Evaluation of Biological and Functional Changes in Healthy Smokers After Switching to THS 2.2 for 26 Weeks

• Sponsor: Philip Morris Products S.A. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02396381
• Collaborator: (none)
• Enrollment: 1,039
• Locations: 19
• Arms: 2
• Actual Duration (Months): 28.7
• Patients Per Site: 54.7
• Patients Per Site Per Month: 1.9

Study Details

Study Description

Brief Summary

The aim of the study is to demonstrate clinical, biological and functional health changes in smokers switching to the candidate modified risk tobacco product: Tobacco Heating System 2.2 (THS 2.2) as compared to smokers continuing smoking their conventional cigarettes (CC) over a 26-week period.

To characterize the study as successful, at least 5 clinical risk endpoints should move in the direction of smoking cessation and these results would be statistically significant. The main analysis will be defined a priori (using the Hailperin-Ruger approach) and will be made between THS 2.2 use and CC use as "per actual product used" and product use categories.

Condition or Disease	Intervention/Treatment	Phase
Smoking	Other: THS 2.2; Other: CC	N/A

Detailed Description

The clinical, biological and functional endpoints to be measured in this study ("smoker's health profile") may characterize the modification of risk of smoking-related diseases.

Clinical risk endpoint to be assessed are selected based on a) their association to smoking-related diseases b) their association to smoking status, c) their reversibility upon smoking cessation, and d) their suitability to be measured with valid and robust methods in clinical studies.

The biological markers, functional markers and biomarkers of exposure (BoExp) with the strongest scientific evidence will constitute the 'smoker's health profile' and will be measured as the primary objective of the study.

Additional endpoints involved in the mechanistic of smoking-related diseases will be studied to provide additional scientific evidence to strengthen the primary objective.

The study will provide a perspective of product usage in a "real world setting" where smoking CC in addition to THS 2.2 may be expected.

Study Design

• Study Type: Interventional
• Actual Enrollment: 1039 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A Randomized, Controlled, 2-arm Parallel Group, Multi-center Study, to Evaluate Biological and Functional Changes in Healthy Smokers Switching to Tobacco Heating System 2.2 (THS 2.2) Compared to Continuing Smoking Conventional Cigarettes for 26 Weeks in an Ambulatory Setting
• Actual Study Start Date: Mar 12, 2015
• Actual Primary Completion Date: Sep 13, 2016
• Actual Study Completion Date: Aug 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: THS 2.2 Ad libitum use of THS 2.2	Other: THS 2.2; Ad libitum use of THS 2.2 in an ambulatory setting for 26 weeks
Active Comparator: CC Ad libitum use of CC	Other: CC; Ad libitum use of CC in an ambulatory setting for 26 weeks

Outcome Measures

Primary Outcome Measures

1. Levels of High Density Lipoprotein C (HDL-C). [26 Weeks]

   Concentrations measured in serum. Geometric Least Squares means are provided as descriptive statistics.

2. Levels of White Blood Cells (WBC). [26 Weeks]

   Concentrations measured in blood. Geometric Least Squares means are provided as descriptive statistics.

3. Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1). [26 Weeks]

   FEV1 post-bronchodilator and expressed as percentage predicted (FEV1 %pred). Geometric Least Squares means are provided as descriptive statistics.

4. Concentrations of Soluble Intercellular Adhesion Molecule 1 (sICAM-1). [26 Weeks]

   Concentrations measured in serum. Geometric Least Squares means are provided as descriptive statistics.

5. Concentrations of 11-dehydrothromboxane B2 (11-DTXB2). [26 Weeks]

   Concentrations measured in urine and expressed as concentration adjusted for creatinine. Geometric Least Squares means are provided as descriptive statistics.

6. Concentrations of 8-epi-prostaglandin F2α (8-epi-PGF2α). [26 Weeks]

   Concentrations measured in urine and expressed as concentration adjusted for creatinine. Geometric Least Squares means are provided as descriptive statistics.

7. Concentrations of Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL). [26 Weeks]

   Concentrations measured in urine and expressed as concentration adjusted for creatinine. Geometric Least Squares means are provided as descriptive statistics.

8. Percent Change From Baseline of Carboxyhemoglobin (COHb) [26 Weeks]

   Carboxyhemoglobin (COHb) is assayed from whole blood. Geometric Least Squares means are provided as descriptive statistics. Expressed as % of saturation of hemoglobin.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 30 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Current healthy smoker as judged by the Principal Investigator(s) or designee(s)

• Minimum age: 30 years old

• Have smoked for the last 10 years

• Have smoked more than 10 non menthol CC/day on average (no brand restriction) over the past year

Exclusion Criteria:

• Clinically relevant medical conditions that in the opinion of the investigators would jeopardize the safety of the participant.

• Subject who has (FEV1/FVC) < 0.7 and FEV1 < 80% predicted value at post-bronchodilator spirometry

• Subject with asthma condition (post-bronchodilator FEV1/FVC < 0.75 and reversibility in FEV1 ≥ 12% and > 200 mL from pre- to post-bronchodilator values)

• Subject who took or is taking concomitant medication which may have an impact on the "smoker's heath profile"

• Female subject is pregnant or breast feeding.

• Female subject who does not agree to use an acceptable method of effective contraception.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Celerion Arizona	Tempe	Arizona	United States	85283
2	Clinical Research West Florida	Clearwater	Florida	United States	33765
3	Covance, Inc	Daytona Beach	Florida	United States	32117
4	Compass Research	Orlando	Florida	United States	32806
5	Clinical Research West Florida	Tampa	Florida	United States	33603
6	Compass Research	The Villages	Florida	United States	32162
7	Central Kentucky Research Associate	Lexington	Kentucky	United States	40509
8	Celerion Lincoln	Lincoln	Nebraska	United States	68502
9	PMG Research of Cary	Cary	North Carolina	United States	27518
10	PMG Research of Charlotte	Charlotte	North Carolina	United States	28209
11	PMG Research of Raleigh	Raleigh	North Carolina	United States	27609
12	PMG Research of Wilmington	Wilmington	North Carolina	United States	28401
13	Midwest Clinical Research Center	Dayton	Ohio	United States	45417
14	PMG Research of Bristol	Bristol	Tennessee	United States	37620
15	NOCCR	Knoxville	Tennessee	United States	37920
16	Benchmark	Austin	Texas	United States	78705
17	Benchmark	Fort Worth	Texas	United States	76135
18	Benchmark	San Angelo	Texas	United States	76904
19	National Clinical Research	Richmond	Virginia	United States	23294

Sponsors and Collaborators

• Philip Morris Products S.A.

Investigators

• Study Chair: Christelle Haziza, PhD, Philip Morris Products S.A.
• Principal Investigator: Danielle Armas, MD, Celerion Arizona
• Principal Investigator: Leonard Dunn, MD, Clinical Research West Florida
• Principal Investigator: Hugh Coleman, MD, Covance
• Principal Investigator: George Stoica, MD, Compass Research
• Principal Investigator: Mark Adams, MD, Central Kentucky Research Associate
• Principal Investigator: Peter Davidson, MD, Celerion Lincoln
• Principal Investigator: John Rubino, MD, PMG Research of Raleigh
• Principal Investigator: George Raad, MD, PMG Research of Charlotte
• Principal Investigator: Kevin Cannon, MD, PMG Research of Wilmington
• Principal Investigator: Derek Schroder, MD, PMG Research of Cary
• Principal Investigator: Stephanie Powell, MD, PMG Research of Bristol
• Principal Investigator: William Smith, MD, NOCCR
• Principal Investigator: Darrell Herrington, MD, Benchmark
• Principal Investigator: Laurence Chu, MD, Benchmark
• Principal Investigator: William Seger, MD, Benchmark
• Principal Investigator: Lon Lynn, MD, Clinical Research West Florida
• Principal Investigator: David Subich, MD, Compass Research
• Principal Investigator: Isabel Kuhare-Arcure, MD, Midwest Clinical Research
• Principal Investigator: Keith Scott, MD, National Clinical Research

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Philip Morris Products S.A.
• ClinicalTrials.gov Identifier: NCT02396381
• Other Study ID Numbers: ZRHR-ERS-09-US; ZRHR-ERS-09-US
• First Posted: Mar 24, 2015
• Last Update Posted: Aug 21, 2019
• Last Verified: Aug 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Philip Morris Products S.A.: Candidate modified risk tobacco product; Conventional cigarette; Exposure response; Smoking; Tobacco Heating System

Study Results

Participant Flow

Pre-assignment Detail	Following randomization of 984 subjects, from 1039 enrolled subjects, one clinical site was terminated from this study due to non-GCP compliance. The safety population of 1012 subjects included all enrolled subjects except 27 subjects from the terminated site.

Arm/Group Title	THS 2.2 Group	CC Group
Arm/Group Description	Randomized to Ad libitum use of THS 2.2 in an ambulatory setting for 26 weeks	Randomized to Ad libitum use of CC in an ambulatory setting for 26 weeks
Period Title: Overall Study
STARTED	488	496
Full Analysis Set - As Exposed (FAS-EX)	414	443
COMPLETED	381	422
NOT COMPLETED	107	74

Baseline Characteristics

Arm/Group Title	THS 2.2 Use	CC Use	Dual Use	Other Use	Total
Arm/Group Description	≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on >50% of days in the analysis period.	≥1 THS 2.2 or CC use, and <1% THS 2.2 use over the entire analysis period and <1% THS 2.2 use on ≥ 50% of days in the analysis period.	≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 <70% over the analysis period, or THS 2.2-use and CC-use categories do not apply to 50% of these days.	Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns between consecutive analysis periods.	Total of all reporting groups
Overall Participants	245	428	142	42	857
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	44.2 (9.64)	45.2 (9.55)	43.8 (9.77)	44.2 (8.14)	44.6 (9.55)
Sex: Female, Male (Count of Participants)
Female	94 38.4%	182 42.5%	63 44.4%	14 33.3%	353 41.2%
Male	151 61.6%	246 57.5%	79 55.6%	28 66.7%	504 58.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	17 6.9%	28 6.5%	7 4.9%	1 2.4%	53 6.2%
Not Hispanic or Latino	228 93.1%	400 93.5%	135 95.1%	41 97.6%	804 93.8%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	2 0.8%	2 0.5%	2 1.4%	0 0%	6 0.7%
Asian	2 0.8%	5 1.2%	0 0%	1 2.4%	8 0.9%
Native Hawaiian or Other Pacific Islander	1 0.4%	2 0.5%	0 0%	0 0%	3 0.4%
Black or African American	42 17.1%	74 17.3%	25 17.6%	10 23.8%	151 17.6%
White	195 79.6%	341 79.7%	113 79.6%	30 71.4%	679 79.2%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	3 1.2%	4 0.9%	2 1.4%	1 2.4%	10 1.2%
BMI (kg/m2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m2]	26.9 (3.99)	27.1 (4.13)	26.9 (4.35)	26.9 (5.12)	27.0 (4.18)

Outcome Measures

1. Primary Outcome

Title	Levels of High Density Lipoprotein C (HDL-C).
Description	Concentrations measured in serum. Geometric Least Squares means are provided as descriptive statistics.
Time Frame	26 Weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set - As Exposed (FAS-EX)

Arm/Group Title	THS 2.2 Use	CC Use	Dual Use	Other Use
Arm/Group Description	≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on >50% of days in the analysis period.	≥1 THS 2.2 or CC use, and <1% THS 2.2 use over the entire analysis period and <1% THS 2.2 use on ≥ 50% of days in the analysis period.	≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 <70% over the analysis period, or THS 2.2-use and CC-use categories do not apply to 50% of these days.	Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns between consecutive analysis periods.
Measure Participants	245	428	142	42
Geometric Mean (95% Confidence Interval) [mg/dL]	54.1	50.9	56.3	52.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	THS 2.2 Use, CC Use
	Comments	The analysis will test if the mean level of HDL-C for THS-use is greater than for CC-use. The following hypothesis will be evaluated: H0: XTHS - XCC ≤ 0.0 HA: XTHS - XCC > 0.0 where XTHS and XCC are the adjusted means of THS-use and CC-use, respectively. H0 is rejected with a type I error α = 1.5625% (one-sided test).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Hailperin-Rüger
	Comments	p-value less than 1.5625% would be considered statistically significant, following test multiplicity adjustment using the Hailperin-Rüger approach
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	3.09
	Confidence Interval	(2-Sided) 96.875%; 1.10 to 5.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Levels of White Blood Cells (WBC).
Description	Concentrations measured in blood. Geometric Least Squares means are provided as descriptive statistics.
Time Frame	26 Weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set - As Exposed (FAS-EX)

Arm/Group Title	THS 2.2 Use	CC Use	Dual Use	Other Use
Arm/Group Description	≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on >50% of days in the analysis period.	≥1 THS 2.2 or CC use, and <1% THS 2.2 use over the entire analysis period and <1% THS 2.2 use on ≥ 50% of days in the analysis period.	≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 <70% over the analysis period, or THS 2.2-use and CC-use categories do not apply to 50% of these days.	Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns between consecutive analysis periods.
Measure Participants	245	428	142	42
Geometric Mean (95% Confidence Interval) [GI/L]	6.98	7.48	7.41	8.71

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	THS 2.2 Use, CC Use
	Comments	The analysis will test if the mean level of WBC for THS-use is lower than for CC-use. The following hypothesis will be evaluated: H0: XTHS - XCC ≥ 0.0 HA: XTHS - XCC < 0.0 where XTHS and XCC are the adjusted means of THS-use and CC-use, respectively. H0 is rejected with a type I error α = 1.5625% (one-sided test).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.001
	Comments
	Method	Hailperin-Rüger
	Comments	p-value less than 1.5625% would be considered statistically significant, following test multiplicity adjustment using the Hailperin-Rüger approach
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.420
	Confidence Interval	(2-Sided) 96.875%; -0.717 to -0.123
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1).
Description	FEV1 post-bronchodilator and expressed as percentage predicted (FEV1 %pred). Geometric Least Squares means are provided as descriptive statistics.
Time Frame	26 Weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set - As Exposed (FAS-EX)

Arm/Group Title	THS 2.2 Use	CC Use	Dual Use	Other Use
Arm/Group Description	≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on >50% of days in the analysis period.	≥1 THS 2.2 or CC use, and <1% THS 2.2 use over the entire analysis period and <1% THS 2.2 use on ≥ 50% of days in the analysis period.	≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 <70% over the analysis period, or THS 2.2-use and CC-use categories do not apply to 50% of these days.	Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns between consecutive analysis periods.
Measure Participants	245	428	142	42
Geometric Mean (95% Confidence Interval) [Percent of predicted FEV1]	95.4	93.4	93.7	94.3

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	THS 2.2 Use, CC Use
	Comments	The analysis will test if the mean level of FEV1 for THS-use is greater than for CC-use. The following hypothesis will be evaluated: H0: XTHS - XCC ≤ 0.0 HA: XTHS - XCC > 0.0 where XTHS and XCC are the adjusted means of THS-use and CC-use, respectively. H0 is rejected with a type I error α = 1.5625% (one-sided test).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.008
	Comments
	Method	Hailperin-Rüger
	Comments	p-value less than 1.5625% would be considered statistically significant, following test multiplicity adjustment using the Hailperin-Rüger approach
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	1.28
	Confidence Interval	(2-Sided) 96.875%; 0.145 to 2.42
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Concentrations of Soluble Intercellular Adhesion Molecule 1 (sICAM-1).
Description	Concentrations measured in serum. Geometric Least Squares means are provided as descriptive statistics.
Time Frame	26 Weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set - As Exposed (FAS-EX)

Arm/Group Title	THS 2.2 Use	CC Use	Dual Use	Other Use
Arm/Group Description	≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on >50% of days in the analysis period.	≥1 THS 2.2 or CC use, and <1% THS 2.2 use over the entire analysis period and <1% THS 2.2 use on ≥ 50% of days in the analysis period.	≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 <70% over the analysis period, or THS 2.2-use and CC-use categories do not apply to 50% of these days.	Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns between consecutive analysis periods.
Measure Participants	245	428	142	42
Geometric Mean (95% Confidence Interval) [ng/mL]	252	266	270	273

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	THS 2.2 Use, CC Use
	Comments	The analysis of sICAM-1 will test if the mean level of this clinical risk endpoint for THS-use is lower relative to CC-use. The following hypothesis will be evaluated: H0: XTHS / XCC ≥ 1.0 HA: XTHS / XCC < 1.0 where XTHS and XCC are the adjusted geometrical means of THS-use and CC-use, respectively. H0 is rejected with a type I error α = 1.5625% (one-sided test).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.030
	Comments
	Method	Hailperin-Rüger
	Comments	p-value less than 1.5625% would be considered statistically significant, following test multiplicity adjustment using the Hailperin-Rüger approach
Method of Estimation	Estimation Parameter	% Reduction
	Estimated Value	2.86
	Confidence Interval	(2-Sided) 96.875%; -0.426 to 6.04
	Parameter Dispersion	Type: Value:
	Estimation Comments	Derived as 1 - LS Mean Ratio (THS / CC)

5. Primary Outcome

Title	Concentrations of 11-dehydrothromboxane B2 (11-DTXB2).
Description	Concentrations measured in urine and expressed as concentration adjusted for creatinine. Geometric Least Squares means are provided as descriptive statistics.
Time Frame	26 Weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set - As Exposed (FAS-EX)

Arm/Group Title	THS 2.2 Use	CC Use	Dual Use	Other Use
Arm/Group Description	≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on >50% of days in the analysis period.	≥1 THS 2.2 or CC use, and <1% THS 2.2 use over the entire analysis period and <1% THS 2.2 use on ≥ 50% of days in the analysis period.	≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 <70% over the analysis period, or THS 2.2-use and CC-use categories do not apply to 50% of these days.	Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns between consecutive analysis periods.
Measure Participants	245	428	142	42
Geometric Mean (95% Confidence Interval) [pg/mg creat]	496	523	532	626

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	THS 2.2 Use, CC Use
	Comments	The analysis of 11-DTX-B2 will test if the mean level of this clinical risk endpoint for THS-use is lower relative to CC-use. The following hypothesis will be evaluated: H0: XTHS / XCC ≥ 1.0 HA: XTHS / XCC < 1.0 where XTHS and XCC are the adjusted geometrical means of THS-use and CC-use, respectively. H0 is rejected with a type I error α = 1.5625% (one-sided test).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.193
	Comments
	Method	Hailperin-Rüger
	Comments	p-value less than 1.5625% would be considered statistically significant, following test multiplicity adjustment using the Hailperin-Rüger approach
Method of Estimation	Estimation Parameter	% Reduction
	Estimated Value	4.74
	Confidence Interval	(2-Sided) 96.875%; -7.5 to 15.6
	Parameter Dispersion	Type: Value:
	Estimation Comments	Derived as 1 - LS Mean Ratio (THS / CC)

6. Primary Outcome

Title	Concentrations of 8-epi-prostaglandin F2α (8-epi-PGF2α).
Description	Concentrations measured in urine and expressed as concentration adjusted for creatinine. Geometric Least Squares means are provided as descriptive statistics.
Time Frame	26 Weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set - As Exposed (FAS-EX)

Arm/Group Title	THS 2.2 Use	CC Use	Dual Use	Other Use
Arm/Group Description	≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on >50% of days in the analysis period.	≥1 THS 2.2 or CC use, and <1% THS 2.2 use over the entire analysis period and <1% THS 2.2 use on ≥ 50% of days in the analysis period.	≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 <70% over the analysis period, or THS 2.2-use and CC-use categories do not apply to 50% of these days.	Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns between consecutive analysis periods.
Measure Participants	245	428	142	42
Geometric Mean (95% Confidence Interval) [pg/mg creat]	321	351	347	335

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	THS 2.2 Use, CC Use
	Comments	The analysis of 8-epi-PGF2α will test if the mean level of this clinical risk endpoint for THS-use is lower relative to CC-use. The following hypothesis will be evaluated: H0: XTHS / XCC ≥ 1.0 HA: XTHS / XCC < 1.0 where XTHS and XCC are the adjusted geometrical means of THS-use and CC-use, respectively. H0 is rejected with a type I error α = 1.5625% (one-sided test).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.018
	Comments
	Method	Hailperin-Rüger
	Comments	p-value less than 1.5625% would be considered statistically significant, following test multiplicity adjustment using the Hailperin-Rüger approach
Method of Estimation	Estimation Parameter	% Reduction
	Estimated Value	6.80
	Confidence Interval	(2-Sided) 96.875%; -0.216 to 13.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Derived as 1 - LS Mean Ratio (THS / CC)

7. Primary Outcome

Title	Concentrations of Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL).
Description	Concentrations measured in urine and expressed as concentration adjusted for creatinine. Geometric Least Squares means are provided as descriptive statistics.
Time Frame	26 Weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set - As Exposed (FAS-EX)

Arm/Group Title	THS 2.2 Use	CC Use	Dual Use	Other Use
Arm/Group Description	≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on >50% of days in the analysis period.	≥1 THS 2.2 or CC use, and <1% THS 2.2 use over the entire analysis period and <1% THS 2.2 use on ≥ 50% of days in the analysis period.	≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 <70% over the analysis period, or THS 2.2-use and CC-use categories do not apply to 50% of these days.	Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns between consecutive analysis periods.
Measure Participants	245	428	142	42
Geometric Mean (95% Confidence Interval) [pg/mg creat]	144	282	286	342

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	THS 2.2 Use, CC Use
	Comments	The analysis of Total NNAL will test if the mean level of this clinical risk endpoint for THS-use is lower relative to CC-use. The following hypothesis will be evaluated: H0: XTHS / XCC ≥ 1.0 HA: XTHS / XCC < 1.0 where XTHS and XCC are the adjusted geometrical means of THS-use and CC-use, respectively. H0 is rejected with a type I error α = 1.5625% (one-sided test).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Hailperin-Rüger
	Comments	p-value less than 1.5625% would be considered statistically significant, following test multiplicity adjustment using the Hailperin-Rüger approach
Method of Estimation	Estimation Parameter	% Reduction
	Estimated Value	43.5
	Confidence Interval	(2-Sided) 96.875%; 33.7 to 51.9
	Parameter Dispersion	Type: Value:
	Estimation Comments	Derived as 1 - LS Mean Ratio (THS / CC)

8. Primary Outcome

Title	Percent Change From Baseline of Carboxyhemoglobin (COHb)
Description	Carboxyhemoglobin (COHb) is assayed from whole blood. Geometric Least Squares means are provided as descriptive statistics. Expressed as % of saturation of hemoglobin.
Time Frame	26 Weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set - As Exposed (FAS-EX)

Arm/Group Title	THS 2.2 Use	CC Use	Dual Use	Other Use
Arm/Group Description	≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on >50% of days in the analysis period.	≥1 THS 2.2 or CC use, and <1% THS 2.2 use over the entire analysis period and <1% THS 2.2 use on ≥ 50% of days in the analysis period.	≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 <70% over the analysis period, or THS 2.2-use and CC-use categories do not apply to 50% of these days.	Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns between consecutive analysis periods.
Measure Participants	245	428	142	42
Geometric Mean (95% Confidence Interval) [percentage change from baseline]	2.84	4.38	4.23	5.59

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	THS 2.2 Use, CC Use
	Comments	The analysis will test if the mean level of COHb for THS-use is lower relative to CC-use. The following hypothesis will be evaluated: H0: XTHS / XCC ≥ 1.0 HA: XTHS / XCC < 1.0 where XTHS and XCC are the adjusted geometrical means of THS-use and CC-use. H0 is rejected with a type I error α = 1.5625% (one-sided test).
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments
	Method	Hailperin-Rüger
	Comments	p-value less than 1.5625% would be considered statistically significant, following test multiplicity adjustment using the Hailperin-Rüger approach
Method of Estimation	Estimation Parameter	% Reduction
	Estimated Value	32.2
	Confidence Interval	(2-Sided) 96.875%; 24.5 to 39
	Parameter Dispersion	Type: Value:
	Estimation Comments	Derived as 1 - LS Mean Ratio (THS / CC)

Adverse Events

Time Frame	The entire study duration per subject was between 32 to 38 weeks, including a Screening period of up to 42 days prior to enrollment, a 6 to 10-day run-in period prior to randomization, followed by a 26 week randomized exposure period. The end of study for a subject was defined as the check-out or the date of early termination of the subject plus the 28 day Safety Follow-up period, unless the subject was lost to follow-up.
Arm/Group Title	THS 2.2 Group		CC Group		Product Test
Arm/Group Description	Randomized to Ad libitum use of THS 2.2 in an ambulatory setting for 26 weeks		Randomized to Ad libitum use of CC in an ambulatory setting for 26 weeks		Enrolled subjects who participated in a product test, but were not randomized.
All Cause Mortality
	THS 2.2 Group		CC Group		Product Test
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/477 (0.4%)		0/483 (0%)		0/52 (0%)
Serious Adverse Events
	THS 2.2 Group		CC Group		Product Test
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	6/477 (1.3%)		7/483 (1.4%)		0/52 (0%)
Infections and infestations
Pneumonia mycoplasmal	1/477 (0.2%)	1	0/483 (0%)	0	0/52 (0%)	0
Cellulitis	0/477 (0%)	0	1/483 (0.2%)	1	0/52 (0%)	0
Pyelonephritis acute, with Urosepsis and Nephrolithiasis	0/477 (0%)	0	1/483 (0.2%)	3	0/52 (0%)	0
Tooth Infection	0/477 (0%)	0	1/483 (0.2%)	1	0/52 (0%)	0
Injury, poisoning and procedural complications
Head injury with seizure	1/477 (0.2%)	2	0/483 (0%)	0	0/52 (0%)	0
Laceration	1/477 (0.2%)	1	0/483 (0%)	0	0/52 (0%)	0
Musculoskeletal and connective tissue disorders
Vertebral osteophyte with Cervical myelopathy	0/477 (0%)	0	1/483 (0.2%)	2	0/52 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Papillary thyroid cancer	0/477 (0%)	0	1/483 (0.2%)	1	0/52 (0%)	0
Metastases to small intestine with anaemia	1/477 (0.2%)	2	0/483 (0%)	0	0/52 (0%)	0
Psychiatric disorders
Completed suicide	1/477 (0.2%)	1	0/483 (0%)	0	0/52 (0%)	0
Suicidal ideation	0/477 (0%)	0	1/483 (0.2%)	1	0/52 (0%)	0
Alcohol abuse	1/477 (0.2%)	1	0/483 (0%)	0	0/52 (0%)	0
Adjustment disorder with depressed mood and bereavement	0/477 (0%)	0	1/483 (0.2%)	2	0/52 (0%)	0
Other (Not Including Serious) Adverse Events
	THS 2.2 Group		CC Group		Product Test
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/477 (4.8%)		29/483 (6%)		0/52 (0%)
Infections and infestations
Upper respiratory tract infection	23/477 (4.8%)	26	29/483 (6%)	33	0/52 (0%)	0

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 specify 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 belong to the Sponsor.