Evaluation of Biological and Functional Changes in Health... | NCT02396381

ID	Type	Description	Link
ZRHR-ERS-09-US	Other Identifier	Philip Morris Products S.A.

Evaluation of Biological and Functional Changes in Health... | NCT02396381 | Trialant

Arms/Interventions Module

Label	Type	Description	Intervention Names
THS 2.2	Experimental	Ad libitum use of THS 2.2	Other: THS 2.2
CC	Active Comparator	Ad libitum use of CC	Other: CC

Name	Type	Description	Arm Group Labels	Other Names
THS 2.2	Other	Ad libitum use of THS 2.2 in an ambulatory setting for 26 weeks	THS 2.2

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Levels of High Density Lipoprotein C (HDL-C).	Concentrations measured in serum. Geometric Least Squares means are provided as descriptive statistics.	26 Weeks
Levels of White Blood Cells (WBC).	Concentrations measured in blood. Geometric Least Squares means are provided as descriptive statistics.	26 Weeks
Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1).	FEV1 post-bronchodilator and expressed as percentage predicted (FEV1 %pred). Geometric Least Squares means are provided as descriptive statistics.	26 Weeks
Concentrations of Soluble Intercellular Adhesion Molecule 1 (sICAM-1).	Concentrations measured in serum. Geometric Least Squares means are provided as descriptive statistics.	26 Weeks
Concentrations of 11-dehydrothromboxane B2 (11-DTXB2).	Concentrations measured in urine and expressed as concentration adjusted for creatinine. Geometric Least Squares means are provided as descriptive statistics.	26 Weeks
Concentrations of 8-epi-prostaglandin F2α (8-epi-PGF2α).	Concentrations measured in urine and expressed as concentration adjusted for creatinine. Geometric Least Squares means are provided as descriptive statistics.	26 Weeks
Concentrations of Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL).

Contacts/Locations Module

Overall Officials

Name	Affiliation	Role
Christelle Haziza, PhD	Philip Morris Products S.A.	Study Chair
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

Facility	Status	City	State	ZIP	Country	Contacts
Celerion Arizona		Tempe	Arizona	85283	United States
Clinical Research West Florida

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
31270101	Result	Ludicke F, Ansari SM, Lama N, Blanc N, Bosilkovska M, Donelli A, Picavet P, Baker G, Haziza C, Peitsch M, Weitkunat R. Effects of Switching to a Heat-Not-Burn Tobacco Product on Biologically Relevant Biomarkers to Assess a Candidate Modified Risk Tobacco Product: A Randomized Trial. Cancer Epidemiol Biomarkers Prev. 2019 Nov;28(11):1934-1943. doi: 10.1158/1055-9965.EPI-18-0915. Epub 2019 Jul 3.
30143474

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	THS 2.2 Group	Randomized to Ad libitum use of THS 2.2 in an ambulatory setting for 26 weeks
FG001	CC Group	Randomized to Ad libitum use of CC in an ambulatory setting for 26 weeks

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Comment	Reasons
Adverse Event		FG0003 subjects FG0012 subjects
Withdrawal by Subject		FG00033 subjects FG00124 subjects
Lost to Follow-up		FG00049 subjects FG00131 subjects
Protocol Violation		FG0001 subjects FG0010 subjects
Site terminated by sponsor		FG0007 subjects FG0018 subjects
Physician Decision		FG0005 subjects FG0015 subjects
Pregnancy		FG0002 subjects FG0010 subjects
Non-compliance with study procedures		FG0001 subjects FG0010 subjects
Moved out of town/state		FG0001 subjects FG0013 subjects
Could not complete visit		FG0001 subjects FG0010 subjects
Possible conflict of interest		FG0001 subjects FG0010 subjects
Randomization/Screening Error		FG0003 subjects FG0011 subjects

Arm/Group Information

ID	Title	Description
BG000	THS 2.2 Use	≥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.
BG001	CC Use	≥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.
BG002	Dual Use	≥ 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.
BG003	Other Use	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.
BG004	Total	Total of all reporting groups

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Standard Deviation

years

Title

Denominators

Categories

Title	Measurements
	BG00044.2± 9.64 BG00145.2± 9.55 BG00243.8± 9.77 BG003

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG00094 BG001182 BG002

Ethnicity (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Hispanic or Latino	BG00017 BG00128 BG002

Race (NIH/OMB)

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
American Indian or Alaska Native	BG0002 BG0012 BG002

BMI

Mean

Standard Deviation

kg/m2

Title

Denominators

Categories

Title	Measurements
	BG00026.9± 3.99 BG00127.1± 4.13 BG002

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Levels of High Density Lipoprotein C (HDL-C).

Concentrations measured in serum.

Geometric Least Squares means are provided as descriptive statistics.

Full Analysis Set - As Exposed (FAS-EX)

Posted

Geometric Mean

95% Confidence Interval

mg/dL

26 Weeks

ID	Title	Description
OG000	THS 2.2 Use	≥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.
OG001	CC Use	≥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.
OG002	Dual Use	≥ 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.
OG003	Other Use	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.

Units	Counts
Participants	OG000245 OG001428 OG002142 OG003

Title

Denominators

Categories

Title	Measurements
	OG00054.1(51.4 to 56.7) OG00150.9(49.4 to 52.4) OG00256.3(52.7 to 59.9) OG003

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	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).	Hailperin-Rüger	p-value less than 1.5625% would be considered statistically significant, following test multiplicity adjustment using the Hailperin-Rüger approach	<0.001		LS Mean Difference	3.09			2-Sided	96.875	1.10	5.09					Other

Primary

Levels of White Blood Cells (WBC).

Concentrations measured in blood.

Geometric Least Squares means are provided as descriptive statistics.

Full Analysis Set - As Exposed (FAS-EX)

Posted

Geometric Mean

95% Confidence Interval

GI/L

26 Weeks

ID	Title	Description
OG000	THS 2.2 Use	≥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.
OG001	CC Use	≥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.
OG002	Dual Use	≥ 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.
OG003	Other Use	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.

Primary

Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1).

FEV1 post-bronchodilator and expressed as percentage predicted (FEV1 %pred).

Geometric Least Squares means are provided as descriptive statistics.

Full Analysis Set - As Exposed (FAS-EX)

Posted

Geometric Mean

95% Confidence Interval

Percent of predicted FEV1

26 Weeks

ID	Title	Description
OG000	THS 2.2 Use	≥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.
OG001	CC Use	≥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.
OG002	Dual Use	≥ 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.
OG003	Other Use	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.

Primary

Concentrations of Soluble Intercellular Adhesion Molecule 1 (sICAM-1).

Concentrations measured in serum.

Geometric Least Squares means are provided as descriptive statistics.

Full Analysis Set - As Exposed (FAS-EX)

Posted

Geometric Mean

95% Confidence Interval

ng/mL

26 Weeks

ID	Title	Description
OG000	THS 2.2 Use	≥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.
OG001	CC Use	≥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.
OG002	Dual Use	≥ 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.
OG003	Other Use	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.

Primary

Concentrations of 11-dehydrothromboxane B2 (11-DTXB2).

Concentrations measured in urine and expressed as concentration adjusted for creatinine.

Geometric Least Squares means are provided as descriptive statistics.

Full Analysis Set - As Exposed (FAS-EX)

Posted

Geometric Mean

95% Confidence Interval

pg/mg creat

26 Weeks

ID	Title	Description
OG000	THS 2.2 Use	≥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.
OG001	CC Use	≥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.
OG002	Dual Use	≥ 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.
OG003	Other Use	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.

Primary

Concentrations of 8-epi-prostaglandin F2α (8-epi-PGF2α).

Concentrations measured in urine and expressed as concentration adjusted for creatinine.

Geometric Least Squares means are provided as descriptive statistics.

Full Analysis Set - As Exposed (FAS-EX)

Posted

Geometric Mean

95% Confidence Interval

pg/mg creat

26 Weeks

ID	Title	Description
OG000	THS 2.2 Use	≥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.
OG001	CC Use	≥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.
OG002	Dual Use	≥ 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.
OG003	Other Use	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.

Primary

Concentrations of Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL).

Concentrations measured in urine and expressed as concentration adjusted for creatinine.

Geometric Least Squares means are provided as descriptive statistics.

Full Analysis Set - As Exposed (FAS-EX)

Posted

Geometric Mean

95% Confidence Interval

pg/mg creat

26 Weeks

ID	Title	Description
OG000	THS 2.2 Use	≥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.
OG001	CC Use	≥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.
OG002	Dual Use	≥ 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.
OG003	Other Use	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.

Primary

Percent Change From Baseline of Carboxyhemoglobin (COHb)

Carboxyhemoglobin (COHb) is assayed from whole blood.

Geometric Least Squares means are provided as descriptive statistics. Expressed as % of saturation of hemoglobin.

Full Analysis Set - As Exposed (FAS-EX)

Posted

Geometric Mean

95% Confidence Interval

percentage change from baseline

26 Weeks

ID	Title	Description
OG000	THS 2.2 Use	≥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.
OG001	CC Use	≥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.
OG002	Dual Use	≥ 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.
OG003	Other Use	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.

Arm/Groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	THS 2.2 Group	Randomized to Ad libitum use of THS 2.2 in an ambulatory setting for 26 weeks	2	477	6	477	23	477
EG001	CC Group	Randomized to Ad libitum use of CC in an ambulatory setting for 26 weeks	0	483	7	483	29	483
EG002	Product Test	Enrolled subjects who participated in a product test, but were not randomized.	0	52	0	52	0	52

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Pneumonia mycoplasmal	Infections and infestations	MedDRA (18.0)	Non-systematic Assessment	EG0001 events1 affected477 at risk EG0010 events0 affected483 at risk EG0020 events0 affected52 at risk
Cellulitis	Infections and infestations	MedDRA (18.0)	Non-systematic Assessment	EG0000 events0 affected477 at risk EG0011 events1 affected483 at risk EG0020 events0 affected52 at risk
Pyelonephritis acute, with Urosepsis and Nephrolithiasis	Infections and infestations	MedDRA (18.0)	Non-systematic Assessment	EG0000 events0 affected477 at risk EG0013 events1 affected483 at risk EG0020 events0 affected52 at risk
Tooth Infection	Infections and infestations	MedDRA (18.0)	Non-systematic Assessment	EG0000 events0 affected477 at risk EG0011 events1 affected483 at risk EG0020 events0 affected52 at risk
Head injury with seizure	Injury, poisoning and procedural complications	MedDRA (18.0)	Non-systematic Assessment	EG0002 events1 affected477 at risk EG0010 events0 affected483 at risk EG0020 events0 affected52 at risk
Laceration	Injury, poisoning and procedural complications	MedDRA (18.0)	Non-systematic Assessment	EG0001 events1 affected477 at risk EG0010 events0 affected483 at risk EG0020 events0 affected52 at risk
Papillary thyroid cancer	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (18.0)	Non-systematic Assessment	EG0000 events0 affected477 at risk EG0011 events1 affected483 at risk EG0020 events0 affected52 at risk
Completed suicide	Psychiatric disorders	MedDRA (18.0)	Non-systematic Assessment	EG0001 events1 affected477 at risk EG0010 events0 affected483 at risk EG0020 events0 affected52 at risk
Suicidal ideation	Psychiatric disorders	MedDRA (18.0)	Non-systematic Assessment	EG0000 events0 affected477 at risk EG0011 events1 affected483 at risk EG0020 events0 affected52 at risk
Alcohol abuse	Psychiatric disorders	MedDRA (18.0)	Non-systematic Assessment	EG0001 events1 affected477 at risk EG0010 events0 affected483 at risk EG0020 events0 affected52 at risk
Adjustment disorder with depressed mood and bereavement	Psychiatric disorders	MedDRA (18.0)	Non-systematic Assessment	EG0000 events0 affected477 at risk EG0012 events1 affected483 at risk EG0020 events0 affected52 at risk
Metastases to small intestine with anaemia	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA (18.0)	Non-systematic Assessment	EG0002 events1 affected477 at risk EG0010 events0 affected483 at risk EG0020 events0 affected52 at risk
Vertebral osteophyte with Cervical myelopathy	Musculoskeletal and connective tissue disorders	MedDRA (18.0)	Non-systematic Assessment	EG0000 events0 affected477 at risk EG0012 events1 affected483 at risk EG0020 events0 affected52 at risk

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Notes	Statistical Information
Upper respiratory tract infection	Infections and infestations	MedDRA (18.0)	Non-systematic Assessment		EG00026 events23 affected477 at risk EG00133 events29 affected483 at risk EG0020 events0 affected52 at risk

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	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).	Hailperin-Rüger	p-value less than 1.5625% would be considered statistically significant, following test multiplicity adjustment using the Hailperin-Rüger approach	0.001		LS Mean Difference	-0.420			2-Sided	96.875	-0.717	-0.123					Superiority

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	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).	Hailperin-Rüger	p-value less than 1.5625% would be considered statistically significant, following test multiplicity adjustment using the Hailperin-Rüger approach	0.008		LS Mean Difference	1.28			2-Sided	96.875	0.145	2.42					Superiority

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	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).	Hailperin-Rüger	p-value less than 1.5625% would be considered statistically significant, following test multiplicity adjustment using the Hailperin-Rüger approach	0.030		% Reduction	2.86			2-Sided	96.875	-0.426	6.04			Derived as 1 - LS Mean Ratio (THS / CC)		Superiority

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	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).	Hailperin-Rüger	p-value less than 1.5625% would be considered statistically significant, following test multiplicity adjustment using the Hailperin-Rüger approach	0.193		% Reduction	4.74			2-Sided	96.875	-7.5	15.6			Derived as 1 - LS Mean Ratio (THS / CC)		Superiority

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	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).	Hailperin-Rüger	p-value less than 1.5625% would be considered statistically significant, following test multiplicity adjustment using the Hailperin-Rüger approach	0.018		% Reduction	6.80			2-Sided	96.875	-0.216	13.3			Derived as 1 - LS Mean Ratio (THS / CC)		Superiority

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	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).	Hailperin-Rüger	p-value less than 1.5625% would be considered statistically significant, following test multiplicity adjustment using the Hailperin-Rüger approach	<0.001		% Reduction	43.5			2-Sided	96.875	33.7	51.9			Derived as 1 - LS Mean Ratio (THS / CC)		Superiority

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	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).	Hailperin-Rüger	p-value less than 1.5625% would be considered statistically significant, following test multiplicity adjustment using the Hailperin-Rüger approach	<0.001		% Reduction	32.2			2-Sided	96.875	24.5	39			Derived as 1 - LS Mean Ratio (THS / CC)		Superiority