A 26-week Extension of the ZRHR-ERS-09-US Study Evaluating Biological and Functional Changes in Healthy Smokers After Switching to THS 2.2

• Sponsor: Philip Morris Products S.A. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02649556
• Collaborator: (none)
• Enrollment: 672
• Locations: 19
• Arms: 2
• Actual Duration (Months): 26.7
• Patients Per Site: 35.4
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

The objective of the ZRHR-ERS-09-EXT-US study is to further assess the effect of the Tobacco Heating System 2.2 (THS 2.2), a candidate Modified Risk Tobacco Product, compared to conventional cigarettes (CC) on the components of the "smokers' health profile" for a prolonged period of 26 weeks, providing additional information to the results of the original study ZRHR-ERS-09-US of 26-week exposure (NCT02396381). In total, the ZRHR-ERS-09-EXT-US study will extend the exposure period to 52 weeks.

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

Detailed Description

The ZRHR-ERS-09-EXT-US study is a 26-week extension of the original study ZRHR-ERS-09-US.

The subjects in the Full Analysis Set - As Exposed (FAS-EX) included subjects for combined analyses from the original six month study (ZRHR-ERS-09-US ) who did not enter the extension study (ZRHR-ERS-09-EXT-US).

This study was conducted as a separate investigation, as a follow-up of the randomized exposure period of the original study, extending the exposure from Week 26 (Visit 10 [V10]) to Week 52 (Visit 16 [V16]), and using the same sites.

Subjects continued to use the product they were randomized to in the original study ZRHR-ERS-09-US (THS 2.2 arm or CC arm).

Study Design

• Study Type: Interventional
• Actual Enrollment: 672 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Other
• Official Title: A 26-week Extension Study to Determine the Biological and Functional Changes in Healthy Smokers Who Switched From Conventional Cigarettes (CC) to Tobacco Heating System 2.2 (THS 2.2) Compared to Those Who Continued to Smoke CC in the ZRHR-ERS-09-US Study
• Actual Study Start Date: Sep 30, 2015
• Actual Primary Completion Date: Mar 13, 2017
• Actual Study Completion Date: Dec 20, 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. The subject's own preferred brands of CC (no brand restriction) continue to be used as the reference product.

Outcome Measures

Primary Outcome Measures

1. Levels of High Density Lipoprotein C (HDL-C). [52 weeks]

   Concentrations (mg/dL) measured in serum. Mean values are provided as descriptive statistics.

2. Levels of White Blood Cells (WBC). [52 weeks]

   Total count in blood (GI/L). Mean values are provided as descriptive statistics.

3. Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1). [52 weeks]

   FEV1 post-bronchodilator and expressed as percentage predicted (FEV1 %pred). Mean values are provided as descriptive statistics.

4. Concentrations of Soluble Intercellular Adhesion Molecule 1 (sICAM-1). [52 weeks]

   Concentrations (ng/mL) measured in serum. Geometric Mean values are provided as descriptive statistics.

5. Concentrations of 11-dehydrothromboxane B2 (11-DTXB2). [52 weeks]

   Concentrations measured in urine and expressed as concentration adjusted for creatinine (pg/mg creat). Geometric Mean values are provided as descriptive statistics.

6. Concentrations of 8-epi-prostaglandin F2α (8-epi-PGF2α). [52 weeks]

   Concentrations measured in urine and expressed as concentration adjusted for creatinine (pg/mg creat). Geometric Mean values are provided as descriptive statistics.

7. Concentrations of Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL). [52 weeks]

   Concentrations measured in urine and expressed as concentration adjusted for creatinine (pg/mg creat). Geometric Mean values are provided as descriptive statistics.

8. Levels of Carboxyhemoglobin (COHb). [52 weeks]

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

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Subject completed V10 of the original study (ZRHR-ERS-09-US).

• The subject is willing to comply to study procedures and to continue to use the product he/she was allocated to during the original study (THS 2.2 or CC) for an additional 26 weeks at V10.

• Subject has given written informed consent to enter the 26-week extension study at V10.

Exclusion Criteria:

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

• As per judgment of the PI(s) or designee(s), the subject cannot participate in the study for any reason (e.g. medical, psychiatric and/or social reason).

• Subject has made an attempt to quit using tobacco-containing products (e.g. CC and THS 2.2) during the original study.

• 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	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: David Subich, MD, Compass Research
• Principal Investigator: Lon Lynn, MD, Clinical Research West Florida
• Principal Investigator: Isabel Kuhare-Arcure, MD, Midwest Clinical Research
• Principal Investigator: Keith Scott, MD, National Clinical Research

Study Documents (Full-Text)

• Study Protocol - Aug 23, 2016
• Statistical Analysis Plan - Dec 8, 2017

More Information

Publications

None provided.

• Responsible Party: Philip Morris Products S.A.
• ClinicalTrials.gov Identifier: NCT02649556
• Other Study ID Numbers: ZRHR-ERS-09-EXT-US; ZRHR-ERS-09-EXT-US
• First Posted: Jan 7, 2016
• Last Update Posted: Dec 4, 2020
• Last Verified: Nov 1, 2020

• 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.: Modified risk tobacco product; Conventional cigarette; Exposure response; Smoking; Tobacco Heating System

Study Results

Participant Flow

Recruitment Details	Of the 984 subjects (488 in the THS arm and 496 in the CC arm) who were enrolled and randomized into the original study, NCT02396381, 672 subjects were enrolled into the extension study (309 in the THS arm and 363 in the CC arm).
Pre-assignment Detail	672 subjects enrolled in the extension study; the 857 subjects in the Full Analysis Set - As Exposed (FAS-EX) included subjects for combined analyses from the original six month study who did not enter the extension study. The analysis was performed according to subjects' exposure over the 12 month period as detailed in "Arm/Group" (Reporting Groups) table.

Arm/Group Title	THS 2.2 Use	CC Use	Dual Use	Other Use
Arm/Group Description	This reporting group comprised 230 subjects. The "THS 2.2 use" product use category was defined as THS use of 70% or more over the entire analysis period. (≥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.)	This reporting group comprised 424 subjects. The "CC use" product use category was defined as THS use of less than 1% over the entire 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.)	This reporting group comprised 152 subjects. The "Dual use" product use category was defined as THS use of less than 70% over the entire 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.)	This reporting group comprised 51 subjects. "Other use" refers to any other product use over the entire analysis period. (Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns.)
Period Title: Overall Study
STARTED	230	424	152	51
COMPLETED	167	312	102	28
NOT COMPLETED	63	112	50	23

Baseline Characteristics

Arm/Group Title	THS 2.2 Use	CC Use	Dual Use	Other Use	Total
Arm/Group Description	The "THS 2.2 use" product use category was defined as THS use of 70% or more over the entire analysis period. (≥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.)	The "CC use" product use category was defined as THS use of less than 1% over the entire 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.)	The "Dual use" product use category was defined as THS use of less than 70% over the entire 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.)	"Other use" refers to any other product use over the entire analysis period. (Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns.)	Total of all reporting groups
Overall Participants	230	424	152	51	857
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	43.8 (9.68)	45.2 (9.54)	44.2 (9.76)	44.5 (8.21)	44.6 (9.55)
Sex: Female, Male (Count of Participants)
Female	87 37.8%	180 42.5%	67 44.1%	19 37.3%	353 41.2%
Male	143 62.2%	244 57.5%	85 55.9%	32 62.7%	504 58.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	17 7.4%	28 6.6%	6 3.9%	2 3.9%	53 6.2%
Not Hispanic or Latino	213 92.6%	396 93.4%	146 96.1%	49 96.1%	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	1 0.4%	2 0.5%	2 1.3%	1 2%	6 0.7%
Asian	2 0.9%	5 1.2%	0 0%	1 2%	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	41 17.8%	73 17.2%	25 16.4%	12 23.5%	151 17.6%
White	182 79.1%	338 79.7%	123 80.9%	36 70.6%	679 79.2%
More than one race	0 0%	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	3 1.3%	4 0.9%	2 1.3%	1 2%	10 1.2%
BMI (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	27.0 (4.06)	27.1 (4.13)	26.9 (4.25)	26.6 (4.91)	27.0 (4.18)

Outcome Measures

1. Primary Outcome

Title	Levels of High Density Lipoprotein C (HDL-C).
Description	Concentrations (mg/dL) measured in serum. Mean values are provided as descriptive statistics.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set - As Exposed Analysis (FAS-EX). Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm/Group Title	THS 2.2 Use	CC Use	Dual Use	Other Use
Arm/Group Description	The "THS 2.2 use" product use category was defined as THS use of 70% or more over the entire analysis period. (≥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.)	The "CC use" product use category was defined as THS use of less than 1% over the entire 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.)	The "Dual use" product use category was defined as THS use of less than 70% over the entire 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.)	"Other use" refers to any other product use over the entire analysis period. (Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns.)
Measure Participants	168	315	103	28
Mean (95% Confidence Interval) [mg/dL]	52.2	50.6	54.0	54.7

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	THS 2.2 Use, CC Use
	Comments	The analysis will determine the effect of THS 2.2 compared to CC at Month 12 on the components of the "smokers' health profile". This study has no formal pre-specified hypotheses associated with the study objectives. Estimates of THS 2.2 effect will be presented by mean of LS Mean difference of HDL-C levels between CC and THS 2.2 and related 95% CI.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	1.75
	Confidence Interval	(2-Sided) 95%; -0.160 to 3.65
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Mixed model conducted on original values with visit, baseline value and its interaction with visit, sex, Caucasian origin, product use pattern category and its interaction with visit, and other baseline covariates relevant for the specific clinical risk endpoint as fixed effect factors and site as a random effect.

2. Primary Outcome

Title	Levels of White Blood Cells (WBC).
Description	Total count in blood (GI/L). Mean values are provided as descriptive statistics.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set - As Exposed Analysis (FAS-EX). Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm/Group Title	THS 2.2 Use	CC Use	Dual Use	Other Use
Arm/Group Description	The "THS 2.2 use" product use category was defined as THS use of 70% or more over the entire analysis period. (≥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.)	The "CC use" product use category was defined as THS use of less than 1% over the entire 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.)	The "Dual use" product use category was defined as THS use of less than 70% over the entire 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.)	"Other use" refers to any other product use over the entire analysis period. (Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns.)
Measure Participants	167	312	102	28
Mean (95% Confidence Interval) [GI/L]	6.73	7.31	7.28	7.57

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	THS 2.2 Use, CC Use
	Comments	The analysis will determine the effect of THS 2.2 compared to CC at Month 12 on the components of the "smokers' health profile". This study has no formal pre-specified hypotheses associated with the study objectives. Estimates of THS 2.2 effect will be presented by mean of LS Mean difference of White Blood Cell counts between CC and THS 2.2 and related 95% CI.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.413
	Confidence Interval	(2-Sided) 95%; -0.694 to -0.131
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Mixed model conducted on original values with visit, baseline value and its interaction with visit, sex, Caucasian origin, product use pattern category and its interaction with visit, and other baseline covariates relevant for the specific clinical risk endpoint as fixed effect factors and site as a random effect.

3. Primary Outcome

Title	Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1).
Description	FEV1 post-bronchodilator and expressed as percentage predicted (FEV1 %pred). Mean values are provided as descriptive statistics.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set - As Exposed Analysis (FAS-EX). Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm/Group Title	THS 2.2 Use	CC Use	Dual Use	Other Use
Arm/Group Description	The "THS 2.2 use" product use category was defined as THS use of 70% or more over the entire analysis period. (≥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.)	The "CC use" product use category was defined as THS use of less than 1% over the entire 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.)	The "Dual use" product use category was defined as THS use of less than 70% over the entire 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.)	"Other use" refers to any other product use over the entire analysis period. (Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns.)
Measure Participants	153	288	95	27
Mean (95% Confidence Interval) [Percent of predicted FEV1]	93.2	92.3	91.1	95.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	THS 2.2 Use, CC Use
	Comments	The analysis will determine the effect of THS 2.2 compared to CC at Month 12 on the components of the "smokers' health profile". This study has no formal pre-specified hypotheses associated with the study objectives. Estimates of THS 2.2 effect will be presented by mean of LS Mean difference of FEV1 levels between CC and THS 2.2 and related 95% CI.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.914
	Confidence Interval	(2-Sided) 95%; -0.339 to 2.17
	Parameter Dispersion	Type: Value:
	Estimation Comments
Other Statistical Analysis		Mixed model conducted on original values with visit, baseline value and its interaction with visit, sex, Caucasian origin, product use pattern category and its interaction with visit, and other baseline covariates relevant for the specific clinical risk endpoint as fixed effect factors and site as a random effect.

4. Primary Outcome

Title	Concentrations of Soluble Intercellular Adhesion Molecule 1 (sICAM-1).
Description	Concentrations (ng/mL) measured in serum. Geometric Mean values are provided as descriptive statistics.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set - As Exposed Analysis (FAS-EX). Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm/Group Title	THS 2.2 Use	CC Use	Dual Use	Other Use
Arm/Group Description	The "THS 2.2 use" product use category was defined as THS use of 70% or more over the entire analysis period. (≥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.)	The "CC use" product use category was defined as THS use of less than 1% over the entire 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.)	The "Dual use" product use category was defined as THS use of less than 70% over the entire 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.)	"Other use" refers to any other product use over the entire analysis period. (Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns.)
Measure Participants	168	315	103	28
Geometric Mean (95% Confidence Interval) [ng/mL]	246	258	269	255

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	THS 2.2 Use, CC Use
	Comments	The analysis will determine the effect of THS 2.2 compared to CC at Month 12 on the components of the "smokers' health profile". This study has no formal pre-specified hypotheses associated with the study objectives. Estimates of THS 2.2 effect will be presented by mean of relative reduction of sICAM-1 levels between CC and THS 2.2 and related 95% CI.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	% Relative Reduction
	Estimated Value	3.11
	Confidence Interval	(2-Sided) 95%; 0.0231 to 6.10
	Parameter Dispersion	Type: Value:
	Estimation Comments	Derived as 100 x (1 - Geometric LS Mean Ratio)
Other Statistical Analysis		Mixed model conducted on log-transformed values with visit, log-transformed baseline value and its interaction with visit, sex, Caucasian origin, product use pattern category and its interaction with visit, and other baseline covariates relevant for the specific clinical risk endpoint as fixed effect factors and site as a random effect

5. Primary Outcome

Title	Concentrations of 11-dehydrothromboxane B2 (11-DTXB2).
Description	Concentrations measured in urine and expressed as concentration adjusted for creatinine (pg/mg creat). Geometric Mean values are provided as descriptive statistics.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set - As Exposed Analysis (FAS-EX). Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm/Group Title	THS 2.2 Use	CC Use	Dual Use	Other Use
Arm/Group Description	The "THS 2.2 use" product use category was defined as THS use of 70% or more over the entire analysis period. (≥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.)	The "CC use" product use category was defined as THS use of less than 1% over the entire 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.)	The "Dual use" product use category was defined as THS use of less than 70% over the entire 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.)	"Other use" refers to any other product use over the entire analysis period. (Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns.)
Measure Participants	166	312	102	27
Geometric Mean (95% Confidence Interval) [pg/mg creat]	582	586	595	536

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	THS 2.2 Use, CC Use
	Comments	The analysis will determine the effect of THS 2.2 compared to CC at Month 12 on the components of the "smokers' health profile". This study has no formal pre-specified hypotheses associated with the study objectives. Estimates of THS 2.2 effect will be presented by mean of relative reduction of 11-DTXB2 levels between CC and THS 2.2 and related 95% CI.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	% Relative Reduction
	Estimated Value	3.44
	Confidence Interval	(2-Sided) 95%; -8.74 to 14.3
	Parameter Dispersion	Type: Value:
	Estimation Comments	Derived as 100 x (1-Geometric LS Mean Ratio)
Other Statistical Analysis		Mixed model conducted on log-transformed values with visit, log-transformed baseline value and its interaction with visit, sex, Caucasian origin, product use pattern category and its interaction with visit, and other baseline covariates relevant for the specific clinical risk endpoint as fixed effect factors and site as a random effect

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 (pg/mg creat). Geometric Mean values are provided as descriptive statistics.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set - As Exposed Analysis (FAS-EX). Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm/Group Title	THS 2.2 Use	CC Use	Dual Use	Other Use
Arm/Group Description	The "THS 2.2 use" product use category was defined as THS use of 70% or more over the entire analysis period. (≥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.)	The "CC use" product use category was defined as THS use of less than 1% over the entire 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.)	The "Dual use" product use category was defined as THS use of less than 70% over the entire 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.)	"Other use" refers to any other product use over the entire analysis period. (Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns.)
Measure Participants	167	312	102	27
Geometric Mean (95% Confidence Interval) [pg/mg creat]	307	327	326	364

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	THS 2.2 Use, CC Use
	Comments	The analysis will determine the effect of THS 2.2 compared to CC at Month 12 on the components of the "smokers' health profile". This study has no formal pre-specified hypotheses associated with the study objectives. Estimates of THS 2.2 effect will be presented by mean of relative reduction of 8-epi-PGF2α levels between CC and THS 2.2 and related 95% CI.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	% Relative Reduction
	Estimated Value	7.15
	Confidence Interval	(2-Sided) 95%; -1.03 to 14.7
	Parameter Dispersion	Type: Value:
	Estimation Comments	Derived as 100 x (1 - Geometric LS Mean Ratio)
Other Statistical Analysis		Mixed model conducted on log-transformed values with visit, log-transformed baseline value and its interaction with visit, sex, Caucasian origin, product use pattern category and its interaction with visit, and other baseline covariates relevant for the specific clinical risk endpoint as fixed effect factors and site as a random effect.

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 (pg/mg creat). Geometric Mean values are provided as descriptive statistics.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set - As Exposed Analysis (FAS-EX). Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm/Group Title	THS 2.2 Use	CC Use	Dual Use	Other Use
Arm/Group Description	The "THS 2.2 use" product use category was defined as THS use of 70% or more over the entire analysis period. (≥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.)	The "CC use" product use category was defined as THS use of less than 1% over the entire 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.)	The "Dual use" product use category was defined as THS use of less than 70% over the entire 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.)	"Other use" refers to any other product use over the entire analysis period. (Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns.)
Measure Participants	167	312	102	27
Geometric Mean (95% Confidence Interval) [pg/mg creat]	133	269	253	304

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	THS 2.2 Use, CC Use
	Comments	The analysis will determine the effect of THS 2.2 compared to CC at Month 12 on the components of the "smokers' health profile". This study has no formal pre-specified hypotheses associated with the study objectives. Estimates of THS 2.2 effect will be presented by mean of relative reduction of Total NNAL levels between CC and THS 2.2 and related 95% CI.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	% Relative Reduction
	Estimated Value	46.3
	Confidence Interval	(2-Sided) 95%; 36.2 to 54.8
	Parameter Dispersion	Type: Value:
	Estimation Comments	Derived as 100 x (1 - Geometric LS Mean Ratio)
Other Statistical Analysis		Mixed model conducted on log-transformed values with visit, log-transformed baseline value and its interaction with visit, sex, Caucasian origin, product use pattern category and its interaction with visit, and other baseline covariates relevant for the specific clinical risk endpoint as fixed effect factors and site as a random effect

8. Primary Outcome

Title	Levels of Carboxyhemoglobin (COHb).
Description	Carboxyhemoglobin (COHb) is assayed from whole blood. Expressed as % of saturation of hemoglobin. Geometric Mean values are provided as descriptive statistics.
Time Frame	52 weeks

Outcome Measure Data

Analysis Population Description

Full Analysis Set - As Exposed Analysis (FAS-EX). Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).

Arm/Group Title	THS 2.2 Use	CC Use	Dual Use	Other Use
Arm/Group Description	The "THS 2.2 use" product use category was defined as THS use of 70% or more over the entire analysis period. (≥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.)	The "CC use" product use category was defined as THS use of less than 1% over the entire 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.)	The "Dual use" product use category was defined as THS use of less than 70% over the entire 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.)	"Other use" refers to any other product use over the entire analysis period. (Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns.)
Measure Participants	141	257	86	26
Geometric Mean (95% Confidence Interval) [percent change]	2.59	4.06	3.92	5.22

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	THS 2.2 Use, CC Use
	Comments	The analysis will determine the effect of THS 2.2 compared to CC at Month 12 on the components of the "smokers' health profile". This study has no formal pre-specified hypotheses associated with the study objectives. Estimates of THS 2.2 effect will be presented by mean of relative reduction of COHb levels between CC and THS 2.2 and related 95% CI.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	% Relative Reduction
	Estimated Value	31.7
	Confidence Interval	(2-Sided) 95%; 23.3 to 39.1
	Parameter Dispersion	Type: Value:
	Estimation Comments	Derived as 100 x (1 - Geometric LS Mean Ratio)
Other Statistical Analysis		Mixed model conducted on log-transformed values with visit, log-transformed baseline value and its interaction with visit, sex, Caucasian origin, product use pattern category and its interaction with visit, and other baseline covariates relevant for the specific clinical risk endpoint as fixed effect factors and site as a random effect.

Adverse Events

Time Frame	18 months (from March 2015 to September 2016)
Adverse Event Reporting Description	Of the 984 subjects who started the original study (NCT02396381), 20 subjects without a valid safety assessment and 24 subjects from a site terminated for non-GCP compliance were excluded from the safety population (N=940). The safety population comprised the 857 subjects of the Full Analysis Set - As Exposed (FAS-EX), who had at least one record of reported product use post randomization, and 83 subjects who were randomized and had at least 1 valid safety assessment.
Arm/Group Title	THS 2.2 Use		CC Use		Dual Use		Other Use
Arm/Group Description	The "THS 2.2 use" product use category was defined as THS use of 70% or more over the entire analysis period. (≥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.)		The "CC use" product use category was defined as THS use of less than 1% over the entire 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.)		The "Dual use" product use category was defined as THS use of less than 70% over the entire 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.) .		"Other use" refers to any other product use over the entire analysis period. (Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns.)
All Cause Mortality
	THS 2.2 Use		CC Use		Dual Use		Other Use
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/241 (0.4%)		1/434 (0.2%)		0/159 (0%)		1/106 (0.9%)
Serious Adverse Events
	THS 2.2 Use		CC Use		Dual Use		Other Use
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/241 (5%)		15/434 (3.5%)		1/159 (0.6%)		1/106 (0.9%)
Cardiac disorders
Acute myocardial infarction	0/241 (0%)	0	1/434 (0.2%)	1	0/159 (0%)	0	0/106 (0%)	0
Gastrointestinal disorders
Pancreatitis chronic	0/241 (0%)	0	1/434 (0.2%)	1	0/159 (0%)	0	0/106 (0%)	0
General disorders
Death	0/241 (0%)	0	1/434 (0.2%)	1	0/159 (0%)	0	0/106 (0%)	0
Infections and infestations
Appendicitis with Peritonitis	1/241 (0.4%)	2	0/434 (0%)	0	0/159 (0%)	0	0/106 (0%)	0
Cellulitis	0/241 (0%)	0	1/434 (0.2%)	1	0/159 (0%)	0	0/106 (0%)	0
Cellulitis staphylococcal	0/241 (0%)	0	1/434 (0.2%)	1	0/159 (0%)	0	0/106 (0%)	0
Epiglottitis	1/241 (0.4%)	1	0/434 (0%)	0	0/159 (0%)	0	0/106 (0%)	0
Influenza	1/241 (0.4%)	1	0/434 (0%)	0	0/159 (0%)	0	0/106 (0%)	0
Pneumonia mycoplasmal	1/241 (0.4%)	1	0/434 (0%)	0	0/159 (0%)	0	0/106 (0%)	0
Tooth infection	0/241 (0%)	0	1/434 (0.2%)	1	0/159 (0%)	0	0/106 (0%)	0
Urosepsis with Nephrolithiasis	0/241 (0%)	0	1/434 (0.2%)	2	0/159 (0%)	0	0/106 (0%)	0
Pyelonephritis Acute	0/241 (0%)	0	1/434 (0.2%)	1	1/159 (0.6%)	1	0/106 (0%)	0
Injury, poisoning and procedural complications
Head injury with Seizure	1/241 (0.4%)	2	0/434 (0%)	0	0/159 (0%)	0	0/106 (0%)	0
Hip fracture	1/241 (0.4%)	1	0/434 (0%)	0	0/159 (0%)	0	0/106 (0%)	0
Laceration	1/241 (0.4%)	1	0/434 (0%)	0	0/159 (0%)	0	0/106 (0%)	0
Multiple fractures	0/241 (0%)	0	0/434 (0%)	0	1/159 (0.6%)	1	0/106 (0%)	0
Rib fracture, Clavicle fracture, Pulmonary contusion, Pleural effusion, and Traumatic Hemothorax	0/241 (0%)	0	1/434 (0.2%)	5	0/159 (0%)	0	0/106 (0%)	0
Foot Fracture	1/241 (0.4%)	1	0/434 (0%)	0	0/159 (0%)	0	0/106 (0%)	0
Musculoskeletal and connective tissue disorders
Costochondritis	1/241 (0.4%)	1	0/434 (0%)	0	0/159 (0%)	0	0/106 (0%)	0
Vertebral osteophyte with Cervical Myelopathy	0/241 (0%)	0	1/434 (0.2%)	2	0/159 (0%)	0	0/106 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	0/241 (0%)	0	1/434 (0.2%)	2	0/159 (0%)	0	0/106 (0%)	0
Metastases to small intestine with Anaemia	0/241 (0%)	0	0/434 (0%)	0	0/159 (0%)	0	1/106 (0.9%)	2
Papillary thyroid cancer	0/241 (0%)	0	1/434 (0.2%)	1	0/159 (0%)	0	0/106 (0%)	0
Nervous system disorders
Transient ischaemic attack	0/241 (0%)	0	1/434 (0.2%)	1	0/159 (0%)	0	0/106 (0%)	0
Psychiatric disorders
Alchohol abuse	0/241 (0%)	0	0/434 (0%)	0	0/159 (0%)	0	1/106 (0.9%)	1
Completed suicide	1/241 (0.4%)	1	0/434 (0%)	0	0/159 (0%)	0	0/106 (0%)	0
Suicidal ideation	0/241 (0%)	0	1/434 (0.2%)	1	0/159 (0%)	0	0/106 (0%)	0
Reproductive system and breast disorders
Menorrhagia	1/241 (0.4%)	1	0/434 (0%)	0	0/159 (0%)	0	0/106 (0%)	0
Respiratory, thoracic and mediastinal disorders
Pneumonia aspiration	1/241 (0.4%)	1	0/434 (0%)	0	0/159 (0%)	0	0/106 (0%)	0
Social circumstances
Bereavement and Adjustment Disorder with Depressed Mood	0/241 (0%)	0	0/434 (0%)	0	0/159 (0%)	0	1/106 (0.9%)	2
Vascular disorders
Peripheral ischaemia	0/241 (0%)	0	1/434 (0.2%)	1	0/159 (0%)	0	0/106 (0%)	0
Other (Not Including Serious) Adverse Events
	THS 2.2 Use		CC Use		Dual Use		Other Use
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	40/241 (16.6%)		87/434 (20%)		26/159 (16.4%)		13/106 (12.3%)
Infections and infestations
Upper respiratory tract infection	21/241 (8.7%)	25	40/434 (9.2%)	45	11/159 (6.9%)	14	8/106 (7.5%)	9
Investigations
Blood triglycerides increased	10/241 (4.1%)	10	26/434 (6%)	28	6/159 (3.8%)	6	1/106 (0.9%)	1
Vascular disorders
Hypertension	9/241 (3.7%)	13	26/434 (6%)	40	9/159 (5.7%)	11	4/106 (3.8%)	5

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.