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This is a single-center, randomized, controlled, open-label, cross-over study with healthy adult smokers. The study will investigate the nicotine pharmacokinetic (PK) profiles of two e-liquid variants used with the P4M3 Gen 2.0 e-cigarette, compared to smoking combustible cigarettes.
In addition, pharmacodynamic (PD) effects (subjective effects and related behavioral assessments), will be evaluated to provide further insights on product evaluation, craving, liking, puffing topography. The study will be conducted with three periods and six sequences in a cross-over design.
This study is exploratory and there is no pre-specified hypothesis to be tested.
The purpose of the study is to evaluate the nicotine pharmacokinetics (PK) profiles of two e-liquid variants used with the P4M3 Gen 2.0 e-cigarette versus cigarettes following a six minutes ad libitum use period. In addition, pharmacodynamic effects (PD), including subjective effects and related behavioral assessments, as well as human puffing topography (HPT) will be evaluated, to provide further insights on P4M3 Gen 2.0 product acceptance and product use. Safety will be assessed throughout the study.
The aim is to evaluate if P4M3 Gen 2.0 can provide an acceptable alternative to smoking cigarettes in terms of both, nicotine delivery and sensorial satisfaction for current adult smokers who would otherwise continue smoking cigarettes.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Product Sequence 1 | Active Comparator | After at least 12 hours of abstinence from the use of any nicotine/tobacco containing products (referred to as nicotine wash-out), subjects will smoke a cigarette or use one of the e-liquid variants with P4M3 Gen 2.0 according to randomized product use sequence ad libitum for 6 minutes (± 30 seconds). CA35 on Day 1; Cig on Day 2; CM35 on Day 3 |
|
| Product Sequence 2 | Active Comparator | After at least 12 hours of abstinence from the use of any nicotine/tobacco containing products (referred to as nicotine wash-out), subjects will smoke a cigarette or use one of the e-liquid variants with P4M3 Gen 2.0 according to randomized product use sequence ad libitum for 6 minutes (± 30 seconds). CA35 on Day 1; CM35 on Day 2; Cig on Day 3 |
|
| Product Sequence 3 | Active Comparator | After at least 12 hours of abstinence from the use of any nicotine/tobacco containing products (referred to as nicotine wash-out), subjects will smoke a cigarette or use one of the e-liquid variants with P4M3 Gen 2.0 according to randomized product use sequence ad libitum for 6 minutes (± 30 seconds). Cig on Day 1; CA35 on Day 2; CM35 on Day 3 |
|
| Product Sequence 4 | Active Comparator | After at least 12 hours of abstinence from the use of any nicotine/tobacco containing products (referred to as nicotine wash-out), subjects will smoke a cigarette or use one of the e-liquid variants with P4M3 Gen 2.0 according to randomized product use sequence ad libitum for 6 minutes (± 30 seconds). Cig on Day 1; CM35 on Day 2; CA35 on Day 3 |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| CA35 | Other | Nicotine concentration: 3.5 % e-liquid flavor: Tobacco |
|
| Measure | Description | Time Frame |
|---|---|---|
| Background-corrected Maximum Plasma Concentration [Cmax] | To measure Cmax from 6 minutes ad libitum use for two e-liquid variants used with the P4M3 Gen 2.0 e-cigarette and for subjects smoking cigarettes. | T0 = start of product use. From day 1 to day 3, blood was drawn 5 minutes prior to T0 (day 1 only), and then 1, 2, 4, 6, 8, 10, 12, 15, 30 minutes, 1, 2, 4, 10 and 24 hours after T0. (Note that sample taken 24 hours after T0 on day 1 and day 2 only.) |
| Background-corrected Time to the Maximum Concentration [Tmax] | To measure Tmax from 6 minutes ad libitum use for two e-liquid variants used with the P4M3 Gen 2.0 e-cigarette and for subjects smoking cigarettes. | T0 = start of product use. From day 1 to day 3, blood was drawn 5 minutes prior to T0 (day 1 only), and then 1, 2, 4, 6, 8, 10, 12, 15, 30 minutes, 1, 2, 4, 10 and 24 hours after T0. (Note that sample taken 24 hours after T0 on day 1 and day 2 only.) |
| Area Under the Background-corrected Concentration-time Curve From Start of Product Use to Time of Last Quantifiable Concentration and Extrapolated to Infinity. | To measure the area under the background-corrected concentration-time curve (AUC) from start of product use from 6 minutes ad libitum use for two e-liquid variants used with the P4M3 Gen 2.0 e-cigarette and for subjects smoking cigarettes. | T0 = start of product use. From day 1 to day 3, blood was drawn 5 minutes prior to T0 (day 1 only), and then 1, 2, 4, 6, 8, 10, 12, 15, 30 minutes, 1, 2, 4, 10 and 24 hours after T0. (Note that sample taken 24 hours after T0 on day 1 and day 2 only.) |
| Maximum Ratio of Background-corrected Concentration Over Time | To measure the maximum ratio of background-corrected concentration over time, from T0 (excluded) to Tmax (included) | T0 = start of product use. From day 1 to day 3, blood was drawn 5 minutes prior to T0 (day 1 only), and then 1, 2, 4, 6, 8, 10, 12, 15, 30 minutes, 1, 2, 4, 10 and 24 hours after T0. (Note that sample taken 24 hours after T0 on day 1 and day 2 only.) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Melanie Fein, MD | High Point Clinical Trials Center (HPCTC) | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| High Point Clinical Trials Center (HPCTC) | High Point | North Carolina | 27265 | United States |
The 36 enrolled subjects were each randomized to one of six possible use sequences of product use.
36 subjects were enrolled in the study, which was conducted at a clinical trial facility managed by a contract research organization.
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| ID | Title | Description |
|---|---|---|
| FG000 | Product Sequence 1 | Subjects randomized to this product use sequence: CA35 on Day 1; Cig on Day 2; CM35 on Day 3 |
| FG001 | Product Sequence 2 | Subjects randomized to this product use sequence: CA35 on Day 1; CM35 on Day 2; Cig on Day 3 |
| FG002 | Product Sequence 3 | Subjects randomized to this product use sequence: Cig on Day 1; CA35 on Day 2; CM35 on Day 3 |
| FG003 | Product Sequence 4 | Subjects randomized to this product use sequence: Cig on Day 1; CM35 on Day 2; CA35 on Day 3 |
| FG004 | Product Sequence 5 | Subjects randomized to this product use sequence: CM35 on Day 1; Cig on Day 2; CA35 on Day 3 |
| FG005 | Product Sequence 6 | Subjects randomized to this product use sequence: CM35 on Day 1; CA35 on Day 2; Cig on Day 3 |
| Title | Milestones | Reasons Not Completed | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | Safety Population | Safety Population = All subjects who were exposed to the investigational product |
| Units | Counts |
|---|---|
| Participants |
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| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Background-corrected Maximum Plasma Concentration [Cmax] | To measure Cmax from 6 minutes ad libitum use for two e-liquid variants used with the P4M3 Gen 2.0 e-cigarette and for subjects smoking cigarettes. | The analysis population was a subset of the Safety Population and consisted of all randomized subjects, without major protocol deviations, for whom at least one nicotine PK parameter could be derived. | Posted | Geometric Mean | 95% Confidence Interval | (ng/mL) | T0 = start of product use. From day 1 to day 3, blood was drawn 5 minutes prior to T0 (day 1 only), and then 1, 2, 4, 6, 8, 10, 12, 15, 30 minutes, 1, 2, 4, 10 and 24 hours after T0. (Note that sample taken 24 hours after T0 on day 1 and day 2 only.) |
|
Adverse events were collected from the signature of the ICF by each subject until the end of the safety follow-up period, a total duration for each subject of up to 34 days.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Safety Population (CA35 Test) | The safety population was a subset of the screened population and consisted of all subjects who gave informed consent, had at least one exposure to P4M3 Gen 2.0, including the product test at Admission (Day -1), and had at least one safety assessment. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Christelle Haziza, Global Head Clinical Research and Execution | Philip Morris Products S.A. | +41 58 242 11 11 | ClinicalTrials.PMI@pmi.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Oct 14, 2021 | Jul 12, 2023 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | Mar 21, 2022 | Jul 12, 2023 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D000072137 | Vaping |
| D012907 | Smoking |
| ID | Term |
|---|---|
| D001519 | Behavior |
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| ID | Term |
|---|---|
| D005353 | Fibronectins |
| ID | Term |
|---|---|
| D008562 | Membrane Glycoproteins |
| D006023 | Glycoproteins |
| D006001 | Glycoconjugates |
| D002241 | Carbohydrates |
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|
| Product Sequence 5 | Active Comparator | After at least 12 hours of abstinence from the use of any nicotine/tobacco containing products (referred to as nicotine wash-out), subjects will smoke a cigarette or use one of the e-liquid variants with P4M3 Gen 2.0 according to randomized product use sequence ad libitum for 6 minutes (± 30 seconds). CM35 on Day 1; Cig on Day 2; CA35 on Day 3 |
|
| Product Sequence 6 | Active Comparator | After at least 12 hours of abstinence from the use of any nicotine/tobacco containing products (referred to as nicotine wash-out), subjects will smoke a cigarette or use one of the e-liquid variants with P4M3 Gen 2.0 according to randomized product use sequence ad libitum for 6 minutes (± 30 seconds). CM35 on Day 1; CA35 on Day 2; Cig on Day 3 |
|
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| CM35 | Other | Nicotine concentration: 3.5 % e-liquid flavor: Menthol |
|
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| Cig | Other | Subjects' preferred brand of commercially available, regular or mentholated cigarettes |
|
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race/Ethnicity, Customized | Count of Participants | Participants |
|
| BMI | Mean | Standard Deviation | kg/m² |
|
| CM35 |
P4M3 Gen 2.0 Classic Menthol 3.5% nicotine |
| OG002 | Cigarettes | Subject's own cigarettes |
|
|
|
| Primary | Background-corrected Time to the Maximum Concentration [Tmax] | To measure Tmax from 6 minutes ad libitum use for two e-liquid variants used with the P4M3 Gen 2.0 e-cigarette and for subjects smoking cigarettes. | The analysis population was a subset of the Safety Population and consisted of all randomized subjects, without major protocol deviations, for whom at least one nicotine PK parameter could be derived. | Posted | Mean | 95% Confidence Interval | minutes | T0 = start of product use. From day 1 to day 3, blood was drawn 5 minutes prior to T0 (day 1 only), and then 1, 2, 4, 6, 8, 10, 12, 15, 30 minutes, 1, 2, 4, 10 and 24 hours after T0. (Note that sample taken 24 hours after T0 on day 1 and day 2 only.) |
|
|
|
|
| Primary | Area Under the Background-corrected Concentration-time Curve From Start of Product Use to Time of Last Quantifiable Concentration and Extrapolated to Infinity. | To measure the area under the background-corrected concentration-time curve (AUC) from start of product use from 6 minutes ad libitum use for two e-liquid variants used with the P4M3 Gen 2.0 e-cigarette and for subjects smoking cigarettes. | The analysis population was a subset of the Safety Population and consisted of all randomized subjects, without major protocol deviations, for whom at least one nicotine PK parameter could be derived. | Posted | Geometric Mean | 95% Confidence Interval | min*ng/mL | T0 = start of product use. From day 1 to day 3, blood was drawn 5 minutes prior to T0 (day 1 only), and then 1, 2, 4, 6, 8, 10, 12, 15, 30 minutes, 1, 2, 4, 10 and 24 hours after T0. (Note that sample taken 24 hours after T0 on day 1 and day 2 only.) |
|
|
|
|
| Primary | Maximum Ratio of Background-corrected Concentration Over Time | To measure the maximum ratio of background-corrected concentration over time, from T0 (excluded) to Tmax (included) | The analysis population was a subset of the Safety Population and consisted of all randomized subjects, without major protocol deviations, for whom at least one nicotine PK parameter could be derived. | Posted | Geometric Mean | 95% Confidence Interval | (ng/mL)/min | T0 = start of product use. From day 1 to day 3, blood was drawn 5 minutes prior to T0 (day 1 only), and then 1, 2, 4, 6, 8, 10, 12, 15, 30 minutes, 1, 2, 4, 10 and 24 hours after T0. (Note that sample taken 24 hours after T0 on day 1 and day 2 only.) |
|
|
|
|
| 0 |
| 35 |
| 0 |
| 35 |
| 0 |
| 35 |
| EG001 | Safety Population (CA35) | The safety population was a subset of the screened population and consisted of all subjects who gave informed consent, had at least one exposure to P4M3 Gen 2.0, including the product test at Admission (Day -1), and had at least one safety assessment. | 0 | 32 | 0 | 32 | 0 | 32 |
| EG002 | Safety Population (CM35) | The safety population was a subset of the screened population and consisted of all subjects who gave informed consent, had at least one exposure to P4M3 Gen 2.0, including the product test at Admission (Day -1), and had at least one safety assessment. | 0 | 33 | 0 | 33 | 0 | 33 |
| EG003 | Cigarettes | The safety population was a subset of the screened population and consisted of all subjects who gave informed consent, had at least one exposure to P4M3 Gen 2.0, including the product test at Admission (Day -1), and had at least one safety assessment. | 0 | 34 | 0 | 34 | 0 | 34 |
We confirm we have the contractual provisions in place which specify that in no event will the study site be allowed to disclose to any third party (or publicly release) any information obtained through the study without the CRO's prior written consent which in turn cannot provide such consent without Sponsor's approval unless such publication is made to satisfy regulatory requirements.
The Intellectual Property rights and research results from the present study belong to the Sponsor.
| D012712 |
| Serum Globulins |
| D005916 | Globulins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D008565 | Membrane Proteins |
| D016326 | Extracellular Matrix Proteins |
| D012596 | Scleroproteins |
|
The objective of this study was to determine the Tmax difference of P4M3 variants:Cigarettes along with the corresponding 95% confidence intervals |
| Wilcoxon signed rank test |
95% confidence intervals are provided for this analysis. |
| Mean Difference (Net) |
| 2.000 |
| 2-Sided |
| 95 |
| 0.00 |
| 4.00 |
Hodges-Lehmann estimator of location shift and Moses 95% CI |
| Other |
| Other |
| The objective of this study was to determine the AUC0-infinity ratio of P4M3 variants:Cigarettes along with the corresponding 95% confidence intervals | Mixed Models Analysis | The model included terms for sequence, period, and product exposure as fixed effects and subject as a categorical random effect. | 95% confidence intervals are provided for this analysis. | Geometric LS Mean Ratio (%) | 26.16 | 2-Sided | 95 | 12.74 | 53.69 | Analysis was performed on log transformed data with Kenward Roger degrees of freedom approximation. Ratio and related 95% CI were derived by exponentiating the estimates obtained on the log scale. | Other |
| Other |
| The objective of this study was to determine the maximum ratio of background-corrected concentration over time of P4M3 variants:Cigarettes along with the corresponding 95% confidence intervals | Mixed Models Analysis | The model included terms for sequence, period, and product exposure as fixed effects and subject as a categorical random effect. | 95% confidence intervals are provided for this analysis. | Geometric LS Mean Ratio (%) | 16.83 | 2-Sided | 95 | 9.93 | 28.53 | Analysis was performed on log transformed data with Kenward Roger degrees of freedom approximation. Ratio and related 95% CI were derived by exponentiating the estimates obtained on the log scale. | Other |