Reduced Exposure Study in Smokers Using the Tobacco Heating System 2.2 (THS 2.2) for 5 Days in a Confinement Setting

• ClinicalTrials.gov Identifier: NCT01970982
• Recruitment Status: Completed
• First Posted: October 28, 2013
• Results First Posted: October 17, 2016
• Last Update Posted: March 12, 2020
• Sponsor: Philip Morris Products S.A.
• Information provided by (Responsible Party): Philip Morris Products S.A.

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Other
• Condition: Smoking
• Interventions: Other: Tobacco Heating System (THS 2.2); Other: Smoking abstinence (SA); Other: Conventional cigarette (CC)
• Enrollment: 166

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

Arm/Group Title	Tobacco Heating System (THS 2.2)	Conventional Cigarette (CC)	Smoking Abstinence (SA)
Arm/Group Description	Ad libitum use of THS 2.2 for 5 days in confinement	Ad libitum use of Subject's own preferred brand of CC for 5 days in confinement	Abstinence from smoking for 5 days in confinement
Period Title: Overall Study
Started	80	40	40
Completed	80	40	38
Not Completed	0	0	2
Reason Not Completed
Withdrawal by Subject	0	0	2

Baseline Characteristics

Arm/Group Title		Tobacco Heating System (THS 2.2)	Conventional Cigarette (CC)	Smoking Abstinence (SA)	Total
Arm/Group Description		Ad libitum use of THS 2.2 for 5 days in confinement	Ad libitum use of Subject's own preferred brand of CC for 5 days in confinement	Abstinence from smoking for 5 days in confinement	Total of all reporting groups
Overall Number of Baseline Participants		80	40	40	160
Baseline Analysis Population Description		The study population consisted of all the randomized subjects who had at least 1 post randomization product use experience (THS 2.2 or CC arms), and 1 valid biomarker of exposure (BoExp) measurement. 160 randomized subjects: 80 in THS 2.2, 40 in CC and 40 in SA 158 completers: 2 subjects (SA arm) voluntarily withdrew on Day 1 and Day 3
Age, Customized; Mean (Standard Deviation); Unit of measure: Years
Between 23 and 65 years	Number Analyzed	80 participants	40 participants	40 participants	160 participants
		37.6 (11.7)	37.2 (11.7)	35.9 (10.6)	37.1 (11.4)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	80 participants	40 participants	40 participants	160 participants
	Female	40 50.0%	20 50.0%	20 50.0%	80 50.0%
	Male	40 50.0%	20 50.0%	20 50.0%	80 50.0%
Daily CC consumption at Screening; Measure Type: Number; Unit of measure: Participants	Number Analyzed	80 participants	40 participants	40 participants	160 participants
10 to 19 cig/day		44	22	21	87
> 19 cig/day		36	18	19	73

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 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/Group Title	Tobacco Heating System (THS 2.2)	Conventional Cigarette (CC)	Smoking Abstinence (SA)
Arm/Group Description:	Ad libitum use of THS 2.2 for 5 days in confinement	Ad libitum use of subject's own preferred brand of CC for 5 days in confinement	Abstinence from smoking for 5 days in confinement
Overall Number of Participants Analyzed	80	40	38
Least Squares Mean (95% Confidence Interval); Unit of Measure: pg/mg creat
	106.25; (93.22 to 121.11)	460.15; (382.54 to 553.51)	91.73; (75.91 to 110.86)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tobacco Heating System (THS 2.2), Conventional Cigarette (CC)
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	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	23.09
	Confidence Interval	(2-Sided) 95%; 18.41 to 28.95
	Estimation Comments	LS mean ratio THS 2.2:CC

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 means are provided as descriptive statistics.
Time Frame	5 days

Outcome Measure Data

Analysis Population Description

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/Group Title	Tobacco Heating System (THS 2.2)	Conventional Cigarette (CC)	Smoking Abstinence (SA)
Arm/Group Description:	Ad libitum use of THS 2.2 for 5 days in confinement	Ad libitum use of subject's own preferred brand of CC for 5 days in confinement	Abstinence from smoking for 5 days in confinement
Overall Number of Participants Analyzed	80	40	38
Least Squares Mean (95% Confidence Interval); Unit of Measure: ng/mg creat
	311.68; (286.43 to 339.16)	589.65; (523.25 to 664.47)	204.23; (180.70 to 230.82)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tobacco Heating System (THS 2.2), Conventional Cigarette (CC)
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	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	52.86
	Confidence Interval	(2-Sided) 95%; 45.67 to 61.17
	Estimation Comments	LS mean ratio THS 2.2:CC

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 means are provided as descriptive statistics.
Time Frame	5 days

Outcome Measure Data

Analysis Population Description

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/Group Title	Tobacco Heating System (THS 2.2)	Conventional Cigarette (CC)	Smoking Abstinence (SA)
Arm/Group Description:	Ad libitum use of THS 2.2 for 5 days in confinement	Ad libitum use of subject's own preferred brand of CC for 5 days in confinement	Abstinence from smoking for 5 days in confinement
Overall Number of Participants Analyzed	80	40	38
Least Squares Mean (95% Confidence Interval); Unit of Measure: pg/mg creat
	142.05; (127.98 to 157.65)	905.89; (781.81 to 1049.67)	122.02; (104.92 to 141.90)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tobacco Heating System (THS 2.2), Conventional Cigarette (CC)
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	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	15.68
	Confidence Interval	(2-Sided) 95%; 13.09 to 18.78
	Estimation Comments	LS mean ratio THS 2.2:CC

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 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/Group Title	Tobacco Heating System (THS 2.2)	Conventional Cigarette (CC)	Smoking Abstinence (SA)
Arm/Group Description:	Ad libitum use of THS 2.2 for 5 days in confinement	Ad libitum use of subject's own preferred brand of CC for 5 days in confinement	Abstinence from smoking for 5 days in confinement
Overall Number of Participants Analyzed	80	40	38
Least Squares Mean (95% Confidence Interval); Unit of Measure: % of saturation of hemoglobin
	2.41; (2.33 to 2.51)	5.13; (4.87 to 5.39)	2.37; (2.24 to 2.50)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Tobacco Heating System (THS 2.2), Conventional Cigarette (CC)
	Comments	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.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.001
	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	47.10
	Confidence Interval	(2-Sided) 95%; 44.30 to 50.08
	Estimation Comments	LS mean ratio THS 2.2:CC

Adverse Events

Time Frame	From the informed consent form (ICF) signature until the end of the safety follow-up period (7 days after discharge of the subject).
Adverse Event Reporting Description	The safety was assessed in the safety population, consisting of 166 subjects: 160 randomized subjects (80 in THS 2.2, 40 in CC and 40 in SA) and 6 subjects exposed to THS 2.2 from the product trial on Day -2 but not randomized.
Arm/Group Title	Tobacco Heating System (THS 2.2)		Conventional Cigarette (CC)		Smoking Abstinence (SA)		Enrolled But Not Randomized
Arm/Group Description	Ad libitum use of THS 2.2 for 5 days in confinement		Ad libitum use of Subject's own preferred brand of CC for 5 days in confinement		Abstinence from smoking for 5 days in confinement		Subjects who tried the THS 2.2 at Admission (Day -2) but were not randomized in 1 of the 3 arms as they were back-up subjects
All-Cause Mortality
	Tobacco Heating System (THS 2.2)		Conventional Cigarette (CC)		Smoking Abstinence (SA)		Enrolled But Not Randomized
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--		--/--		--/--
Serious Adverse Events
	Tobacco Heating System (THS 2.2)		Conventional Cigarette (CC)		Smoking Abstinence (SA)		Enrolled But Not Randomized
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/80 (0.00%)		0/40 (0.00%)		0/40 (0.00%)		0/6 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Tobacco Heating System (THS 2.2)		Conventional Cigarette (CC)		Smoking Abstinence (SA)		Enrolled But Not Randomized
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/80 (2.50%)		2/40 (5.00%)		0/40 (0.00%)		0/6 (0.00%)
Investigations
Blood triglycerides increased * 1	2/80 (2.50%)	2	2/40 (5.00%)	2	0/40 (0.00%)	0	0/6 (0.00%)	0
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA (16.0)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

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.

Results Point of Contact

• Name/Title: Christelle HAZIZA, PhD
• Organization: Philip Morris Products S.A.
• Phone: +41 (58) 242 2625
• EMail: Christelle.Haziza@pmi.com

• Responsible Party: Philip Morris Products S.A.
• ClinicalTrials.gov Identifier: NCT01970982
• Other Study ID Numbers: ZRHR-REXC-04-JP; ZRHR-REXC-04-JP ( Other Identifier: Philip Morris Products S.A. )
• First Submitted: October 18, 2013
• First Posted: October 28, 2013
• Results First Submitted: January 26, 2016
• Results First Posted: October 17, 2016
• Last Update Posted: March 12, 2020