Smoking
Conditions
Keywords
Candidate modified risk tobacco product, Conventional cigarette, Reduced exposure, HPHCs, Confinement
Brief summary
The overall goal of the study is to evaluate if the ad libitum use of the Tobacco Heating System 2.2 (THS 2.2) for 5 consecutive days by adult Japanese healthy smokers affects the levels of biomarkers of exposure for selected harmful and potentially harmful constituents (HPHCs) compared to smoking conventional cigarettes (CC) and smoking abstinence (SA).
Interventions
THS 2.2 ad libitum for 5 days in confinement
SA for 5 days in confinement
Subject's own preferred brand of CC ad libitum for 5 days in confinement
Sponsors
Philip Morris Products S.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
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 non-menthol CCs per day (no brand restrictions) for the last 4 weeks, based on self reporting. * 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). * The subject has received medication within 14 days or within 5 half-lives of the medication (whichever is longer), which has an impact on CYP1A2 or CYP2A6 activity. * For women: Subject is pregnant or is breast feeding. * For women: Subject does not agree to use an acceptable method of effective contraception.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Concentration of Monohydroxybutenyl Mercapturic Acid (MHBMA) | 5 days | Concentrations measured at Day 5 in urine, adjusted for creatinine. Geometric Least Squares LS) means are provided as descriptive statistics. |
| Concentration of 3-hydroxypropylmercapturic Acid (3-HPMA) | 5 days | Concentrations measured at Day 5 in urine, adjusted for creatinine. Geometric Least Squares means are provided as descriptive statistics. |
| Concentration of S-phenylmercapturic Acid (S-PMA) | 5 days | Concentrations measured at Day 5 in urine, adjusted for creatinine. Geometric Least Squares means are provided as descriptive statistics. |
| Levels of Carboxyhemoglobin (COHb) | 5 days | % COHb blood measurements performed in the evening of Day 5, expressed as % of saturation of hemoglobin. Geometric Least Squares means are provided as descriptive statistics. |
Countries
Japan
Participant flow
Recruitment details
Study initiated (first subject screened): 23 July 2013 At admission (Day -2), all the subjects performed a product trial of the THS 2.2. During the baseline period, they continued smoking their single preferred brand of CC. Then, on Day 0, subjects were randomized to one of the 3 study arms (THS 2.2, CC or SA) in a 2:1:1 ratio.
Pre-assignment details
Enrolled and randomized population = 160 subjects * 80 subjects in THS 2.2 * 40 subjects in CC * 40 subjects in SA Number of subjects enrolled but NOT randomized (who tried the THS 2.2 at Day -2) = 6
Participants by arm
| Arm | Count |
|---|---|
| Tobacco Heating System (THS 2.2) Ad libitum use of THS 2.2 for 5 days in confinement | 80 |
| Conventional Cigarette (CC) Ad libitum use of Subject's own preferred brand of CC for 5 days in confinement | 40 |
| Smoking Abstinence (SA) Abstinence from smoking for 5 days in confinement | 40 |
| Total | 160 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Tobacco Heating System (THS 2.2) | Conventional Cigarette (CC) | Smoking Abstinence (SA) | Total |
|---|---|---|---|---|
| Age, Customized Between 23 and 65 years | 37.6 years STANDARD_DEVIATION 11.7 | 37.2 years STANDARD_DEVIATION 11.7 | 35.9 years STANDARD_DEVIATION 10.6 | 37.1 years STANDARD_DEVIATION 11.4 |
| Daily CC consumption at Screening 10 to 19 cig/day | 44 participants | 22 participants | 21 participants | 87 participants |
| Daily CC consumption at Screening > 19 cig/day | 36 participants | 18 participants | 19 participants | 73 participants |
| Sex: Female, Male Female | 40 Participants | 20 Participants | 20 Participants | 80 Participants |
| Sex: Female, Male Male | 40 Participants | 20 Participants | 20 Participants | 80 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 | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 2 / 80 | 2 / 40 | 0 / 40 | 0 / 6 |
| serious Total, serious adverse events | 0 / 80 | 0 / 40 | 0 / 40 | 0 / 6 |
Outcome results
Primary
Concentration of 3-hydroxypropylmercapturic Acid (3-HPMA)
Concentrations measured at Day 5 in urine, adjusted for creatinine. Geometric Least Squares means are provided as descriptive statistics.
Time frame: 5 days
Population: The analysis was performed on the full analysis set (FAS) population.~The FAS consisted of all the randomized subjects who had at least 1 post randomization product use experience (if randomized to THS 2.2 or CC) and had at least 1 valid BoExp measurement (THS 2.2, CC, SA arms).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Tobacco Heating System (THS 2.2) | Concentration of 3-hydroxypropylmercapturic Acid (3-HPMA) | 311.68 ng/mg creat |
| Conventional Cigarette (CC) | Concentration of 3-hydroxypropylmercapturic Acid (3-HPMA) | 589.65 ng/mg creat |
| Smoking Abstinence (SA) | Concentration of 3-hydroxypropylmercapturic Acid (3-HPMA) | 204.23 ng/mg creat |
Comparison: The hypothesis to be tested is that the geometric mean level on Day 5 of the biomarker of exposure for THS 2.2 is lower relative to CC.~Analysis of the BoExp was conducted on the natural log scale in order to test the following hypothesis (one sided test with 2.5% type I error probability):~* Null hypothesis (H0): m1≥m2~* Alternative hypothesis (H1): m1\<m2 Where m1 and m2 are the geometric means of the BoExp levels on Day 5 for THS 2.2 and CC respectively.p-value: <0.00195% CI: [45.67, 61.17]ANCOVA
Primary
Concentration of Monohydroxybutenyl Mercapturic Acid (MHBMA)
Concentrations measured at Day 5 in urine, adjusted for creatinine. Geometric Least Squares LS) means are provided as descriptive statistics.
Time frame: 5 days
Population: The analysis was performed on the full analysis set (FAS) population.~The FAS consisted of all the randomized subjects who had at least 1 post randomization product use experience (if randomized to THS 2.2 or CC) and had at least 1 valid biomarker of exposure (BoExp) measurement (THS 2.2, CC, SA arms).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Tobacco Heating System (THS 2.2) | Concentration of Monohydroxybutenyl Mercapturic Acid (MHBMA) | 106.25 pg/mg creat |
| Conventional Cigarette (CC) | Concentration of Monohydroxybutenyl Mercapturic Acid (MHBMA) | 460.15 pg/mg creat |
| Smoking Abstinence (SA) | Concentration of Monohydroxybutenyl Mercapturic Acid (MHBMA) | 91.73 pg/mg creat |
Comparison: The hypothesis to be tested is that the geometric mean level on Day 5 of the biomarker of exposure for THS 2.2 is lower relative to CC.~Analysis of the BoExp was conducted on the natural log scale in order to test the following hypothesis (one sided test with 2.5% type I error probability):~* Null hypothesis (H0): m1≥m2~* Alternative hypothesis (H1): m1\<m2 Where m1 and m2 are the geometric means of the BoExp levels on Day 5 for THS 2.2 and CC respectively.p-value: <0.00195% CI: [18.41, 28.95]ANCOVA
Primary
Concentration of S-phenylmercapturic Acid (S-PMA)
Concentrations measured at Day 5 in urine, adjusted for creatinine. Geometric Least Squares means are provided as descriptive statistics.
Time frame: 5 days
Population: The analysis was performed on the full analysis set (FAS) population.~The FAS consisted of all the randomized subjects who had at least 1 post randomization product use experience (if randomized to THS 2.2 or CC) and had at least 1 valid BoExp measurement (THS 2.2, CC, SA arms).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Tobacco Heating System (THS 2.2) | Concentration of S-phenylmercapturic Acid (S-PMA) | 142.05 pg/mg creat |
| Conventional Cigarette (CC) | Concentration of S-phenylmercapturic Acid (S-PMA) | 905.89 pg/mg creat |
| Smoking Abstinence (SA) | Concentration of S-phenylmercapturic Acid (S-PMA) | 122.02 pg/mg creat |
Comparison: The hypothesis to be tested is that the geometric mean level on Day 5 of the biomarker of exposure for THS 2.2 is lower relative to CC.~Analysis of the BoExp was conducted on the natural log scale in order to test the following hypothesis (one sided test with 2.5% type I error probability):~* Null hypothesis (H0): m1≥m2~* Alternative hypothesis (H1): m1\<m2 Where m1 and m2 are the geometric means of the BoExp levels on Day 5 for THS 2.2 and CC respectively.p-value: <0.00195% CI: [13.09, 18.78]ANCOVA
Primary
Levels of Carboxyhemoglobin (COHb)
% COHb blood measurements performed in the evening of Day 5, expressed as % of saturation of hemoglobin. Geometric Least Squares means are provided as descriptive statistics.
Time frame: 5 days
Population: The analysis was performed on the full analysis set (FAS) population.~The FAS consisted of all the randomized subjects who had at least 1 post randomization product use experience (if randomized to THS 2.2 or CC) and had at least 1 valid BoExp measurement (THS 2.2, CC, SA arms).
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Tobacco Heating System (THS 2.2) | Levels of Carboxyhemoglobin (COHb) | 2.41 % of saturation of hemoglobin |
| Conventional Cigarette (CC) | Levels of Carboxyhemoglobin (COHb) | 5.13 % of saturation of hemoglobin |
| Smoking Abstinence (SA) | Levels of Carboxyhemoglobin (COHb) | 2.37 % of saturation of hemoglobin |
Comparison: The hypothesis to be tested is that the geometric mean level on Day 5 of the biomarker of exposure for THS 2.2 is lower relative to CC.~Analysis of the BoExp was conducted on the natural log scale in order to test the following hypothesis (one sided test with 2.5% type I error probability):~* Null hypothesis (H0): m1≥m2~* Alternative hypothesis (H1): m1\<m2 Where m1 and m2 are the geometric means of the BoExp levels on Day 5 for THS 2.2 and CC respectively.p-value: <0.00195% CI: [44.3, 50.08]ANCOVA