Smoking
Conditions
Keywords
Smoking, Nicotine absorption, Candidate modified risk tobacco product, Conventional cigarette, Nicotine replacement therapy: nasal spray
Brief summary
The primary objective of the study is to evaluate the pharmacokinetic (PK) profiles (rate and amount of nicotine absorbed) after a single use of the THS 2.2 Menthol (mTHS 2.2) compared to a single use of the menthol conventional cigarette (mCC) and nicotine nasal spray (NNS).
Interventions
Sponsors
Philip Morris Products S.A.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
22 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Subject is aged from 22 to 65 years (inclusive). * Smoking, healthy subject as judged by the Investigator. * Subject smoked at least 10 commercially available menthol CCs per day (with brand restrictions) over the last 4 weeks. * Subject has smoked for at least the last 3 consecutive years.
Exclusion criteria
* As per Investigator judgment, the subject cannot participate in the study for any reason (e.g., medical, psychiatric, and/or social reason). * Subject has received medication within 14 days or within 5 half-lives of a drug (whichever is longer) which has an impact on CYP2A6 activity. * Female subject is pregnant or breast feeding. * Female subject does not agree to use an acceptable method of effective contraception.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Concentration (Cmax) of Nicotine Following Single Use of mTHS 2.2, mCC and NNS | 3 days | Derived from multiple blood sampling on Day 1 and Day 3 (1 blood sampling pre-product use and multiple blood sampling over 24 hours post-product use). Geometric Least Squares (geometric LS) means are provided. |
| Area Under the Plasma Nicotine Concentration-Time Curve From Time Zero (Pre-product Use) to Last Time Point [AUC(0-last)] Following Single Use of mTHS 2.2, mCC and NNS | 3 days | Derived from multiple blood sampling on Day 1 and Day 3 (1 blood sampling pre-product use and multiple blood sampling over 24 hours post-product use). Geometric Least Squares means are provided. |
Countries
United States
Participant flow
Recruitment details
Study initiated (first subject screened): 02 October 2013 At admission (Day -1), all the subjects performed a product trial (mTHS 2.2 and subsequently NNS). From enrollment, they were asked to remain abstinent from smoking for at least 24 hours (Day 0) before being randomized on Day 1 into 1 of the 4 sequences.
Pre-assignment details
Enrolled population = 64 subjects: 2 exposed to mTHS 2.2 and NNS at Admission but not randomized and 62 randomized as described below: * Sequence mTHS 2.2 then mCC: 22 subjects * Sequence mCC then mTHS 2.2: 22 subjects * Sequence mTHS 2.2 then NNS: 9 subjects * Sequence NNS then mTHS 2.2: 9 subjects
Participants by arm
| Arm | Count |
|---|---|
| Group 1 This population comprises the following sequences:
* Sequence mTHS 2.2 then mCC
* Sequence mCC then mTHS 2.2 | 41 |
| Group 2 This population comprises the following sequences:
* Sequence mTHS 2.2 then NNS
* Sequence NNS then mTHS 2.2 | 17 |
| Total | 58 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| First Intervention (Day 1) | Withdrawal by Subject | 0 | 1 | 0 | 1 |
| Second Intervention (Day 3) | Withdrawal by Subject | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Group 2 | Total | Group 1 |
|---|---|---|---|
| Age, Continuous | 33.8 years STANDARD_DEVIATION 6.93 | 35.9 years STANDARD_DEVIATION 9 | 36.7 years STANDARD_DEVIATION 9.68 |
| International Organization for Standardization (ISO) nicotine yield ≤ 1.0 mg | 11 participants | 32 participants | 21 participants |
| International Organization for Standardization (ISO) nicotine yield > 1.0 mg | 6 participants | 26 participants | 20 participants |
| Sex: Female, Male Female | 9 Participants | 29 Participants | 20 Participants |
| Sex: Female, Male Male | 8 Participants | 29 Participants | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 12 / 44 | 5 / 18 | 0 / 2 |
| serious Total, serious adverse events | 0 / 44 | 0 / 18 | 0 / 2 |
Outcome results
Primary
Area Under the Plasma Nicotine Concentration-Time Curve From Time Zero (Pre-product Use) to Last Time Point [AUC(0-last)] Following Single Use of mTHS 2.2, mCC and NNS
Derived from multiple blood sampling on Day 1 and Day 3 (1 blood sampling pre-product use and multiple blood sampling over 24 hours post-product use). Geometric Least Squares means are provided.
Time frame: 3 days
Population: PK populations consisted of all the randomized subjects who completed at least 1 of the single use days (Days 1 or 3), and for whom at least 1 PK parameter could be derived. Subjects with major protocol deviations that impacted the evaluability of the results were excluded from the PK populations.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| mTHS 2.2 - Group 1 | Area Under the Plasma Nicotine Concentration-Time Curve From Time Zero (Pre-product Use) to Last Time Point [AUC(0-last)] Following Single Use of mTHS 2.2, mCC and NNS | 16.53 h*ng/mL |
| mCC - Group 1 | Area Under the Plasma Nicotine Concentration-Time Curve From Time Zero (Pre-product Use) to Last Time Point [AUC(0-last)] Following Single Use of mTHS 2.2, mCC and NNS | 29.71 h*ng/mL |
| mTHS 2.2 - Group 2 | Area Under the Plasma Nicotine Concentration-Time Curve From Time Zero (Pre-product Use) to Last Time Point [AUC(0-last)] Following Single Use of mTHS 2.2, mCC and NNS | 15.59 h*ng/mL |
| NNS - Group 2 | Area Under the Plasma Nicotine Concentration-Time Curve From Time Zero (Pre-product Use) to Last Time Point [AUC(0-last)] Following Single Use of mTHS 2.2, mCC and NNS | 8.72 h*ng/mL |
Comparison: The objective of this study was to determine the point estimate and precision of the nicotine bioavailability (ratio of mTHS 2.2:mCC) for AUC(0-last), therefore, there was no statistical hypothesis to be tested for this objective.95% CI: [43.3, 71.5]ANOVA
Primary
Maximum Concentration (Cmax) of Nicotine Following Single Use of mTHS 2.2, mCC and NNS
Derived from multiple blood sampling on Day 1 and Day 3 (1 blood sampling pre-product use and multiple blood sampling over 24 hours post-product use). Geometric Least Squares (geometric LS) means are provided.
Time frame: 3 days
Population: Pharmacokinetics (PK) populations consisted of all the randomized subjects who completed at least 1 of the single use days (Days 1 or 3), and for whom at least 1 PK parameter could be derived. Subjects with major protocol deviations that impacted the evaluability of the results were excluded from the PK populations.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| mTHS 2.2 - Group 1 | Maximum Concentration (Cmax) of Nicotine Following Single Use of mTHS 2.2, mCC and NNS | 7.40 ng/mL |
| mCC - Group 1 | Maximum Concentration (Cmax) of Nicotine Following Single Use of mTHS 2.2, mCC and NNS | 13.08 ng/mL |
| mTHS 2.2 - Group 2 | Maximum Concentration (Cmax) of Nicotine Following Single Use of mTHS 2.2, mCC and NNS | 8.40 ng/mL |
| NNS - Group 2 | Maximum Concentration (Cmax) of Nicotine Following Single Use of mTHS 2.2, mCC and NNS | 3.23 ng/mL |
Comparison: The objective of this study was to determine the point estimate and precision of the nicotine bioavailability (ratio of mTHS 2.2:mCC) for Cmax, therefore, there was no statistical hypothesis to be tested for this objective.95% CI: [44.21, 72.39]ANOVA