Reduced Exposure Study Using THS 2.2 Menthol With 5 Days in a Confinement Setting and 85 Days in an Ambulatory Setting

• Sponsor: Philip Morris Products S.A. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01970995
• Collaborator: (none)
• Enrollment: 160
• Location: 1
• Arms: 3
• Duration (Months): 15
• Patients Per Site Per Month: 10.7

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Smoking	Other: THS 2.2 Menthol (mTHS 2.2); Other: Smoking Abstinence (SA); Other: Menthol Conventional Cigarette (mCC)	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 160 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A Randomized, Controlled, Multi-center Study to Demonstrate Reductions in Exposure to Selected Smoke Constituents in Smokers Switching to THS 2.2 Menthol or Smoking Abstinence Compared to Smoking Menthol Conventional Cigarettes, for 90 Days
• Study Start Date: Aug 1, 2013
• Actual Primary Completion Date: Jul 1, 2014
• Actual Study Completion Date: Nov 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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	Other: THS 2.2 Menthol (mTHS 2.2); THS 2.2 Menthol ad libitum for 5 days in confinement prolonged by 85 days in an ambulatory setting
Active Comparator: Smoking abstinence (SA) Abstinence from smoking for 5 Days in a Confinement Setting and 85 Days in an Ambulatory Setting	Other: Smoking Abstinence (SA); SA for 5 days in confinement prolonged by 85 days in an ambulatory setting
Active Comparator: 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	Other: Menthol Conventional Cigarette (mCC); Subject's own preferred brand of mCC ad libitum for 5 days in confinement prolonged by 85 days in an ambulatory setting

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 23 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Osaki Hospital Tokyo Heart Center, 5-4-12, Kitashinagawa, Shinagawa-ku	Tokyo		Japan

Sponsors and Collaborators

• Philip Morris Products S.A.

Investigators

• Principal Investigator: Masahiro Endo, MD, Osaki Hospital Tokyo Heart Center
• Study Chair: Christelle Haziza, PhD, Philip Morris Products S.A.

Study Documents (Full-Text)

• Study Protocol - Apr 7, 2014
• Statistical Analysis Plan - Nov 7, 2014

More Information

Publications

None provided.

• Responsible Party: Philip Morris Products S.A.
• ClinicalTrials.gov Identifier: NCT01970995
• Other Study ID Numbers: ZRHM-REXA-07-JP; ZRHM-REXA-07-JP
• First Posted: Oct 28, 2013
• Last Update Posted: Mar 23, 2020
• Last Verified: Mar 1, 2020

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Keywords provided by Philip Morris Products S.A.: Candidate modified risk tobacco product; Conventional cigarettes; Reduced exposure; HPHCs; Ambulatory
• Additional relevant MeSH terms: Menthol

Study Results

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 Detail	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

Arm/Group Title	THS 2.2 Menthol (mTHS 2.2)	Menthol Conventional Cigarette (mCC)	Smoking Abstinence (SA)
Arm/Group Description	Ad libitum use of THS 2.2 Menthol for 5 days in a confinement setting and 85 days in an ambulatory setting	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	Abstinence from smoking for 5 days in a confinement setting and 85 days in an ambulatory setting
Period Title: Confinement Period (Population at Day 5)
STARTED	78	42	40
COMPLETED	77	41	39
NOT COMPLETED	1	1	1
Period Title: Confinement Period (Population at Day 5)
STARTED	77	41	39
COMPLETED	76	41	38
NOT COMPLETED	1	0	1

Baseline Characteristics

Arm/Group Title	THS 2.2 Menthol (mTHS 2.2)	Menthol Conventional Cigarette (mCC)	Smoking Abstinence (SA)	Total
Arm/Group Description	Ad libitum use of THS 2.2 Menthol for 5 days in a confinement setting and 85 days in an ambulatory setting	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	Abstinence from smoking for 5 days in a confinement setting and 85 days in an ambulatory setting	Total of all reporting groups
Overall Participants	78	42	40	160
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	37.1 (10.58)	37.4 (11.23)	37.0 (9.96)	37.2 (10.54)
Sex: Female, Male (Count of Participants)
Female	33 42.3%	17 40.5%	18 45%	68 42.5%
Male	45 57.7%	25 59.5%	22 55%	92 57.5%
Daily mCC consumption at Screening (participants) [Number]
10 to 19 cig/day	40 51.3%	23 54.8%	21 52.5%	84 52.5%
> 19 cig/day	38 48.7%	19 45.2%	19 47.5%	76 47.5%

Outcome Measures

1. Primary Outcome

Title	Concentration of Monohydroxybutenyl Mercapturic Acid (MHBMA)
Description	Concentrations measured at Day 5 in urine, adjusted for creatinine. Geometric Least Squares (LS) means are provided as descriptive statistics.
Time Frame	5 days

Outcome Measure Data

Analysis Population Description

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/Group Title	THS 2.2 Menthol (mTHS 2.2)	Menthol Conventional Cigarette (mCC)	Smoking Abstinence (SA)
Arm/Group Description	Ad libitum use of THS 2.2 Menthol for 5 days in a confinement setting and 85 days in an ambulatory setting	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	Abstinence from smoking for 5 days in a confinement setting and 85 days in an ambulatory setting
Measure Participants	76	42	39
Least Squares Mean (95% Confidence Interval) [pg/mg creat]	83.21	617.04	83.57

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	THS 2.2 Menthol (mTHS 2.2), Menthol Conventional Cigarette (mCC)
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments	The primary endpoints were tested using a multiple testing procedure to preserve the overall alpha level by simultaneously testing the endpoints using a closed procedure with each test performed at an alpha level of 2.5% one sided.
	Method	ANCOVA
	Comments	ANCOVA model on MHBMA levels with product, sex, cigarette consumption, and baseline value as covariates.
Method of Estimation	Estimation Parameter	Geometric LS Mean Ratio
	Estimated Value	13.49
	Confidence Interval	(2-Sided) 95%; 10.96 to 16.60
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric LS mean ratio mTHS 2.2:mCC

2. Primary Outcome

Title	Concentration of 3-hydroxypropylmercapturic Acid (3-HPMA)
Description	Concentrations measured at Day 5 in urine, adjusted for creatinine. Geometric Least Squares (LS) means are provided as descriptive statistics.
Time Frame	5 days

Outcome Measure Data

Analysis Population Description

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/Group Title	THS 2.2 Menthol (mTHS 2.2)	Menthol Conventional Cigarette (mCC)	Smoking Abstinence (SA)
Arm/Group Description	Ad libitum use of THS 2.2 Menthol for 5 days in a confinement setting and 85 days in an ambulatory setting	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	Abstinence from smoking for 5 days in a confinement setting and 85 days in an ambulatory setting
Measure Participants	76	42	39
Least Squares Mean (95% Confidence Interval) [ng/mg creat]	304.56	601.11	183.61

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	THS 2.2 Menthol (mTHS 2.2), Menthol Conventional Cigarette (mCC)
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments	The primary endpoints were tested using a multiple testing procedure to preserve the overall alpha level by simultaneously testing the endpoints using a closed procedure with each test performed at an alpha level of 2.5% one sided.
	Method	ANCOVA
	Comments	ANCOVA model on 3-HPMA levels with product, sex, cigarette consumption, and baseline value as covariates.
Method of Estimation	Estimation Parameter	Geometric LS Mean Ratio
	Estimated Value	50.67
	Confidence Interval	(2-Sided) 95%; 44.88 to 57.20
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric LS mean ratio mTHS 2.2:mCC

3. Primary Outcome

Title	Concentration of S-phenylmercapturic Acid (S-PMA)
Description	Concentrations measured at Day 5 in urine, adjusted for creatinine. Geometric Least Squares (LS) means are provided as descriptive statistics.
Time Frame	5 days

Outcome Measure Data

Analysis Population Description

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/Group Title	THS 2.2 Menthol (mTHS 2.2)	Menthol Conventional Cigarette (mCC)	Smoking Abstinence (SA)
Arm/Group Description	Ad libitum use of THS 2.2 Menthol for 5 days in a confinement setting and 85 days in an ambulatory setting	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	Abstinence from smoking for 5 days in a confinement setting and 85 days in an ambulatory setting
Measure Participants	76	42	39
Least Squares Mean (95% Confidence Interval) [pg/mg creat]	119.18	1086.89	104.83

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	THS 2.2 Menthol (mTHS 2.2), Menthol Conventional Cigarette (mCC)
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments	The primary endpoints were tested using a multiple testing procedure to preserve the overall alpha level by simultaneously testing the endpoints using a closed procedure with each test performed at an alpha level of 2.5% one sided.
	Method	ANCOVA
	Comments	ANCOVA model on S-PMA levels with product, sex, cigarette consumption, and baseline value as covariates.
Method of Estimation	Estimation Parameter	Geometric LS Mean Ratio
	Estimated Value	10.97
	Confidence Interval	(2-Sided) 95%; 9.26 to 12.99
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric LS mean ratio mTHS 2.2:mCC

4. Primary Outcome

Title	Levels of Carboxyhemoglobin (COHb)
Description	% 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

Outcome Measure Data

Analysis Population Description

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/Group Title	THS 2.2 Menthol (mTHS 2.2)	Menthol Conventional Cigarette (mCC)	Smoking Abstinence (SA)
Arm/Group Description	Ad libitum use of THS 2.2 Menthol for 5 days in a confinement setting and 85 days in an ambulatory setting	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	Abstinence from smoking for 5 days in a confinement setting and 85 days in an ambulatory setting
Measure Participants	76	42	39
Least Squares Mean (95% Confidence Interval) [% of saturation of hemoglobin]	2.47	5.49	2.49

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	THS 2.2 Menthol (mTHS 2.2), Menthol Conventional Cigarette (mCC)
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments	The primary endpoints were tested using a multiple testing procedure to preserve the overall alpha level by simultaneously testing the endpoints using a closed procedure with each test performed at an alpha level of 2.5% one sided.
	Method	ANCOVA
	Comments	ANCOVA model on COHb levels with product, sex, cigarette consumption, and baseline value as covariates.
Method of Estimation	Estimation Parameter	Geometric LS Mean Ratio
	Estimated Value	44.94
	Confidence Interval	(2-Sided) 95%; 42.11 to 47.97
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric LS mean ratio mTHS 2.2:mCC

5. Primary Outcome

Title	Concentration of Total 4-(Methylnitrosamino)-1-(3- Pyridyl)-1-butanol) (Total NNAL)
Description	Concentrations measured at Day 90 in urine, adjusted for creatinine. Geometric Least Squares (LS) means are provided as descriptive statistics.
Time Frame	90 days

Outcome Measure Data

Analysis Population Description

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/Group Title	THS 2.2 Menthol (mTHS 2.2)	Menthol Conventional Cigarette (mCC)	Smoking Abstinence (SA)
Arm/Group Description	Ad libitum use of THS 2.2 Menthol for 5 days in a confinement setting and 85 days in an ambulatory setting	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	Abstinence from smoking for 5 days in a confinement setting and 85 days in an ambulatory setting
Measure Participants	70	41	37
Least Squares Mean (95% Confidence Interval) [pg/mg creat]	22.48	96.65	14.90

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	THS 2.2 Menthol (mTHS 2.2), Menthol Conventional Cigarette (mCC)
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	<.001
	Comments	The primary endpoints were tested using a multiple testing procedure to preserve the overall alpha level by simultaneously testing the endpoints using a closed procedure with each test performed at an alpha level of 2.5% one sided.
	Method	ANCOVA
	Comments	ANCOVA model on Total NNAL levels with product, sex, cigarette consumption, and baseline value as covariates
Method of Estimation	Estimation Parameter	Geometric LS Mean Ratio
	Estimated Value	23.25
	Confidence Interval	(2-Sided) 95%; 17.38 to 31.11
	Parameter Dispersion	Type: Value:
	Estimation Comments	Geometric LS mean ratio mTHS 2.2:mCC

Adverse Events

Time Frame	From the informed consent form signature until the end of the safety follow-up period, up to 150 days (including a screening period of up to 28 days, a 9-day confinement period followed by a 85-day ambulatory setting, and by a 28-day safety follow-up period (28 days after discharge of the subject or early discontinuation)).
Adverse Event Reporting Description	The safety was assessed in the safety population, consisting of 160 subjects: 160 randomized subjects (78 in mTHS 2.2, 42 in mCC and 40 in SA) and no subject exposed to mTHS 2.2 from the product trial on Day -2 but not randomized.
Arm/Group Title	THS 2.2 Menthol (mTHS 2.2)		Menthol Conventional Cigarette (mCC)		Smoking Abstinence (SA)
Arm/Group Description	Ad libitum use of THS 2.2 Menthol for 5 days in a confinement setting and 85 days in an ambulatory setting		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		Abstinence from smoking for 5 days in a confinement setting and 85 days in an ambulatory setting
All Cause Mortality
	THS 2.2 Menthol (mTHS 2.2)		Menthol Conventional Cigarette (mCC)		Smoking Abstinence (SA)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	THS 2.2 Menthol (mTHS 2.2)		Menthol Conventional Cigarette (mCC)		Smoking Abstinence (SA)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/78 (0%)		0/42 (0%)		0/40 (0%)
Other (Not Including Serious) Adverse Events
	THS 2.2 Menthol (mTHS 2.2)		Menthol Conventional Cigarette (mCC)		Smoking Abstinence (SA)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/78 (20.5%)		4/42 (9.5%)		4/40 (10%)
Investigations
Haemoglobin decreased	11/78 (14.1%)	13	3/42 (7.1%)	5	3/40 (7.5%)	4
Neutrophil count decreased	5/78 (6.4%)	5	1/42 (2.4%)	1	2/40 (5%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

We confirm we have the contractual provisions in place which specifies that in no event will the study site be allowed to disclose to any third party (or publicly release) any information obtained through the study without the CRO's prior written consent which in turn cannot provide such consent without Sponsor's approval unless such publication is made to satisfy regulatory requirements. The Intellectual Property rights and research results from the present study belongs to the Sponsor.