Nicotine Pharmacokinetics and Pharmacodynamics, Safety and Tolerability of P3P

• ClinicalTrials.gov Identifier: NCT03369340
• Recruitment Status: Completed
• First Posted: December 12, 2017
• Results First Posted: January 31, 2020
• Last Update Posted: January 31, 2020
• Sponsor: Philip Morris Products S.A.
• Information provided by (Responsible Party): Philip Morris Products S.A.

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Pharmacokinetics	Other: P3P 1; Other: P3P 2; Other: P3P 3; Other: P3P 4	Not Applicable

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 19 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Intervention Model Description: A single-center, open-label, randomized, crossover study.
• Masking: None (Open Label)
• Masking Description: Sponsor staff, Investigator, the subjects and the investigational site will be blinded to the randomization sequences until they are assigned. Subjects will not be informed of the complete sequence to which they have been assigned.
• Primary Purpose: Other
• Official Title: 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
• Actual Study Start Date: November 7, 2017
• Actual Primary Completion Date: February 1, 2018
• Actual Study Completion Date: May 2, 2018

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Product Sequence 1; 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; 2 mg of nicotine; no flavor; nicotine powder particle size of 2.25 ± 0.2 μm; Other: P3P 2; 2 mg of nicotine; flavor; nicotine powder particle size of 2.25 ± 0.2 μm; Other: P3P 3; 1 mg of nicotine; flavor; nicotine powder particle size of 2.25 ± 0.2 μm; Other: P3P 4; 2 mg of nicotine; flavor; nicotine powder particle size of 1.8 ± 0.2 μm
Active Comparator: Product Sequence 2; 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; 2 mg of nicotine; no flavor; nicotine powder particle size of 2.25 ± 0.2 μm; Other: P3P 2; 2 mg of nicotine; flavor; nicotine powder particle size of 2.25 ± 0.2 μm; Other: P3P 3; 1 mg of nicotine; flavor; nicotine powder particle size of 2.25 ± 0.2 μm; Other: P3P 4; 2 mg of nicotine; flavor; nicotine powder particle size of 1.8 ± 0.2 μm
Active Comparator: Product Sequence 3; 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; 2 mg of nicotine; no flavor; nicotine powder particle size of 2.25 ± 0.2 μm; Other: P3P 2; 2 mg of nicotine; flavor; nicotine powder particle size of 2.25 ± 0.2 μm; Other: P3P 3; 1 mg of nicotine; flavor; nicotine powder particle size of 2.25 ± 0.2 μm; Other: P3P 4; 2 mg of nicotine; flavor; nicotine powder particle size of 1.8 ± 0.2 μm
Active Comparator: Product Sequence 4; 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; 2 mg of nicotine; no flavor; nicotine powder particle size of 2.25 ± 0.2 μm; Other: P3P 2; 2 mg of nicotine; flavor; nicotine powder particle size of 2.25 ± 0.2 μm; Other: P3P 3; 1 mg of nicotine; flavor; nicotine powder particle size of 2.25 ± 0.2 μm; Other: P3P 4; 2 mg of nicotine; flavor; nicotine powder particle size of 1.8 ± 0.2 μm
Active Comparator: Product Sequence 5; 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; 2 mg of nicotine; no flavor; nicotine powder particle size of 2.25 ± 0.2 μm; Other: P3P 2; 2 mg of nicotine; flavor; nicotine powder particle size of 2.25 ± 0.2 μm; Other: P3P 3; 1 mg of nicotine; flavor; nicotine powder particle size of 2.25 ± 0.2 μm; Other: P3P 4; 2 mg of nicotine; flavor; nicotine powder particle size of 1.8 ± 0.2 μm
Active Comparator: Product Sequence 6; 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; 2 mg of nicotine; no flavor; nicotine powder particle size of 2.25 ± 0.2 μm; Other: P3P 2; 2 mg of nicotine; flavor; nicotine powder particle size of 2.25 ± 0.2 μm; Other: P3P 3; 1 mg of nicotine; flavor; nicotine powder particle size of 2.25 ± 0.2 μm; Other: P3P 4; 2 mg of nicotine; flavor; nicotine powder particle size of 1.8 ± 0.2 μm

Outcome Measures

Primary Outcome Measures :

1. Plasma Nicotine Concentration-time Profile [ Time Frame: 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 ]
   To measure the plasma nicotine concentration-time profile of four P3P variants from the fixed puffing regimen, following correction of baseline nicotine levels.
2. Maximum Plasma Concentration [Cmax] [ Time Frame: 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 ]
   To measure the maximum nicotine plasma concentration [Cmax] of four P3P variants from the fixed puffing regimen, following correction of baseline nicotine levels.
3. Time to the Maximum Nicotine Concentration [Tmax] [ Time Frame: 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 ]
   To measure the time to maximum nicotine concentration [Tmax] of four P3P variants from the fixed puffing regimen, following correction of baseline nicotine levels.
4. Area Under the Concentration-time Curve From Start of Product Use (T0 Fix) to 4 Hours [AUCfix (0-4h)] [ Time Frame: 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 ]
   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.

Secondary Outcome Measures :

1. Plasma Nicotine Concentration-time Profile [ Time Frame: 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 ]
   To measure the plasma nicotine concentration-time profile of four P3P variants from the ad libitum use period, following correction of baseline nicotine levels.
2. Peak Plasma Nicotine Concentration [Cpeak] [ Time Frame: 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 ]
   To measure the Peak plasma nicotine concentration [Cpeak] of four P3P variants from the ad libitum use period, following correction of baseline nicotine levels.
3. Time to Peak Plasma Nicotine Concentration [Tpeak] [ Time Frame: 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 ]
   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.
4. Trough Plasma Nicotine Concentration [Ctrough] [ Time Frame: 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 ]
   To measure the trough plasma nicotine concentration [Ctrough] of four P3P variants from the ad libitum use period, following correction of baseline nicotine levels.
5. Average of Plasma Nicotine Concentration From T0 ad Lib to 1 Hour [Caverage] [ Time Frame: 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 ]
   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
6. Area Under the Concentration-time Curve From Start of Product Use (T0 ad Lib) to 4 Hours [AUCad Lib (0-4h)] [ Time Frame: 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 ]
   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.
7. AUC of Craving for a Cigarette During and After the Fixed Puffing Regimen [ Time Frame: During and up to 4 hours post-product use on days 1, 2, 3 and 4 ]
   Measured on a Visual Analogue Scale (VAS) of 0 (no craving) to 100 (strong craving).
8. AUC Craving for a Cigarette During and After the ad Libitum Use Period [ Time Frame: During and up to 4 hours post-product use on days 1, 2, 3 and 4 ]
   Measured on a Visual Analogue Scale (VAS) of 0 (no craving) to 100 (strong craving).
9. Product Evaluation [ Time Frame: Within 60 minutes after the ad libitum use session on days 1, 2, 3 and 4 ]
   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).
10. Sensory Parameters [ Time Frame: Within 60 minutes after the ad libitum use session on days 1, 2, 3 and 4 ]
    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).
11. Human Puffing Topography (HPT) Parameters (Puff Volume) of Four P3P Variants During the Fixed Puffing Regimen Period. [ Time Frame: During fixed puffing product use on days 1, 2, 3 and 4 ]
    Descriptive statistics of total puff volume and average puff volume, of four P3P variants, during the fixed puffing regimen period.
12. Human Puffing Topography (HPT) Parameters (Puff Volume) of Four P3P Variants During the ad Libitum Use Period. [ Time Frame: During ad libitum product use on days 1, 2, 3 and 4 ]
    Descriptive statistics of total puff volume and average puff volume, of four P3P variants, during the ad libitum use period.
13. Amount of Powder Aerosolized From P3P From the Fixed Puffing Regimen. [ Time Frame: Before and after fixed puffing product use on days 1, 2, 3 and 4 ]
    Descriptive statistics of P3P weight before use, and after use, for the fixed puffing regimen.
14. Amount of Powder Aerosolized From P3P From the ad Libitum Use Period (Per Product Used). [ Time Frame: Before and after ad libitum product use on days 1, 2, 3 and 4 ]
    P3P weight before use, and after use, to determine the amount of powder aerosolized from P3P during Ad Libitum use (per product used).

Eligibility Criteria

• Ages Eligible for Study: 21 Years to 65 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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.

Contacts and Locations

Locations

Switzerland

CROSS Research

Arzo, Ticino, Switzerland, 6864

Sponsors and Collaborators

Philip Morris Products S.A.

Investigators

• Study Chair: Christelle Haziza, PhD; Philip Morris Products S.A.
• Principal Investigator: Milko Radicioni, MD; CROSS Research, Arzo, Ticino, Switzerland

  Study Documents (Full-Text)

Documents provided by Philip Morris Products S.A.:

Study Protocol  [PDF] July 24, 2017

Statistical Analysis Plan  [PDF] April 30, 2018

More Information

• Responsible Party: Philip Morris Products S.A.
• ClinicalTrials.gov Identifier: NCT03369340
• Other Study ID Numbers: P3P-PK-01-CH
• First Posted: December 12, 2017
• Results First Posted: January 31, 2020
• Last Update Posted: January 31, 2020
• Last Verified: January 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Philip Morris Products S.A.:

Nicotine; Nicotine-containing product