Smoking
Conditions
Keywords
Candidate modified risk tobacco product, Conventional cigarettes, Reduced exposure, HPHCs, Ambulatory
Brief summary
The main goal of the study is to evaluate if the ad libitum use of the THS 2.2 Menthol (mTHS 2.2) for 5 days in confinement and after 85 days of product use in an ambulatory setting, by Japanese adult healthy smokers results in a reduction in the levels of biomarkers of exposure for selected harmful and potentially harmful smoke constituents (HPHCs) compared to smokers continuing smoking their own preferred brand of menthol conventional cigarette (mCC) and smoking abstinence (SA). Smokers who remained abstinent from SA were used as a benchmark to provide context to the exposure reduction.
Interventions
THS 2.2 Menthol ad libitum for 5 days in confinement prolonged by 85 days in an ambulatory setting
SA for 5 days in confinement prolonged by 85 days in an ambulatory setting
Subject's own preferred brand of mCC ad libitum for 5 days in confinement prolonged by 85 days in an ambulatory setting
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 mCCs 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 cytochrome P450 1 A2 (CYP1A2) or cytochrome P450 2 A6 (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 Total 4-(Methylnitrosamino)-1-(3- Pyridyl)-1-butanol) (Total NNAL) | 90 days | Concentrations measured at Day 90 in urine, adjusted for creatinine. Geometric Least Squares (LS) means are provided as descriptive statistics. |
| 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 (LS) 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 (LS) 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): 01 August 2013 At admission (Day -2), all the subjects performed a product trial of the THS 2.2 Menthol. During the baseline period, they continued smoking their single preferred brand of mCC. Then, on Day 0, they were randomized to one of the 3 study arms (mTHS 2.2, mCC or SA) in a 2:1:1 ratio.
Pre-assignment details
Enrolled and randomized population = 160 subjects * 78 subjects in mTHS 2.2 * 42 subjects in mCC * 40 subjects in SA Number of subjects enrolled but NOT randomized (who tried the mTHS 2.2 at Day -2) = 0
Participants by arm
| Arm | Count |
|---|---|
| THS 2.2 Menthol (mTHS 2.2) Ad libitum use of THS 2.2 Menthol for 5 days in a confinement setting and 85 days in an ambulatory setting | 78 |
| Menthol Conventional Cigarette (mCC) Ad libitum use of subject's own preferred brand of mCC for 5 days in a confinement setting and 85 days in an ambulatory setting | 42 |
| Smoking Abstinence (SA) Abstinence from smoking for 5 days in a confinement setting and 85 days in an ambulatory setting | 40 |
| Total | 160 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Confinement Period (Population at Day 5) | Withdrawal by Subject | 1 | 1 | 1 |
| End of Study (Population at Day 90) | Withdrawal by Subject | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | THS 2.2 Menthol (mTHS 2.2) | Menthol Conventional Cigarette (mCC) | Smoking Abstinence (SA) | Total |
|---|---|---|---|---|
| Age, Continuous | 37.1 years STANDARD_DEVIATION 10.58 | 37.4 years STANDARD_DEVIATION 11.23 | 37.0 years STANDARD_DEVIATION 9.96 | 37.2 years STANDARD_DEVIATION 10.54 |
| Daily mCC consumption at Screening 10 to 19 cig/day | 40 participants | 23 participants | 21 participants | 84 participants |
| Daily mCC consumption at Screening > 19 cig/day | 38 participants | 19 participants | 19 participants | 76 participants |
| Sex: Female, Male Female | 33 Participants | 17 Participants | 18 Participants | 68 Participants |
| Sex: Female, Male Male | 45 Participants | 25 Participants | 22 Participants | 92 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 | 16 / 78 | 4 / 42 | 4 / 40 |
| serious Total, serious adverse events | 0 / 78 | 0 / 42 | 0 / 40 |
Outcome results
Primary
Concentration of 3-hydroxypropylmercapturic Acid (3-HPMA)
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 Per Protocol set (PP) which included all randomized subjects who had no major protocol deviation impacting the evaluability during the confinement period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| THS 2.2 Menthol (mTHS 2.2) | Concentration of 3-hydroxypropylmercapturic Acid (3-HPMA) | 304.56 ng/mg creat |
| Menthol Conventional Cigarette (mCC) | Concentration of 3-hydroxypropylmercapturic Acid (3-HPMA) | 601.11 ng/mg creat |
| Smoking Abstinence (SA) | Concentration of 3-hydroxypropylmercapturic Acid (3-HPMA) | 183.61 ng/mg creat |
Comparison: The hypothesis to be tested is that the geometric mean level on Day 5 of the biomarker of exposure for mTHS 2.2 is lower relative to mCC.~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 mTHS 2.2 and mCC respectively.p-value: <0.00195% CI: [44.88, 57.2]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 Per Protocol set (PP) which included all randomized subjects who had no major protocol deviation impacting the evaluability during the confinement period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| THS 2.2 Menthol (mTHS 2.2) | Concentration of Monohydroxybutenyl Mercapturic Acid (MHBMA) | 83.21 pg/mg creat |
| Menthol Conventional Cigarette (mCC) | Concentration of Monohydroxybutenyl Mercapturic Acid (MHBMA) | 617.04 pg/mg creat |
| Smoking Abstinence (SA) | Concentration of Monohydroxybutenyl Mercapturic Acid (MHBMA) | 83.57 pg/mg creat |
Comparison: The hypothesis to be tested is that the geometric mean level on Day 5 of the biomarker of exposure for mTHS 2.2 is lower relative to mCC.~Analysis of the biomarker of exposure (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 mTHS 2.2 and mCC respectively.p-value: <0.00195% CI: [10.96, 16.6]ANCOVA
Primary
Concentration of S-phenylmercapturic Acid (S-PMA)
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 Per Protocol set (PP) which included all randomized subjects who had no major protocol deviation impacting the evaluability during the confinement period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| THS 2.2 Menthol (mTHS 2.2) | Concentration of S-phenylmercapturic Acid (S-PMA) | 119.18 pg/mg creat |
| Menthol Conventional Cigarette (mCC) | Concentration of S-phenylmercapturic Acid (S-PMA) | 1086.89 pg/mg creat |
| Smoking Abstinence (SA) | Concentration of S-phenylmercapturic Acid (S-PMA) | 104.83 pg/mg creat |
Comparison: The hypothesis to be tested is that the geometric mean level on Day 5 of the biomarker of exposure for mTHS 2.2 is lower relative to mCC.~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 mTHS 2.2 and mCC respectively.p-value: <0.00195% CI: [9.26, 12.99]ANCOVA
Primary
Concentration of Total 4-(Methylnitrosamino)-1-(3- Pyridyl)-1-butanol) (Total NNAL)
Concentrations measured at Day 90 in urine, adjusted for creatinine. Geometric Least Squares (LS) means are provided as descriptive statistics.
Time frame: 90 days
Population: The analysis was performed on the Per Protocol set (PP) which included all randomized subjects who had no major protocol deviation impacting the evaluability during the period Day 60 to Day 90.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| THS 2.2 Menthol (mTHS 2.2) | Concentration of Total 4-(Methylnitrosamino)-1-(3- Pyridyl)-1-butanol) (Total NNAL) | 22.48 pg/mg creat |
| Menthol Conventional Cigarette (mCC) | Concentration of Total 4-(Methylnitrosamino)-1-(3- Pyridyl)-1-butanol) (Total NNAL) | 96.65 pg/mg creat |
| Smoking Abstinence (SA) | Concentration of Total 4-(Methylnitrosamino)-1-(3- Pyridyl)-1-butanol) (Total NNAL) | 14.90 pg/mg creat |
Comparison: The hypothesis to be tested is that the geometric mean level on Day 90 of the biomarker of exposure for mTHS 2.2 is lower relative to mCC.~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 90 for mTHS 2.2 and mCC respectively.p-value: <0.00195% CI: [17.38, 31.11]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 Per Protocol set (PP) which included all randomized subjects who had no major protocol deviation impacting the evaluability during the confinement period.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| THS 2.2 Menthol (mTHS 2.2) | Levels of Carboxyhemoglobin (COHb) | 2.47 % of saturation of hemoglobin |
| Menthol Conventional Cigarette (mCC) | Levels of Carboxyhemoglobin (COHb) | 5.49 % of saturation of hemoglobin |
| Smoking Abstinence (SA) | Levels of Carboxyhemoglobin (COHb) | 2.49 % 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 mTHS 2.2 is lower relative to mCC.~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 mTHS 2.2 and mCC respectively.p-value: <0.00195% CI: [42.11, 47.97]ANCOVA