Nicotine Pharmacokinetics and Pharmacodynamics, Safety and Tolerability of P3P

Study Overview
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Brief Summary
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This is a single-center, open-label, randomized, crossover study to evaluate the pharmacokinetic (PK) profiles of four P3P variants (differing in nicotine aerosol particle size, nicotine concentration and in the absence or presence of a flavoring system), following a fixed puffing regimen and an ad libitum use period. In addition, pharmacodynamic (PD) effects (subjective effects and related behavioral assessments), as well as human puffing topography, will be evaluated, to provide further insights on product safety, acceptance, and use.

Detailed Description
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The goal of the proposed study is to evaluate the pharmacokinetic profiles of four P3P variants. Variants with two different nicotine contents (1 mg/product and 2 mg/product), two different nicotine aersol particle sizes and presence/absence of a flavoring system will be tested to identify which one would yield plasma nicotine concentrations as close as possible to those achieved after smoking a single cigarette. All of the subjects will initially use the lowest nicotine content product (P3P 3). Subject will continue the study using the three remaining products (P3P 1, P3P 2 and P3P 4) containing 2 mg nicotine/product in a randomly assigned sequence. Two product use regimens: fixed puffing and ad libitum use will be applied to provide insight into nicotine absorption. The fixed puffing regimen with consistent use conditions across subjects will be applied in order to minimize variability. The 1 hour ad libitum use period will provide information on nicotine PK and product acceptance when subjects use the P3P according to their own puffing behavior which is closer to a real-world setting. Safety and tolerability will also be assessed throughout the study.

Official Title
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A Single-center, Open-label, Randomized, Crossover Study to Investigate the Nicotine Pharmacokinetic Profile, Pharmacodynamics, Safety and Tolerability of Four P3P Variants in Smoking Healthy Adult Subjects

Conditions
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Pharmacokinetics

Intervention / Treatment
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* Other: P3P 1
* Other: P3P 2
* Other: P3P 3
* Other: P3P 4


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 between 21 and 65 years old. Subject is Caucasian. Smoking, healthy subject as judged by the Investigator or designee based on available assessments from the screening period. Subject has been smoking at least 10 commercially available cigarettes per day at least for the last 4 weeks prior to Screening Visit. Smoking status will be verified based on a urinary cotinine test (cotinine ≥ 200 ng/mL). Subject has been smoking for at least the last 3 years prior to Screening Visit. Subject does not plan to quit smoking in the next 2 months after the Screening Visit. Exclusion criteria: Female subject is pregnant or breastfeeding. Female subject uses estrogen-containing hormonal contraception or hormone replacement therapy.

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: Crossover Assignment
Interventional Model Description: A single-center, open-label, randomized, crossover study.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Product Sequence 1<br>Subjects will be exposed to P3P 3 on day 1 of the study, then randomized to follow a sequence of product exposure comprised of: P3P 2 on Day 2; P3P 4 on Day 3; P3P 1 on Day 4 | Other: P3P 1<br>* 2 mg of nicotine; no flavor; nicotine powder particle size of 2.25 ± 0.2 μm<br>Other: P3P 2<br>* 2 mg of nicotine; flavor; nicotine powder particle size of 2.25 ± 0.2 μm<br>Other: P3P 3<br>* 1 mg of nicotine; flavor; nicotine powder particle size of 2.25 ± 0.2 μm<br>Other: P3P 4<br>* 2 mg of nicotine; flavor; nicotine powder particle size of 1.8 ± 0.2 μm<br>|
| Active Comparator: Product Sequence 2<br>Subjects will be exposed to P3P 3 on day 1 of the study, then randomized to follow a sequence of product exposure comprised of: P3P 4 on Day 2; P3P 1 on Day 3; P3P 2 on Day 4 | Other: P3P 1<br>* 2 mg of nicotine; no flavor; nicotine powder particle size of 2.25 ± 0.2 μm<br>Other: P3P 2<br>* 2 mg of nicotine; flavor; nicotine powder particle size of 2.25 ± 0.2 μm<br>Other: P3P 3<br>* 1 mg of nicotine; flavor; nicotine powder particle size of 2.25 ± 0.2 μm<br>Other: P3P 4<br>* 2 mg of nicotine; flavor; nicotine powder particle size of 1.8 ± 0.2 μm<br>|
| Active Comparator: Product Sequence 3<br>Subjects will be exposed to P3P 3 on day 1 of the study, then randomized to follow a sequence of product exposure comprised of: P3P 1 on Day 2; P3P 2 on Day 3; P3P 4 on Day 4 | Other: P3P 1<br>* 2 mg of nicotine; no flavor; nicotine powder particle size of 2.25 ± 0.2 μm<br>Other: P3P 2<br>* 2 mg of nicotine; flavor; nicotine powder particle size of 2.25 ± 0.2 μm<br>Other: P3P 3<br>* 1 mg of nicotine; flavor; nicotine powder particle size of 2.25 ± 0.2 μm<br>Other: P3P 4<br>* 2 mg of nicotine; flavor; nicotine powder particle size of 1.8 ± 0.2 μm<br>|
| Active Comparator: Product Sequence 4<br>Subjects will be exposed to P3P 3 on day 1 of the study, then randomized to follow a sequence of product exposure comprised of: P3P 1 on Day 2; P3P 4 on Day 3; P3P 2 on Day 4 | Other: P3P 1<br>* 2 mg of nicotine; no flavor; nicotine powder particle size of 2.25 ± 0.2 μm<br>Other: P3P 2<br>* 2 mg of nicotine; flavor; nicotine powder particle size of 2.25 ± 0.2 μm<br>Other: P3P 3<br>* 1 mg of nicotine; flavor; nicotine powder particle size of 2.25 ± 0.2 μm<br>Other: P3P 4<br>* 2 mg of nicotine; flavor; nicotine powder particle size of 1.8 ± 0.2 μm<br>|
| Active Comparator: Product Sequence 5<br>Subjects will be exposed to P3P 3 on day 1 of the study, then randomized to follow a sequence of product exposure comprised of: P3P 2 on Day 2; P3P 1 on Day 3; P3P 4 on Day 4 | Other: P3P 1<br>* 2 mg of nicotine; no flavor; nicotine powder particle size of 2.25 ± 0.2 μm<br>Other: P3P 2<br>* 2 mg of nicotine; flavor; nicotine powder particle size of 2.25 ± 0.2 μm<br>Other: P3P 3<br>* 1 mg of nicotine; flavor; nicotine powder particle size of 2.25 ± 0.2 μm<br>Other: P3P 4<br>* 2 mg of nicotine; flavor; nicotine powder particle size of 1.8 ± 0.2 μm<br>|
| Active Comparator: Product Sequence 6<br>Subjects will be exposed to P3P 3 on day 1 of the study, then randomized to follow a sequence of product exposure comprised of: P3P 4 on Day 2; P3P 2 on Day 3; P3P 1 on Day 4 | Other: P3P 1<br>* 2 mg of nicotine; no flavor; nicotine powder particle size of 2.25 ± 0.2 μm<br>Other: P3P 2<br>* 2 mg of nicotine; flavor; nicotine powder particle size of 2.25 ± 0.2 μm<br>Other: P3P 3<br>* 1 mg of nicotine; flavor; nicotine powder particle size of 2.25 ± 0.2 μm<br>Other: P3P 4<br>* 2 mg of nicotine; flavor; nicotine powder particle size of 1.8 ± 0.2 μm<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Nicotine Concentration-time Profile | To measure the plasma nicotine concentration-time profile of four P3P variants from the fixed puffing regimen, following correction of baseline nicotine levels. | Derived from multiple blood sampling (measured at 2 mins, 4 mins, 7 mins, 10 mins, 15 mins, 30 mins, 1 hour, 2 hours, and 4 hours post-product use) on Days 1, 2, 3 and 4 | 
| Maximum Plasma Concentration [Cmax] | To measure the maximum nicotine plasma concentration [Cmax] of four P3P variants from the fixed puffing regimen, following correction of baseline nicotine levels. | Derived from multiple blood sampling (measured at 2 mins, 4 mins, 7 mins, 10 mins, 15 mins, 30 mins, 1 hour, 2 hours, and 4 hours post-product use) on Days 1, 2, 3 and 4 | 
| Time to the Maximum Nicotine Concentration [Tmax] | To measure the time to maximum nicotine concentration [Tmax] of four P3P variants from the fixed puffing regimen, following correction of baseline nicotine levels. | Derived from multiple blood sampling (measured at 2 mins, 4 mins, 7 mins, 10 mins, 15 mins, 30 mins, 1 hour, 2 hours, and 4 hours post-product use) on Days 1, 2, 3 and 4 | 
| Area Under the Concentration-time Curve From Start of Product Use (T0 Fix) to 4 Hours [AUCfix (0-4h)] | To measure the area under the plasma concentration-time curve of four P3P variants from the fixed puffing regimen, following correction of baseline nicotine levels. | Derived from multiple blood sampling (measured at 2 mins, 4 mins, 7 mins, 10 mins, 15 mins, 30 mins, 1 hour, 2 hours, and 4 hours post-product use) on Days 1, 2, 3 and 4 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Plasma Nicotine Concentration-time Profile | To measure the plasma nicotine concentration-time profile of four P3P variants from the ad libitum use period, following correction of baseline nicotine levels. | Derived from multiple blood sampling (measured at 10 mins, 20 mins, 30 mins, 40 mins, 1 hour, 2 hours, and 4 hours during and post-ad libitum use) on Days 1, 2, 3 and 4 | 
| Peak Plasma Nicotine Concentration [Cpeak] | To measure the Peak plasma nicotine concentration [Cpeak] of four P3P variants from the ad libitum use period, following correction of baseline nicotine levels. | Derived from multiple blood sampling (measured at 10 mins, 20 mins, 30 mins, 40 mins, 1 hour, 2 hours, and 4 hours during and post-ad libitum use) on Days 1, 2, 3 and 4 | 
| Time to Peak Plasma Nicotine Concentration [Tpeak] | To measure the time to peak plasma nicotine concentration [Tpeak] of four P3P variants from the ad libitum use period, following correction of baseline nicotine levels. | Derived from multiple blood sampling (measured at 10 mins, 20 mins, 30 mins, 40 mins, 1 hour, 2 hours, and 4 hours during and post-ad libitum use) on Days 1, 2, 3 and 4 | 
| Trough Plasma Nicotine Concentration [Ctrough] | To measure the trough plasma nicotine concentration [Ctrough] of four P3P variants from the ad libitum use period, following correction of baseline nicotine levels. | Derived from multiple blood sampling (measured at 10 mins, 20 mins, 30 mins, 40 mins, 1 hour, 2 hours, and 4 hours during and post-ad libitum use) on Days 1, 2, 3 and 4 | 
| Average of Plasma Nicotine Concentration From T0 ad Lib to 1 Hour [Caverage] | To measure the average of plasma nicotine concentration [Caverage], of four P3P variants from the ad libitum use period, following correction of baseline nicotine levels | Derived from multiple blood sampling (measured at 10 mins, 20 mins, 30 mins, 40 mins, 1 hour during ad libitum use) on Days 1, 2, 3 and 4 | 
| Area Under the Concentration-time Curve From Start of Product Use (T0 ad Lib) to 4 Hours [AUCad Lib (0-4h)] | To measure the area under the plasma concentration-time curve of four P3P variants from the ad libitum use period, following correction of baseline nicotine levels. | Derived from multiple blood sampling (measured at 10 mins, 20 mins, 30 mins, 40 mins, 1 hour, 2 hours, and 4 hours during and post-ad libitum use) on Days 1, 2, 3 and 4 | 
| AUC of Craving for a Cigarette During and After the Fixed Puffing Regimen | Measured on a Visual Analogue Scale (VAS) of 0 (no craving) to 100 (strong craving). | During and up to 4 hours post-product use on days 1, 2, 3 and 4 | 
| AUC Craving for a Cigarette During and After the ad Libitum Use Period | Measured on a Visual Analogue Scale (VAS) of 0 (no craving) to 100 (strong craving). | During and up to 4 hours post-product use on days 1, 2, 3 and 4 | 
| Product Evaluation | Measured with an adapted version of the modified Cigarette Evaluation Questionnaire (adapted mCEQ) following the ad libitum use period. Assessed on a 7-point scale, ranging from 1 (not at all) to 7 (extremely). | Within 60 minutes after the ad libitum use session on days 1, 2, 3 and 4 | 
| Sensory Parameters | Measured with a Sensory Questionnaire (SQ) following the ad libitum use period. Response to each question is assessed on a 7-point scale, ranging from 1 (not at all) to 7 (extremely). | Within 60 minutes after the ad libitum use session on days 1, 2, 3 and 4 | 
| Human Puffing Topography (HPT) Parameters (Puff Volume) of Four P3P Variants During the Fixed Puffing Regimen Period. | Descriptive statistics of total puff volume and average puff volume, of four P3P variants, during the fixed puffing regimen period. | During fixed puffing product use on days 1, 2, 3 and 4 | 
| Human Puffing Topography (HPT) Parameters (Puff Volume) of Four P3P Variants During the ad Libitum Use Period. | Descriptive statistics of total puff volume and average puff volume, of four P3P variants, during the ad libitum use period. | During ad libitum product use on days 1, 2, 3 and 4 | 
| Amount of Powder Aerosolized From P3P From the Fixed Puffing Regimen. | Descriptive statistics of P3P weight before use, and after use, for the fixed puffing regimen. | Before and after fixed puffing product use on days 1, 2, 3 and 4 | 
| Amount of Powder Aerosolized From P3P From the ad Libitum Use Period (Per Product Used). | P3P weight before use, and after use, to determine the amount of powder aerosolized from P3P during Ad Libitum use (per product used). | Before and after ad libitum product use on days 1, 2, 3 and 4 | 

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