Study to Investigate the Nicotine Pharmacokinetic Profiles and Pharmacodynamic Effects of P4M3 Variants

Study Overview
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Brief Summary
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This is a single-center, open-label, concentration-ranging study to evaluate the nicotine PK profile and PD effects in healthy adult experienced users of closed tank/cartridge e-cigarettes using four different variants of P4M3 (nicotine concentration of 1.7%, 1.7% with 1.1% lactic acid [LA], 3% with 1.1% LA, and 4% with 2% LA) or their own e-cigarettes.

Detailed Description
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The goal of the study is to evaluate the nicotine concentration profiles and derived PK parameters, subjective effects, behavioral parameters, including puffing topography parameters of P4M3 with four different variants of P4M3, in experienced e-cigarette users after a single-use experience with fixed puffing regime and after ad libitum use of P4M3. Four variants of P4M3 will be evaluated together with subjects' own e-cigarettes to evaluate the relationship between the e-liquid composition (nicotine concentrations and presence of lactic acid) and the amount of nicotine absorbed, the speed of absorption, and the puffing topography.

Official Title
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A Single-center, Open-label, Concentration-ranging Study to Investigate the Nicotine Pharmacokinetic Profiles and Pharmacodynamic Effects of the P4M3 Variants

Conditions
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Vaping, Nicotine Absorption

Intervention / Treatment
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* Other: E-cigarette
* Other: P4M3-1.7%
* Other: P4M3-1.7%LA
* Other: P4M3-3%LA
* Other: P4M3-4%LA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject has signed the informed consent form (ICF) and is able to understand the information provided in the ICF. Subject is 21 to 65 years of age, inclusive, at the Screening Visit. Subject is a former daily cigarette smoker who smoked at least 100 cigarettes or more in his/her life and ceased smoking at least 3 months prior to the Screening Visit. Subject has been using a commercially available, nicotine-containing closed tank/cartridge e-cigarette daily for at least 3 months prior to the Screening Visit. Subject has a urine cotinine test ≥200 ng/mL at the Screening Visit and Admission. Exclusion Criteria: Subject has a clinically relevant disease which requires medication which as per the judgment of the Investigator would jeopardize the safety of the subject. Subject has abnormal renal function test result or subject with a creatinine clearance <60 mL/minute at the Screening Visit, confirmed on repeat testing. Subject has elevated liver function test results at the Screening Visit. Subject has bilirubin >1.5X ULN at the Screening Visit. Subject has FEV1/FVC <0.7 and FEV1 <80% predicted value at post-bronchodilator spirometry at the Screening Visit. Subject has asthma condition at the Screening Visit. Subject has received medication within 14 days or within 5 half-lives of the drug (whichever is longer) prior to Admission, which has an impact on cytochrome P450 (CYP) 2A6 activity. Subject has a carbon monoxide (CO) breath test ≥ 10 ppm at the Screening Visit or Admission. Subject has a body mass index (BMI) <18.5 kg/m2 or BMI ≥35 kg/m2 at the Screening Visit. Subject has a positive serology test for human immunodeficiency virus (HIV) 1/2, hepatitis B, or hepatitis C at the Screening Visit. Subject has clinically significant ECG findings at the Screening Visit. Subject has participated in a clinical study within 3 months prior to the Screening Visit. Subject smokes cigarettes or uses other tobacco products. Female subject of childbearing potential who is pregnant or breastfeeding. Female subject of childbearing potential who does not agree to use an acceptable method of effective contraception..

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Product Exposure Sequence 1<br>Subjects will be randomized to follow a sequence of product exposure comprised of : Subject's own e-cigarette; P4M3-1.7%; P4M3-1.7%LA; P4M3-3%LA; and P4M3-4%LA | Other: E-cigarette<br>* Subject's own e-cigarette<br>Other: P4M3-1.7%<br>* P4M3 e-liquid concentration of 1.7% nicotine without lactic acid<br>Other: P4M3-1.7%LA<br>* P4M3 e-liquid concentration of 1.7% nicotine with lactic acid<br>Other: P4M3-3%LA<br>* P4M3 e-liquid concentration of 3% nicotine with lactic acid<br>Other: P4M3-4%LA<br>* P4M3 e-liquid concentration of 4% nicotine with lactic acid<br>|
| Experimental: Product Exposure Sequence 2<br>Subjects will be randomized to follow a sequence of product exposure comprised of : Subject's own e-cigarette; P4M3-1.7%LA; P4M3-1.7%; P4M3-3%LA; and P4M3-4%LA | Other: E-cigarette<br>* Subject's own e-cigarette<br>Other: P4M3-1.7%<br>* P4M3 e-liquid concentration of 1.7% nicotine without lactic acid<br>Other: P4M3-1.7%LA<br>* P4M3 e-liquid concentration of 1.7% nicotine with lactic acid<br>Other: P4M3-3%LA<br>* P4M3 e-liquid concentration of 3% nicotine with lactic acid<br>Other: P4M3-4%LA<br>* P4M3 e-liquid concentration of 4% nicotine with lactic acid<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Nicotine Concentration Versus Time Profile | To measure total and background-corrected plasma nicotine concentration versus time profiles from 60 minutes of ad libitum use. | From Day -1 (baseline) to Day 4 | 
| Peak Plasma Nicotine Concentration [cCpeak] | To measure background-corrected peak plasma nicotine concentration [cCpeak] from 60 minutes of ad libitum use. | From Day -1 (baseline) to Day 4 | 
| Time to Peak Plasma Nicotine Concentration [Tpeak] | To measure the time to peak plasma nicotine concentration [tpeak] from 60 minutes of ad libitum use. | From Day -1 (baseline) to Day 4 | 
| Background-corrected Trough Plasma Nicotine Concentration [cCtrough] | To measure background-corrected trough plasma nicotine concentration [cCtrough] from 60 minutes of ad libitum use. | From Day -1 (baseline) to Day 4 | 
| Background-corrected Average of Plasma Nicotine Concentration [cCaverage] | To measure background-corrected average of plasma nicotine concentration between 0 to 1 hour [cCaverage] from 60 minutes of ad libitum use. | From Day -1 (baseline) to Day 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total and Background-corrected Plasma Nicotine Concentration Versus Time Profiles | To measure the total and background-corrected plasma nicotine concentration versus time profiles of the P4M3 variants and subjects' own e-cigarette from the fixed puffing regimen. | From Day -1 (baseline) to Day 4 | 
| Background-corrected Maximum Plasma Concentration [cCmax] | To measure the background-corrected maximum plasma concentration [cCmax] of the P4M3 variants and subjects' own e-cigarette from the fixed puffing regimen. | From Day -1 (baseline) to Day 4 | 
| Time to the Maximum Concentration [Tmax] | To measure the time to the maximum concentration [tmax] of the P4M3 variants and subjects' own e-cigarette from the fixed puffing regimen. | From Day -1 (baseline) to Day 4 | 
| Background-corrected Area Under the Concentration-time Curve [cAUC(0-4h)] | To measure the background-corrected area under the concentration-time curve, which is above the corrected baseline from the start of product use to 4 hours [cAUC(0-4h)], of the P4M3 variants and subjects' own e-cigarette from the fixed puffing regimen. | From Day -1 (baseline) to Day 4 | 
| Subjective Effects of P4M3 Use | Measured with an adapted version of the modified Cigarette Evaluation Questionnaire (adapted mCEQ) within 60 minutes after the ad libitum use session. Assessed on a 7-point scale, ranging from 1 (not at all) to 7 (extremely). | From Day -1 (baseline) to Day 4 | 
| Area Under the Curve of Craving for an Electronic Cigarette | Measured on a Visual Analogue Scale (VAS) of 0 (no craving) to 100 (strong craving), before and after the fixed puffing regimen and ad libitum use period. (The VAS craving was measured from 0 to 100 on a 100 mm scale.) The data below present the Area under the VAS craving score-time curve from the start of product use to 4 hours. The area under the curve for VAS craving is an integrated measurement of the VAS craving taking into account several timepoints. AUC was calculated using a trapezoidal rule between timepoints without normalization. | From Day -1 (baseline) to Day 4 | 
| Sensory Parameters (Fixed Puffing Regimen) | Measured with a Sensory Questionnaire (SQ) within 60 minutes after each fixed puffing regimen use period. Response to each question is assessed on a 7-point scale, ranging from 1 (not at all) to 7 (extremely). | From Day 1 to Day 4 | 
| Sensory Parameters (ad Libitum Use) | Measured with a Sensory Questionnaire (SQ) within 60 minutes after each ad libitum use period. Response to each question is assessed on a 7-point scale, ranging from 1 (not at all) to 7 (extremely). | From Day 1 to Day 4 | 
| Human Puffing Topography (HPT) of the P4M3 Variants and the Subjects' Own E-cigarette | Total Puff Volume measured for the P4M3 variants and the subjects' own e-cigarette from the fixed puffing regimen and the 60 minutes ad libitum use. | From Day -1 (baseline) to Day 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nicotine-containing product, Alternative to cigarettes