heart rate and blood pressure will be measured 15 minutes before and 2, 10, 15, 30, 60, 120, and 180 minutes after the last puff. Post-use withdrawal, craving, reward, and satisfaction will be assessed 10 minutes and 1 and 3 hours after the last puff. Respiratory Symptoms will be assessed at baseline and 5 minutes after the last puff. Ten minutes post-use, the direct effects will also be assessed.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Nicotine Peak Plasma Concentration (Cmax) | Comparison of nicotine Cmax between groups | Blood samples collection: 15 minutes before and 2, 5, 15, 30, 60, 120, and 180 minutes after the last puff | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area under the plasma concentration versus time curve (AUC) | Comparison of the nicotine AUC between groups | Blood samples collection: 15 minutes before and 2, 5, 15, 30, 60, 120, and 180 minutes after the last puff | 
| Time at which the Cmax is observed (Tmax) | Comparison of the nicotine Tmax between groups | Blood samples collection: 15 minutes before and 2, 5, 15, 30, 60, 120, and 180 minutes after the last puff | 
| Elimination half-life (t1/2) | Comparison of t1/2 between groups | Blood samples collection: 15 minutes before and 2, 5, 15, 30, 60, 120, and 180 minutes after the last puff | 
| Genotyping of the hepatic cytochrome P450 enzyme CYP2A6 | CYP2A6 genotype (allele variants) | Blood sample collection during first session | 
| Nicotine metabolite ratio (NMR) | Nicotine clearance assessed using 3'-hydroxycotinine/cotinine ratios | Assessed at screening visit | 
| Modified Minnesota Nicotine Withdrawal Scale (MNWS) | Excluding items relating to sleep disturbance and constipation, including eight items (angry/irritable/frustrated, anxious/nervous, depressed mood/sad, desire or craving to smoke, difficulty concentrating, increased appetite/hungry, restless and impatient), rated on a 0=none to 4=severe scale | Baseline, 10 minutes and 1 and 3 hours after the last puff | 
| Tiffany Questionnaire on Smoking Urges-Brief (QSU) total (global) craving score | Mean of ten items, rated on a 1=strongly disagree to 7=strongly agree scale | Baseline, 10 minutes and 1 and 3 hours after the last puff | 
| Positive and Negative Affect Schedule (PANAS) | Including items assigned as Positive or Negative Affect (each score is the sum of ten items, rated on a 1=very slightly/not at all to 5=extremely scale) | Baseline, 10 minutes and 1 and 3 hours after the last puff | 
| Respiratory symptoms | Yes/no: shortness of breath, wheezing, cough, phlegm | At baseline and 5 minutes after the last puff | 
| Direct effects | E.g. satisfying, calming, pleasant, vape another one right now, assessed using visual analog scales (0-100 mm) with a single word scored from left (not at all) to right (extremely) | Ten minutes post-use | 
| Heart rate | Heart rate measurements (bpm) | 15 minutes before and 2, 10, 15, 30, 60, 120, and 180 minutes after the last puff | 
| Systolic blood pressure | Systolic blood pressure measurements (mmHg) | 15 minutes before and 2, 10, 15, 30, 60, 120, and 180 minutes after the last puff | 
| Diastolic blood pressure | Diastolic blood pressure measurements (mmHg) | 15 minutes before and 2, 10, 15, 30, 60, 120, and 180 minutes after the last puff | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
nicotine, pharmacokinetics, pharmacodynamics