Pharmacokinetics and Acute Effects of Multiple Dose of Nicotine: Electronic Cigarette and Cigarette

Study Overview
=================
Brief Summary
-----------------
The purposes of this study are 1) to determine the pharmacokinetics of nicotine after multiple dose administration by electronic cigarette and 2) to compare the acute effects of multiple dose of nicotine administrated by electronic cigarette compared with those obteined by cigarette.

Detailed Description
-----------------
Electronic cigarettes (e-cigarettes) are battery-operated devices that deliver nicotine via inhaled vapour or vaping. At present, e-cigarettes are becoming increasingly popular among smokers worldwide. However, knowledge about e-cigarette nicotine pharmacology remains limited. The aims of this study are 1) to determine the pharmacokinetics of nicotine after multiple dose administration by electronic cigarette and 2) to compare the acute effects of multiple dose of nicotine administrated by electronic cigarette compared with those obteined by cigarette.

Official Title
-----------------
Pharmacokinetics and Acute Effects of Multiple Dose of Nicotine Administered by Electronic Cigarette and Cigarette

Conditions
-----------------
Nicotine Use Disorder

Intervention / Treatment
-----------------
* Drug: Nicotine
* Drug: Nicotine


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Understanding and accepting the study procedures and signing the informed consent. Male adults volunteers (18-45 years old). Clinical history and physical examination demonstrating no organic or psychiatric disorders. The ECG and general blood and urine laboratory tests performed before the study should be within normal ranges. Minor or occasional changes from normal ranges are accepted if, in the investigator's opinion, considering the current state of the art, they are not clinically significant, are not life-threatening for the subjects and do not interfere with the product assessment. These changes and their non-relevance will be justified in writing specifically. Present use of nicotine without serious adverse reactions. Smokers ≥ 3 cigarettes/day. Exclusion Criteria: Having suffered any cardiovascular and/or respiratory disease in the three months prior to the study start. History of drug dependence (except for nicotine dependence). Daily consumption >4 standard units of ethanol. Regular use of any drug in the month prior to the study sessions. The treatment with single or limited doses of symptomatic medicinal products in the week prior to the study sessions will not be a reason for exclusion if it is calculated that it has been cleared completely the day of the experimental session. Having suffered any organic disease or major surgery in the three months prior to the study start. Blood donation 12 weeks before or participation in other clinical trials with drugs in the previous 12 weeks. History or clinical evidence of gastrointestinal, liver, renal or other disorders which may lead to suspecting a disorder in drug absorption, distribution, metabolism or excretion, or that suggest gastrointestinal irritation due to drugs. Subjects unable to understand the nature, consequences of the study and the procedures requested to be followed. Use of any drug or substance inhibitor of cytochrome P-450-1A6 (CYP1A6) (p.e. raloxifene, coumarins, etc)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
-----------------
Male

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

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

Design Details

Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Electronic cigarette<br>Multiple dose Nicotine 0.8 mg, administrated by electronic cigarette (10 puffs) + Nicotine 0.8 mg, administrated by electronic cigarette (10 puffs) separated by 60 minutes | Drug: Nicotine<br>* Multiple dose nicotine<br>* Other names: Nhoss®;|
| Active Comparator: Cigarette<br>Multiple dose Nicotine 0.8 mg, administrated by cigarette (10 puffs) + Nicotine 0.8 mg, administrated by cigarette (10 puffs) separated by 60 minutes | Drug: Nicotine<br>* Multiple dose nicotine<br>* Other names: Marlboro®;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-Time Curve (AUC 0-24h) | Calculation of AUC of the concentrations of nicotine and its metabolites in blood | From baseline (pre-dose, 0h) to 5, 15, 30, 45, 55, 65, 75, 90, 105, 120 and 24h post-dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Area Under the Concentration-Time Curve (AUC 0-24h) | Calculation of AUC of the concentrations of nicotine and its metabolites in urine | From baseline (pre-dose, 0h) to 55, 120 min, 6, 12 and 24h | 
| Area Under the Concentration-Time Curve (AUC 0-24h) | Calculation of AUC of the concentrations of nicotine and its metabolites in oral fluid | From baseline (pre-dose, 0h) to 15, 30, 45, 55, 65, 75, 90, 105, 120 min, 6, 12 and 24h | 
| Number of Participants with Serious and Non-Serious Adverse Events | Collection of adverse effects spontaneously reported by the participants and/or observed by the investigators | 2 days after each substance administration | 
| Elimination half-life | Calculation of elimination hal-life from concentrations of nicotine and its metabolites in plasma-blood, urine and oral fluid. | From baseline to 24h post-dose | 
| Changes in blood pressure | Measure of blood pressure (systolic and diastolic blood pressure) | From pre-dose (baseline) to 120 min post-dose | 
| Changes in heart rate | Measure of heart rate (pulse) | From pre-dose (baseline) to 120 min post-dose | 
| Changes in expired carbon monoxide (CO) aire | Measure of expired CO aire using a BreathCO monitor | From pre-dose (baseline) to 120 min post-dose | 
| Changes in pupil diameter | Measure of pupil diameter using a Haab pupil gauge | From pre-dose (baseline) to 120 min post-dose | 
| Changes in oral temperature | Measure of temperature in mouth using automatic thermometer | From pre-dose (baseline) to 120 min post-dose | 
| Changes in subjective effects | Subjective effects will be measured using rate scales (visual analogue scales) including measures of good effects and other feelings induced by nicotine | From pre-dose (baseline) to 120 min post-dose | 
| Changes in nicotine abstinence symptoms | Nicotine abstinence symptoms will be measured using rate scales (visual analogue scales) including items sensitive to nicotine effects | From pre-dose (baseline) to 120 min post-dose | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Nicotine, Electronic cigarette, Cigarette