Smoking
Conditions
Keywords
Smoking, Nicotine absorption, Candidate modified risk tobacco product, Cigarette, Nicotine replacement therapy, Nicotine gum
Brief summary
The primary objective of this clinical study is to evaluate the pharmacokinetic (PK) profile (rate and amount of nicotine absorbed) following a single use of the THS 2.2 Menthol (mTHS), a candidate Modified Risk Tobacco Product, compared to the PK profiles from a single use of a menthol cigarette (mCC) and from a single use of nicotine replacement therapy gum (NRT).
Interventions
Sponsors
Philip Morris Products S.A.
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
23 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
* Subject is Japanese. * Smoking, healthy subject as judged by the Investigator. * Subject has smoked at least 10 commercially available mCCs per day (no brand restrictions) for the last 4 weeks. * Subject has smoked for at least the last 3 consecutive years. * Subject does not plan to quit smoking in the next 3 months.
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 medication (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, mCC and NRT | Blood taken 15 minutes prior to T0, 2, 4, 6, 8, 10, 15, 30, 45 minutes, 1, 2, 4, 6, 9, 12, and 24 hours after T0 | T0 = start of single product use. 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. |
| Area Under the Plasma Concentration-Time Curve From Time Zero (Pre-product Use) to Last Time Point [AUC(0-last)] Following Single Use of mTHS, mCC and NRT | Blood taken 15 minutes prior to T0, 2, 4, 6, 8, 10, 15, 30, 45 minutes, 1, 2, 4, 6, 9, 12, and 24 hours after T0 | T0 = start of single product use. 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
Japan
Participant flow
Recruitment details
Study initiated (first subject screened): 01 August 2013 At admission (Day -1), all the subjects performed a product trial (Tobacco Sticks and subsequently NRT gum). 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 = 73 subjects: 11 exposed to mTHS and NRT at Admission but not randomized and 62 randomized as described below: * Sequence mTHS then mCC: 22 subjects * Sequence mCC then mTHS: 22 subjects * Sequence mTHS then NRT: 9 subjects * Sequence NRT then mTHS: 9 subjects
Participants by arm
| Arm | Count |
|---|---|
| Group 1 This population comprises the following sequences:
* Sequence mTHS then mCC
* Sequence mCC then mTHS | 43 |
| Group 2 This population comprises the following sequences:
* Sequence mTHS then NRT
* Sequence NRT then mTHS | 18 |
| Total | 61 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| First Intervention (Day 1) | Withdrawal by Subject | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Group 2 | Total | Group 1 |
|---|---|---|---|
| Age, Customized Between 23 and 65 years | 30.7 years STANDARD_DEVIATION 7.8 | 32.6 years STANDARD_DEVIATION 9.44 | 33.4 years STANDARD_DEVIATION 10.03 |
| International Organization for Standardization (ISO) nicotine level ≤ 0.6 mg | 10 participants | 35 participants | 25 participants |
| International Organization for Standardization (ISO) nicotine level > 0.6 to ≤ 1 mg | 8 participants | 26 participants | 18 participants |
| Sex: Female, Male Female | 9 Participants | 29 Participants | 20 Participants |
| Sex: Female, Male Male | 9 Participants | 32 Participants | 23 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 | 0 / 44 | 1 / 18 | 0 / 11 |
| serious Total, serious adverse events | 0 / 44 | 0 / 18 | 0 / 11 |
Outcome results
Primary
Area Under the Plasma Concentration-Time Curve From Time Zero (Pre-product Use) to Last Time Point [AUC(0-last)] Following Single Use of mTHS, mCC and NRT
T0 = start of single product use. 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: Blood taken 15 minutes prior to T0, 2, 4, 6, 8, 10, 15, 30, 45 minutes, 1, 2, 4, 6, 9, 12, and 24 hours after T0
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 - Group 1 | Area Under the Plasma Concentration-Time Curve From Time Zero (Pre-product Use) to Last Time Point [AUC(0-last)] Following Single Use of mTHS, mCC and NRT | 23.99 ng*h/mL |
| mCC - Group 1 | Area Under the Plasma Concentration-Time Curve From Time Zero (Pre-product Use) to Last Time Point [AUC(0-last)] Following Single Use of mTHS, mCC and NRT | 24.45 ng*h/mL |
| mTHS - Group 2 | Area Under the Plasma Concentration-Time Curve From Time Zero (Pre-product Use) to Last Time Point [AUC(0-last)] Following Single Use of mTHS, mCC and NRT | 15.61 ng*h/mL |
| NRT - Group 2 | Area Under the Plasma Concentration-Time Curve From Time Zero (Pre-product Use) to Last Time Point [AUC(0-last)] Following Single Use of mTHS, mCC and NRT | 27.94 ng*h/mL |
Comparison: The objective of this study was to determine the point estimate and precision of the nicotine bioavailability (ratio of mTHS:mCC) for AUC(0-last), therefore, there was no statistical hypothesis to be tested for this objective.95% CI: [80.61, 119.46]ANOVA
Primary
Maximum Concentration (Cmax) of Nicotine Following Single Use of mTHS, mCC and NRT
T0 = start of single product use. 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: Blood taken 15 minutes prior to T0, 2, 4, 6, 8, 10, 15, 30, 45 minutes, 1, 2, 4, 6, 9, 12, and 24 hours after T0
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 - Group 1 | Maximum Concentration (Cmax) of Nicotine Following Single Use of mTHS, mCC and NRT | 10.70 ng/mL |
| mCC - Group 1 | Maximum Concentration (Cmax) of Nicotine Following Single Use of mTHS, mCC and NRT | 12.09 ng/mL |
| mTHS - Group 2 | Maximum Concentration (Cmax) of Nicotine Following Single Use of mTHS, mCC and NRT | 7.64 ng/mL |
| NRT - Group 2 | Maximum Concentration (Cmax) of Nicotine Following Single Use of mTHS, mCC and NRT | 7.52 ng/mL |
Comparison: The objective of this study was to determine the point estimate and precision of the nicotine bioavailability (ratio of mTHS:mCC) for Cmax, therefore, there was no statistical hypothesis to be tested for this objective.95% CI: [68.64, 114.03]ANOVA