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

• ClinicalTrials.gov Identifier: NCT02649556
• Recruitment Status: Completed
• First Posted: January 7, 2016
• Results First Posted: December 4, 2020
• Last Update Posted: December 4, 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: THS 2.2; Other: CC
• Enrollment: 672

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 Details	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 Number of Baseline Participants		230	424	152	51	857
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	230 participants	424 participants	152 participants	51 participants	857 participants
		43.8 (9.68)	45.2 (9.54)	44.2 (9.76)	44.5 (8.21)	44.6 (9.55)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	230 participants	424 participants	152 participants	51 participants	857 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); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	230 participants	424 participants	152 participants	51 participants	857 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 0.0%	0 0.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	230 participants	424 participants	152 participants	51 participants	857 participants
	American Indian or Alaska Native	1 0.4%	2 0.5%	2 1.3%	1 2.0%	6 0.7%
	Asian	2 0.9%	5 1.2%	0 0.0%	1 2.0%	8 0.9%
	Native Hawaiian or Other Pacific Islander	1 0.4%	2 0.5%	0 0.0%	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 0.0%	0 0.0%
	Unknown or Not Reported	3 1.3%	4 0.9%	2 1.3%	1 2.0%	10 1.2%
BMI; Mean (Standard Deviation); Unit of measure: Kg/m^2
	Number Analyzed	230 participants	424 participants	152 participants	51 participants	857 participants
		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.)
Overall Number of Participants Analyzed	168	315	103	28
Mean (95% Confidence Interval); Unit of Measure: mg/dL
	52.2; (49.5 to 54.8)	50.6; (48.9 to 52.3)	54.0; (49.7 to 58.4)	54.7; (49.2 to 60.3)

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	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	1.75
	Confidence Interval	(2-Sided) 95%; -0.160 to 3.65
	Estimation Comments	[Not Specified]
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.)
Overall Number of Participants Analyzed	167	312	102	28
Mean (95% Confidence Interval); Unit of Measure: GI/L
	6.73; (6.47 to 6.99)	7.31; (7.07 to 7.54)	7.28; (6.85 to 7.71)	7.57; (6.85 to 8.29)

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	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	-0.413
	Confidence Interval	(2-Sided) 95%; -0.694 to -0.131
	Estimation Comments	[Not Specified]
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.)
Overall Number of Participants Analyzed	153	288	95	27
Mean (95% Confidence Interval); Unit of Measure: Percent of predicted FEV1
	93.2; (91.1 to 95.2)	92.3; (90.7 to 94.0)	91.1; (88.2 to 94.1)	95.2; (90.1 to 100)

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	[Not Specified]
Method of Estimation	Estimation Parameter	LS Mean Difference
	Estimated Value	0.914
	Confidence Interval	(2-Sided) 95%; -0.339 to 2.17
	Estimation Comments	[Not Specified]
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.)
Overall Number of Participants Analyzed	168	315	103	28
Geometric Mean (95% Confidence Interval); Unit of Measure: ng/mL
	246; (230 to 263)	258; (244 to 272)	269; (252 to 286)	255; (222 to 292)

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	[Not Specified]
Method of Estimation	Estimation Parameter	% Relative Reduction
	Estimated Value	3.11
	Confidence Interval	(2-Sided) 95%; 0.0231 to 6.10
	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.)
Overall Number of Participants Analyzed	166	312	102	27
Geometric Mean (95% Confidence Interval); Unit of Measure: pg/mg creat
	582; (518 to 654)	586; (538 to 638)	595; (510 to 693)	536; (396 to 727)

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	[Not Specified]
Method of Estimation	Estimation Parameter	% Relative Reduction
	Estimated Value	3.44
	Confidence Interval	(2-Sided) 95%; -8.74 to 14.3
	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.)
Overall Number of Participants Analyzed	167	312	102	27
Geometric Mean (95% Confidence Interval); Unit of Measure: pg/mg creat
	307; (279 to 338)	327; (307 to 348)	326; (293 to 362)	364; (289 to 458)

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	[Not Specified]
Method of Estimation	Estimation Parameter	% Relative Reduction
	Estimated Value	7.15
	Confidence Interval	(2-Sided) 95%; -1.03 to 14.7
	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.)
Overall Number of Participants Analyzed	167	312	102	27
Geometric Mean (95% Confidence Interval); Unit of Measure: pg/mg creat
	133; (105 to 168)	269; (238 to 305)	253; (207 to 309)	304; (214 to 431)

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	[Not Specified]
Method of Estimation	Estimation Parameter	% Relative Reduction
	Estimated Value	46.3
	Confidence Interval	(2-Sided) 95%; 36.2 to 54.8
	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.)
Overall Number of Participants Analyzed	141	257	86	26
Geometric Mean (95% Confidence Interval); Unit of Measure: percent change
	2.59; (2.24 to 3.01)	4.06; (3.77 to 4.38)	3.92; (3.44 to 4.46)	5.22; (4.47 to 6.11)

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	[Not Specified]
Method of Estimation	Estimation Parameter	% Relative Reduction
	Estimated Value	31.7
	Confidence Interval	(2-Sided) 95%; 23.3 to 39.1
	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 (%)		Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	1/241 (0.41%)		1/434 (0.23%)		0/159 (0.00%)		1/106 (0.94%)
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 (4.98%)		15/434 (3.46%)		1/159 (0.63%)		1/106 (0.94%)
Cardiac disorders
Acute myocardial infarction * 1	0/241 (0.00%)	0	1/434 (0.23%)	1	0/159 (0.00%)	0	0/106 (0.00%)	0
Gastrointestinal disorders
Pancreatitis chronic * 1	0/241 (0.00%)	0	1/434 (0.23%)	1	0/159 (0.00%)	0	0/106 (0.00%)	0
General disorders
Death * 1	0/241 (0.00%)	0	1/434 (0.23%)	1	0/159 (0.00%)	0	0/106 (0.00%)	0
Infections and infestations
Appendicitis with Peritonitis * 1	1/241 (0.41%)	2	0/434 (0.00%)	0	0/159 (0.00%)	0	0/106 (0.00%)	0
Cellulitis * 1	0/241 (0.00%)	0	1/434 (0.23%)	1	0/159 (0.00%)	0	0/106 (0.00%)	0
Cellulitis staphylococcal * 1	0/241 (0.00%)	0	1/434 (0.23%)	1	0/159 (0.00%)	0	0/106 (0.00%)	0
Epiglottitis * 1	1/241 (0.41%)	1	0/434 (0.00%)	0	0/159 (0.00%)	0	0/106 (0.00%)	0
Influenza * 1	1/241 (0.41%)	1	0/434 (0.00%)	0	0/159 (0.00%)	0	0/106 (0.00%)	0
Pneumonia mycoplasmal * 1	1/241 (0.41%)	1	0/434 (0.00%)	0	0/159 (0.00%)	0	0/106 (0.00%)	0
Tooth infection * 1	0/241 (0.00%)	0	1/434 (0.23%)	1	0/159 (0.00%)	0	0/106 (0.00%)	0
Urosepsis with Nephrolithiasis * 1	0/241 (0.00%)	0	1/434 (0.23%)	2	0/159 (0.00%)	0	0/106 (0.00%)	0
Pyelonephritis Acute * 1	0/241 (0.00%)	0	1/434 (0.23%)	1	1/159 (0.63%)	1	0/106 (0.00%)	0
Injury, poisoning and procedural complications
Head injury with Seizure * 1	1/241 (0.41%)	2	0/434 (0.00%)	0	0/159 (0.00%)	0	0/106 (0.00%)	0
Hip fracture * 1	1/241 (0.41%)	1	0/434 (0.00%)	0	0/159 (0.00%)	0	0/106 (0.00%)	0
Laceration * 1	1/241 (0.41%)	1	0/434 (0.00%)	0	0/159 (0.00%)	0	0/106 (0.00%)	0
Multiple fractures * 1	0/241 (0.00%)	0	0/434 (0.00%)	0	1/159 (0.63%)	1	0/106 (0.00%)	0
Rib fracture, Clavicle fracture, Pulmonary contusion, Pleural effusion, and Traumatic Hemothorax * 1	0/241 (0.00%)	0	1/434 (0.23%)	5	0/159 (0.00%)	0	0/106 (0.00%)	0
Foot Fracture * 1	1/241 (0.41%)	1	0/434 (0.00%)	0	0/159 (0.00%)	0	0/106 (0.00%)	0
Musculoskeletal and connective tissue disorders
Costochondritis * 1	1/241 (0.41%)	1	0/434 (0.00%)	0	0/159 (0.00%)	0	0/106 (0.00%)	0
Vertebral osteophyte with Cervical Myelopathy * 1	0/241 (0.00%)	0	1/434 (0.23%)	2	0/159 (0.00%)	0	0/106 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer * 1	0/241 (0.00%)	0	1/434 (0.23%)	2	0/159 (0.00%)	0	0/106 (0.00%)	0
Metastases to small intestine with Anaemia * 1	0/241 (0.00%)	0	0/434 (0.00%)	0	0/159 (0.00%)	0	1/106 (0.94%)	2
Papillary thyroid cancer * 1	0/241 (0.00%)	0	1/434 (0.23%)	1	0/159 (0.00%)	0	0/106 (0.00%)	0
Nervous system disorders
Transient ischaemic attack * 1	0/241 (0.00%)	0	1/434 (0.23%)	1	0/159 (0.00%)	0	0/106 (0.00%)	0
Psychiatric disorders
Alchohol abuse * 1	0/241 (0.00%)	0	0/434 (0.00%)	0	0/159 (0.00%)	0	1/106 (0.94%)	1
Completed suicide * 1	1/241 (0.41%)	1	0/434 (0.00%)	0	0/159 (0.00%)	0	0/106 (0.00%)	0
Suicidal ideation * 1	0/241 (0.00%)	0	1/434 (0.23%)	1	0/159 (0.00%)	0	0/106 (0.00%)	0
Reproductive system and breast disorders
Menorrhagia * 1	1/241 (0.41%)	1	0/434 (0.00%)	0	0/159 (0.00%)	0	0/106 (0.00%)	0
Respiratory, thoracic and mediastinal disorders
Pneumonia aspiration * 1	1/241 (0.41%)	1	0/434 (0.00%)	0	0/159 (0.00%)	0	0/106 (0.00%)	0
Social circumstances
Bereavement and Adjustment Disorder with Depressed Mood * 1	0/241 (0.00%)	0	0/434 (0.00%)	0	0/159 (0.00%)	0	1/106 (0.94%)	2
Vascular disorders
Peripheral ischaemia * 1	0/241 (0.00%)	0	1/434 (0.23%)	1	0/159 (0.00%)	0	0/106 (0.00%)	0
1 Term from vocabulary, MedDRA (18.0); * Indicates events were collected by non-systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	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 (16.60%)		87/434 (20.05%)		26/159 (16.35%)		13/106 (12.26%)
Infections and infestations
Upper respiratory tract infection * 1	21/241 (8.71%)	25	40/434 (9.22%)	45	11/159 (6.92%)	14	8/106 (7.55%)	9
Investigations
Blood triglycerides increased * 1	10/241 (4.15%)	10	26/434 (5.99%)	28	6/159 (3.77%)	6	1/106 (0.94%)	1
Vascular disorders
Hypertension * 1	9/241 (3.73%)	13	26/434 (5.99%)	40	9/159 (5.66%)	11	4/106 (3.77%)	5
1 Term from vocabulary, MedDRA (18.0); * Indicates events were collected by non-systematic assessment

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 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.

Results Point of Contact

• Name/Title: Christelle Haziza
• Organization: Philip Morris Products S.A.
• Phone: +41 58 242 11 11
• EMail: christelle.haziza@pmi.com

• 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 ( Other Identifier: Philip Morris Products S.A. )
• First Submitted: January 5, 2016
• First Posted: January 7, 2016
• Results First Submitted: May 25, 2020
• Results First Posted: December 4, 2020
• Last Update Posted: December 4, 2020