Smoking
Conditions
Keywords
Smoking, Nicotine absorption, Candidate modified risk tobacco product, Cigarettes, Nicotine Replacement Therapy gum (NRT gum)
Brief summary
The overall goal of the study is to evaluate the pharmacokinetic (PK) profile (rate and the amount of nicotine absorbed) following a single use of the THS 2.2, a candidate Modified Risk Tobacco Product, compared to the PK profiles from a single use of a cigarette (CC) and from a single use of nicotine gum in a Japanese population.
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 smokes at least 10 commercially available CCs per day (no brand restrictions) for the last 4 weeks. * 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 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 THS 2.2, CC 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 THS 2.2, CC 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): 31 July 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 one of four product use sequences.
Pre-assignment details
Enrolled population = 65 subjects: 3 subjects exposed to THS 2.2 and NRT gum at Admission but not randomized and 62 randomized to one of the four product use sequences described below: * Product Use Sequence THS 2.2 then CC: 22 subjects * Product Use Sequence CC then THS 2.2: 22 subjects * Product Use Sequence THS 2.2 then NRT: 9 subjects * Product Use Sequence NRT then THS 2.2: 9 subjects
Participants by arm
| Arm | Count |
|---|---|
| THS 2.2 - CC This population was randomized to the following product use sequence:
THS 2.2 then CC | 22 |
| CC -THS 2.2 This population was randomized to the following product use sequence:
CC then THS 2.2 | 22 |
| THS 2.2 - NRT This population was randomized to the following product use sequence:
THS 2.2 then NRT | 9 |
| NRT - THS 2.2 This population was randomized to the following product use sequence:
NRT then THS 2.2 | 9 |
| Enrolled But Not Randomized This population comprised enrolled subjects who tried the THS 2.2 at Admission (Day -1) but were not randomized to a product use sequence. | 3 |
| Total | 65 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| First Intervention (Day 1) | Withdrawal by Subject | 1 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | THS 2.2 - CC | CC -THS 2.2 | THS 2.2 - NRT | NRT - THS 2.2 | Enrolled But Not Randomized | Total |
|---|---|---|---|---|---|---|
| Age, Customized Between 23 and 65 years | 32.9 years STANDARD_DEVIATION 7.56 | 32.7 years STANDARD_DEVIATION 9.84 | 34.7 years STANDARD_DEVIATION 12.36 | 36.9 years STANDARD_DEVIATION 8.71 | 42.7 years STANDARD_DEVIATION 11.85 | 34.1 years STANDARD_DEVIATION 9.45 |
| International Organization for Standardization (ISO) nicotine level ≤ 0.6 mg | 14 participants | 8 participants | 6 participants | 4 participants | 0 participants | 32 participants |
| International Organization for Standardization (ISO) nicotine level > 0.6 to ≤ 1 mg | 8 participants | 14 participants | 3 participants | 5 participants | 3 participants | 33 participants |
| Sex: Female, Male Female | 11 Participants | 13 Participants | 6 Participants | 4 Participants | 0 Participants | 34 Participants |
| Sex: Female, Male Male | 11 Participants | 9 Participants | 3 Participants | 5 Participants | 3 Participants | 31 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 44 | 0 / 44 | 0 / 18 | 0 / 3 |
| other Total, other adverse events | 1 / 44 | 1 / 44 | 2 / 18 | 0 / 3 |
| serious Total, serious adverse events | 0 / 44 | 0 / 44 | 0 / 18 | 0 / 3 |
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 THS 2.2, CC 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) |
|---|---|---|
| THS 2.2 - 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 THS 2.2, CC and NRT | 23.75 ng*h/mL |
| CC - 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 THS 2.2, CC and NRT | 24.66 ng*h/mL |
| THS 2.2 - 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 THS 2.2, CC and NRT | 18.92 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 THS 2.2, CC and NRT | 14.88 ng*h/mL |
Comparison: The objective of this study was to determine the point estimate and precision of the nicotine bioavailability (ratio of THS 2.2:CC) for AUC(0-last), therefore, there was no statistical hypothesis to be tested for this objective.95% CI: [85.1, 109.07]ANOVA
Primary
Maximum Concentration (Cmax) of Nicotine Following Single Use of THS 2.2, CC 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) |
|---|---|---|
| THS 2.2 - Group 1 | Maximum Concentration (Cmax) of Nicotine Following Single Use of THS 2.2, CC and NRT | 14.30 ng/mL |
| CC - Group 1 | Maximum Concentration (Cmax) of Nicotine Following Single Use of THS 2.2, CC and NRT | 13.82 ng/mL |
| THS 2.2 - Group 2 | Maximum Concentration (Cmax) of Nicotine Following Single Use of THS 2.2, CC and NRT | 11.53 ng/mL |
| NRT - Group 2 | Maximum Concentration (Cmax) of Nicotine Following Single Use of THS 2.2, CC and NRT | 4.80 ng/mL |
Comparison: The objective of this study was to determine the point estimate and precision of the nicotine bioavailability (ratio of THS 2.2:CC) for Cmax, therefore, there was no statistical hypothesis to be tested for this objective.95% CI: [84.94, 126.11]ANOVA