Reduced Exposure Study Using CHTP 1.0 During 5 Days in Confinement.

• ClinicalTrials.gov Identifier: NCT02503254
• Recruitment Status: Completed
• First Posted: July 20, 2015
• Results First Posted: March 10, 2017
• Last Update Posted: January 30, 2023
• 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: CHTP 1.0; Other: Conventional Cigarette (CC)
• Enrollment: 85

Participant Flow

Recruitment Details	Study initiated (first subject screened): 04 July 2015 At admission (Day -3), all the subjects performed a product trial of the CHTP 1.0. During the baseline period, they continued smoking their single preferred brand of CC. Then, on Day -1, subjects were randomized to one of the two study arms (CHTP 1.0 or CC) in a 1:1 ratio.
Pre-assignment Details	Enrolled and randomized population = 80 subjects; 41 subjects in CHTP 1.0 arm; 39 subjects in CC arm Number of subjects enrolled but NOT randomized (who tried the CHTP 1.0 at Day -3) = 5

Arm/Group Title	CHTP 1.0	Conventional Cigarette (CC)
Arm/Group Description	Ad libitum use of the Carbon Heated Tobacco Product 1.0 (CHTP 1.0) for 5 days in confinement	Ad libitum use of subject's own preferred brand of CC for 5 days in confinement
Period Title: Overall Study
Started	41	39
Completed	41	39
Not Completed	0	0

Baseline Characteristics

Arm/Group Title		CHTP 1.0	Conventional Cigarette (CC)	Total
Arm/Group Description		Ad libitum use of the Carbon Heated Tobacco Product 1.0 (CHTP 1.0) for 5 days in confinement	Ad libitum use of subject's own preferred brand of CC for 5 days in confinement	Total of all reporting groups
Overall Number of Baseline Participants		41	39	80
Baseline Analysis Population Description		The study population consisted of all the randomized subjects who had at least 1 post randomization product use experience (CHTP 1.0 or CC), and at least 1 valid non-safety assessment. 80 randomized subjects: 41 in CHTP 1.0 and 39 in CC study arms. All the randomized subjects completed the study.
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	41 participants	39 participants	80 participants
		34.1 (10.45)	32.7 (10.97)	33.5 (10.66)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	41 participants	39 participants	80 participants
	Female	21 51.2%	20 51.3%	41 51.2%
	Male	20 48.8%	19 48.7%	39 48.8%
International Organization for Standardization (ISO) nicotine level; Measure Type: Count of Participants; Unit of measure: Participants	Number Analyzed	41 participants	39 participants	80 participants
≤ 0.6 mg		32 78.0%	34 87.2%	66 82.5%
> 0.6 to ≤ 1 mg		9 22.0%	5 12.8%	14 17.5%

Outcome Measures

1. Primary Outcome

Title	Concentration of Monohydroxybutenyl Mercapturic Acid (MHBMA)
Description	Concentrations measured on 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 (CHTP 1.0 or CC) and had at least 1 non-safety assessment.

Arm/Group Title	CHTP 1.0	Conventional Cigarette (CC)
Arm/Group Description:	Ad libitum use of the Carbon Heated Tobacco Product 1.0 (CHTP 1.0) for 5 days in confinement	Ad libitum use of subject's own preferred brand of CC for 5 days in confinement
Overall Number of Participants Analyzed	41	39
Least Squares Mean (95% Confidence Interval); Unit of Measure: pg/mg creat
	327.08; (282.39 to 378.84)	1903.61; (1637.48 to 2212.99)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CHTP 1.0, Conventional Cigarette (CC)
	Comments	The hypothesis to be tested is that the geometric mean level on Day 5 of the biomarker of exposure for CHTP 1.0 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 CHTP 1.0 and CC, respectively.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
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 a two-sided alpha level of 5%.
	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 Reduction
	Estimated Value	82.82
	Confidence Interval	(2-Sided) 95%; 78.79 to 86.09
	Estimation Comments	Geometric LS Mean Reduction = 100 - (CHTP 1.0 : CC ratio) Expressed as %

2. Primary Outcome

Title	Concentration of 3-hydroxypropylmercapturic Acid (3-HPMA)
Description	Concentrations measured on 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 (CHTP 1.0 or CC) and had at least 1 non-safety assessment.

Arm/Group Title	CHTP 1.0	Conventional Cigarette (CC)
Arm/Group Description:	Ad libitum use of the Carbon Heated Tobacco Product 1.0 (CHTP 1.0) for 5 days in confinement	Ad libitum use of subject's own preferred brand of CC for 5 days in confinement
Overall Number of Participants Analyzed	41	39
Least Squares Mean (95% Confidence Interval); Unit of Measure: ng/mg creat
	464.27; (432.13 to 498.80)	1272.96; (1182.66 to 1370.15)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CHTP 1.0, Conventional Cigarette (CC)
	Comments	The hypothesis to be tested is that the geometric mean level on Day 5 of the biomarker of exposure for CHTP 1.0 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 CHTP 1.0 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 a two-sided alpha level of 5%.
	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 Reduction
	Estimated Value	63.53
	Confidence Interval	(2-Sided) 95%; 59.55 to 67.12
	Estimation Comments	Geometric LS Mean Reduction = 100 - (CHTP 1.0 : CC ratio) Expressed as %

3. Primary Outcome

Title	Concentration of S-phenylmercapturic Acid (S-PMA)
Description	Concentrations measured on 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 (CHTP 1.0 or CC) and had at least 1 non-safety assessment.

Arm/Group Title	CHTP 1.0	Conventional Cigarette (CC)
Arm/Group Description:	Ad libitum use of the Carbon Heated Tobacco Product 1.0 (CHTP 1.0) for 5 days in confinement	Ad libitum use of subject's own preferred brand of CC for 5 days in confinement
Overall Number of Participants Analyzed	41	39
Least Squares Mean (95% Confidence Interval); Unit of Measure: pg/mg creat
	352.39; (321.26 to 386.54)	2971.98; (2703.14 to 3267.55)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CHTP 1.0, Conventional Cigarette (CC)
	Comments	The hypothesis to be tested is that the geometric mean level on Day 5 of the biomarker of exposure for CHTP 1.0 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 CHTP 1.0 and CC, respectively.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
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 a two-sided alpha level of 5%.
	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 Reduction
	Estimated Value	88.14
	Confidence Interval	(2-Sided) 95%; 86.46 to 89.62
	Estimation Comments	Geometric LS Mean Reduction = 100 - (CHTP 1.0 : CC ratio) Expressed as %

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: all randomized subjects who had at least 1 post randomization product use experience (CHTP 1.0 or CC) and had at least 1 non-safety assessment.

However, due to sample issues such as clotting, COHb assessment results could not be generated for some of the subjects.

Arm/Group Title	CHTP 1.0	Conventional Cigarette (CC)
Arm/Group Description:	Ad libitum use of the Carbon Heated Tobacco Product 1.0 (CHTP 1.0) for 5 days in confinement	Ad libitum use of subject's own preferred brand of CC for 5 days in confinement
Overall Number of Participants Analyzed	32	26
Least Squares Mean (95% Confidence Interval); Unit of Measure: percentage of saturation of hemoglobin
	2.660; (2.316 to 3.054)	6.460; (5.531 to 7.544)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	CHTP 1.0, Conventional Cigarette (CC)
	Comments	The hypothesis to be tested is that the geometric mean level on Day 5 of the biomarker of exposure for CHTP 1.0 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 CHTP 1.0 and CC respectively.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]
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	58.83
	Confidence Interval	(2-Sided) 95%; 49.30 to 66.56
	Estimation Comments	Geometric LS Mean Reduction = 100 - (CHTP 1.0 : CC ratio) Expressed as %

Adverse Events

Time Frame	From the informed consent form signature until the end of the safety follow-up period, up to 58 days (including a screening period of up to 42 days, a 9-day confinement period followed by a 7-day safety follow-up period (7 days after discharge of the subject or early discontinuation)).
Adverse Event Reporting Description	The safety was assessed in the safety population, consisting of 85 subjects: 80 randomized subjects (41 in CHTP 1.0 and 39 in CC) and 5 subjects exposed to CHTP 1.0 during the product trial on Day -3 but not randomized.
Arm/Group Title	CHTP 1.0		Conventional Cigarette (CC)		Enrolled But Not Randomized
Arm/Group Description	Ad libitum use of the Carbon Heated Tobacco Product 1.0 (CHTP 1.0) for 5 days in confinement		Ad libitum use of subject's own preferred brand of CC for 5 days in confinement		Subjects who tried the CHTP 1.0 at Admission (Day -3) but were not randomized
All-Cause Mortality
	CHTP 1.0		Conventional Cigarette (CC)		Enrolled But Not Randomized
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	--/--		--/--		--/--
Serious Adverse Events
	CHTP 1.0		Conventional Cigarette (CC)		Enrolled But Not Randomized
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/41 (0.00%)		0/39 (0.00%)		1/5 (20.00%)
Injury, poisoning and procedural complications
Concussion * 1 [1]	0/41 (0.00%)	0	0/39 (0.00%)	0	1/5 (20.00%)	1
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA 18.0; [1] Concussion was considered to be moderate in intensity and not related to the CHTP 1.0 or CC but to study procedures. This serious adverse event was considered to have resolved after 4 days. The subject had no ongoing medical conditions at Screening
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	CHTP 1.0		Conventional Cigarette (CC)		Enrolled But Not Randomized
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/41 (65.85%)		14/39 (35.90%)		5/5 (100.00%)
Blood and lymphatic system disorders
Leukocytosis * 1	2/41 (4.88%)	2	0/39 (0.00%)	0	1/5 (20.00%)	1
Gastrointestinal disorders
Nausea * 1	0/41 (0.00%)	0	1/39 (2.56%)	1	1/5 (20.00%)	1
Vomiting * 1	0/41 (0.00%)	0	0/39 (0.00%)	0	2/5 (40.00%)	2
General disorders
Vessel puncture site haematoma * 1	0/41 (0.00%)	0	2/39 (5.13%)	2	0/5 (0.00%)	0
Hepatobiliary disorders
Hyperbilirubinaemia * 1	0/41 (0.00%)	0	2/39 (5.13%)	2	1/5 (20.00%)	1
Injury, poisoning and procedural complications
Head injury * 1	0/41 (0.00%)	0	0/39 (0.00%)	0	1/5 (20.00%)	1
Metabolism and nutrition disorders
Hypertriglyceridaemia * 1	0/41 (0.00%)	0	2/39 (5.13%)	2	2/5 (40.00%)	2
Hyperkalaemia * 1	0/41 (0.00%)	0	1/39 (2.56%)	1	1/5 (20.00%)	1
Hyperglycaemia * 1	0/41 (0.00%)	0	0/39 (0.00%)	0	1/5 (20.00%)	1
Nervous system disorders
Headache * 1	19/41 (46.34%)	21	9/39 (23.08%)	13	3/5 (60.00%)	3
Syncope * 1	2/41 (4.88%)	2	1/39 (2.56%)	1	1/5 (20.00%)	1
Psychiatric disorders
Agitation * 1	0/41 (0.00%)	0	0/39 (0.00%)	0	1/5 (20.00%)	1
Renal and urinary disorders
Leukocyturia * 1	1/41 (2.44%)	1	0/39 (0.00%)	0	1/5 (20.00%)	1
Respiratory, thoracic and mediastinal disorders
Cough * 1	13/41 (31.71%)	17	0/39 (0.00%)	0	0/5 (0.00%)	0
* Indicates events were collected by non-systematic assessment; 1 Term from vocabulary, MedDRA 18.0

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: Cam Tuan Tran
• Organization: Philip Morris Products S.A.
• Phone: +41 (58) 242 2620
• EMail: CamTuan.Tran@pmi.com

Publications of Results:

Tran CT, Bosilkovska M, de La Bourdonnaye G, Blanc N, Haziza C. Reduced levels of biomarkers of exposure in smokers switching to the Carbon-Heated Tobacco Product 1.0: a controlled, randomized, open-label 5-day exposure trial. Sci Rep. 2020 Nov 5;10(1):19227. doi: 10.1038/s41598-020-76222-y.

• Responsible Party: Philip Morris Products S.A.
• ClinicalTrials.gov Identifier: NCT02503254
• Other Study ID Numbers: P2R-REXC-06-EU; P2R-REXC-06-EU ( Other Identifier: Philip Morris Products S.A. )
• First Submitted: July 17, 2015
• First Posted: July 20, 2015
• Results First Submitted: November 4, 2016
• Results First Posted: March 10, 2017
• Last Update Posted: January 30, 2023