Reduced Exposure Study Using THS 2.2 Menthol With 5 Days... | NCT01989156

ID	Type	Description	Link
ZRHM-REXA-08-US	Other Identifier	Philip Morris Products S.A.

Reduced Exposure Study Using THS 2.2 Menthol With 5 Days... | NCT01989156 | Trialant

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
THS 2.2 Menthol (mTHS 2.2)	Experimental	Ad libitum use of THS 2.2 Menthol for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting	Other: THS 2.2 Menthol (mTHS 2.2)
Menthol Conventional Cigarette (mCC)	Active Comparator	Ad libitum use of subject's own preferred brand of mCC for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting	Other: Menthol Conventional Cigarette (mCC)
Smoking abstinence (SA)	Sham Comparator	Abstinence from smoking for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting	Other: Smoking Abstinence (SA)

Interventions

Name	Type	Description	Arm Group Labels	Other Names
THS 2.2 Menthol (mTHS 2.2)	Other	THS 2.2 Menthol ad libitum for 5 days in confinement prolonged by 86 days in an ambulatory setting	THS 2.2 Menthol (mTHS 2.2)

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Concentration of Monohydroxybutenylmercapturic Acid (MHBMA)	Concentrations measured in urine, adjusted for creatinine, at Day 5 for the smokers of all arms (mTHS, mCC and SA). Geometric Least Squares means are provided as descriptive statistics.	5 days
Concentration of 3-hydroxypropylmercapturic Acid (3-HPMA)	Concentrations measured in urine, adjusted for creatinine, at Day 5 for the smokers of all arms (mTHS, mCC and SA). Geometric Least Squares means are provided as descriptive statistics.	5 days
Concentration of S-phenylmercapturic Acid (S-PMA)	Concentrations measured in urine, adjusted for creatinine, at Day 5 for the smokers of all arms (mTHS, mCC and SA). Geometric Least Squares means are provided as descriptive statistics.	5 days
Levels of Total 4-(Methylnitrosamino)-1-(3- Pyridyl)-1-butanol (Total NNAL)	Concentrations measured in urine, adjusted for creatinine, at Day 90 for the smokers of all arms (mTHS, mCC and SA). Geometric Least Squares means are provided as descriptive statistics.	90 days
Levels of Carboxyhemoglobin (COHb)	Carboxyhemoglobin (COHb) is assayed from whole blood. Expressed as % of saturation of hemoglobin. Blood measurements performed in the evening of Day 5, for the smokers of all arms (mTHS, mCC and SA). Geometric Least Squares means are provided as descriptive statistics.	5 days

Contacts/Locations Module

Overall Officials

Name	Affiliation	Role
William Lewis, MD	Covance Dallas	Principal Investigator
Frank Farmer, MD	Covance Daytona Beach	Principal Investigator
Christelle Haziza, PhD	Philip Morris Products S.A.	Study Chair

Facility	Status	City	State	ZIP	Country	Contacts
Covance Daytona Beach, 1900 Mason Ave., Suite 140		Daytona Beach	Florida	32117	United States
Covance Dallas, 1341 W. Mockingbird Ln., Ste 400E

References Module

Citations

PubMed Identifier	Type	Citation	Retractions
31125079	Derived	Haziza C, de La Bourdonnaye G, Donelli A, Skiada D, Poux V, Weitkunat R, Baker G, Picavet P, Ludicke F. Favorable Changes in Biomarkers of Potential Harm to Reduce the Adverse Health Effects of Smoking in Smokers Switching to the Menthol Tobacco Heating System 2.2 for 3 Months (Part 2). Nicotine Tob Res. 2020 Apr 17;22(4):549-559. doi: 10.1093/ntr/ntz084.
30722062

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	THS 2.2 Menthol (mTHS 2.2)	Ad libitum use of THS 2.2 Menthol for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting
FG001	Menthol Conventional Cigarette (mCC)

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Document Section

Large Document Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Apr 14, 2014	Mar 9, 2020

Type	Comment	Reasons
Withdrawal by Subject		FG0000 subjects FG0011 subjects FG0023 subjects
Patient Anxiety		FG0000 subjects FG0010 subjects FG0021 subjects
Adverse Event		FG0000 subjects FG0010 subjects FG0021 subjects

End of Study (Population at Day 90)

Type	Comment	Milestone Data
STARTED		FG00080 subjects FG00140 subjects FG00234 subjects
COMPLETED		FG00073 subjects FG00135 subjects FG00231 subjects
NOT COMPLETED		FG0007 subjects FG0015 subjects FG0023 subjects

Type	Comment	Reasons
Withdrawal by Subject		FG0002 subjects FG0012 subjects FG0022 subjects
Lost to Follow-up		FG000

Arm/Group Information

ID	Title	Description
BG000	THS 2.2 Menthol (mTHS 2.2)	Ad libitum use of THS 2.2 Menthol for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting
BG001	Menthol Conventional Cigarette (mCC)	Ad libitum use of subject's own preferred brand of mCC for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting
BG002	Smoking Abstinence (SA)	Abstinence from smoking for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting
BG003	Total	Total of all reporting groups

Units	Counts
Participants	BG00080 BG00141 BG00239 BG003160

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
	BG00039.2± 11.72 BG00133.7± 10.17 BG00238.8± 11.42 BG003

Sex: Female, Male

Count of Participants

Participants

Title

Denominators

Categories

Title	Measurements
Female	BG00032 BG00117 BG002

Daily mCC consumption at screening

Number

participants

Title

Denominators

Categories

10 to 19 cig/day

Title	Measurements
	BG00043 BG00121 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

Concentration of Monohydroxybutenylmercapturic Acid (MHBMA)

Concentrations measured in urine, adjusted for creatinine, at Day 5 for the smokers of all arms (mTHS, mCC and SA). Geometric Least Squares means are provided as descriptive statistics.

The analysis was performed on the Per Protocol set (PP) which included all randomized subjects who had no major protocol deviation impacting the evaluability during the confinement period.

Posted

Geometric Mean

95% Confidence Interval

pg/mg creat

5 days

ID	Title	Description
OG000	THS 2.2 Menthol (mTHS 2.2)	Ad libitum use of THS 2.2 Menthol for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting
OG001	Menthol Conventional Cigarette (mCC)	Ad libitum use of subject's own preferred brand of mCC for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting
OG002	Smoking Abstinence (SA)	Abstinence from smoking for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting

Units	Counts
Participants	OG00065 OG00130 OG00221

Title

Denominators

Categories

Title	Measurements
	OG000110.96(93.49 to 131.68) OG001882.25(687.25 to 1132.57) OG00294.97(70.67 to 127.61)

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 hypothesis to be tested is that the geometric mean level on Day 5 of the biomarker of exposure for mTHS 2.2 is lower relative to mCC. Analysis of the biomarkers of exposure (BoExp) was conducted on the natural log scale in order to test the following hypothesis (one sided test with 2.5% type I error probability): Null hypothesis (H0): m1≥m2 Alternative hypothesis (H1): m1\	ANCOVA	ANCOVA model on MHBMA levels with product, sex, cigarette consumption, and baseline value as covariates.	<0.001	The primary endpoints were tested using a multiple testing procedure to preserve the overall alpha level by simultaneously testing the endpoints using a closed procedure with each test performed at an alpha level of 2.5% one sided.	Geometric LS Mean Ratio	12.58			2-Sided	95	9.27	17.05

Primary

Concentration of 3-hydroxypropylmercapturic Acid (3-HPMA)

Concentrations measured in urine, adjusted for creatinine, at Day 5 for the smokers of all arms (mTHS, mCC and SA). Geometric Least Squares means are provided as descriptive statistics.

The analysis was performed on the Per Protocol set (PP) which included all randomized subjects who had no major protocol deviation impacting the evaluability during the confinement period.

Posted

Geometric Mean

95% Confidence Interval

ng/mg creat

5 days

ID	Title	Description
OG000	THS 2.2 Menthol (mTHS 2.2)	Ad libitum use of THS 2.2 Menthol for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting
OG001	Menthol Conventional Cigarette (mCC)	Ad libitum use of subject's own preferred brand of mCC for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting
OG002	Smoking Abstinence (SA)	Abstinence from smoking for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting

Primary

Concentration of S-phenylmercapturic Acid (S-PMA)

Concentrations measured in urine, adjusted for creatinine, at Day 5 for the smokers of all arms (mTHS, mCC and SA). Geometric Least Squares means are provided as descriptive statistics.

The analysis was performed on the Per Protocol set (PP) which included all randomized subjects who had no major protocol deviation impacting the evaluability during the confinement period.

Posted

Geometric Mean

95% Confidence Interval

pg/mg creat

5 days

ID	Title	Description
OG000	THS 2.2 Menthol (mTHS 2.2)	Ad libitum use of THS 2.2 Menthol for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting
OG001	Menthol Conventional Cigarette (mCC)	Ad libitum use of subject's own preferred brand of mCC for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting
OG002	Smoking Abstinence (SA)	Abstinence from smoking for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting

Primary

Levels of Total 4-(Methylnitrosamino)-1-(3- Pyridyl)-1-butanol (Total NNAL)

Concentrations measured in urine, adjusted for creatinine, at Day 90 for the smokers of all arms (mTHS, mCC and SA). Geometric Least Squares means are provided as descriptive statistics.

The analysis was performed on the Per Protocol set (PP) which included all randomized subjects who had no major protocol deviation impacting the evaluability during the confinement period.

Posted

Geometric Mean

95% Confidence Interval

pg/mg creat

90 days

ID	Title	Description
OG000	THS 2.2 Menthol (mTHS 2.2)	Ad libitum use of THS 2.2 Menthol for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting
OG001	Menthol Conventional Cigarette (mCC)	Ad libitum use of subject's own preferred brand of mCC for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting
OG002	Smoking Abstinence (SA)	Abstinence from smoking for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting

Primary

Levels of Carboxyhemoglobin (COHb)

Carboxyhemoglobin (COHb) is assayed from whole blood. Expressed as % of saturation of hemoglobin. Blood measurements performed in the evening of Day 5, for the smokers of all arms (mTHS, mCC and SA). Geometric Least Squares means are provided as descriptive statistics.

The analysis was performed on the Per Protocol set (PP) which included all randomized subjects who had no major protocol deviation impacting the evaluability during the confinement period.

Posted

Geometric Mean

95% Confidence Interval

% of saturation of hemoglobin

5 days

ID	Title	Description
OG000	THS 2.2 Menthol (mTHS 2.2)	Ad libitum use of THS 2.2 Menthol for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting
OG001	Menthol Conventional Cigarette (mCC)	Ad libitum use of subject's own preferred brand of mCC for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting
OG002	Smoking Abstinence (SA)	Abstinence from smoking for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting

Arm/Groups

ID	Title	Description	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	THS 2.2 Menthol (mTHS 2.2)	Ad libitum use of THS 2.2 Menthol for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting	80	31	80
EG001	Menthol Conventional Cigarette (mCC)	Ad libitum use of subject's own preferred brand of mCC for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting	41	12	41
EG002	Smoking Abstinence (SA)	Abstinence from smoking for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting	39	16	39

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Upper respiratory tract infection	Infections and infestations	MedDRA 16.0	Non-systematic Assessment	EG0003 events3 affected80 at risk EG0014 events4 affected41 at risk EG0021 events1 affected39 at risk
Muscle strain	Injury, poisoning and procedural complications	MedDRA 16.0	Non-systematic Assessment	EG0000 events0 affected80 at risk EG0010 events0 affected41 at risk EG0022 events2 affected39 at risk
Blood triglycerides increased	Investigations	MedDRA 16.0	Non-systematic Assessment	EG0002 events2 affected80 at risk EG0013 events2 affected41 at risk EG0022 events2 affected39 at risk
Haemoglobin decreased	Investigations	MedDRA 16.0	Non-systematic Assessment	EG00014 events11 affected80 at risk EG0015 events4 affected41 at risk EG0028 events6 affected39 at risk
Lymphocyte count increased	Investigations	MedDRA 16.0	Non-systematic Assessment	EG0007 events6 affected80 at risk EG0012 events2 affected41 at risk EG0021 events1 affected39 at risk
Dizziness	Nervous system disorders	MedDRA 16.0	Non-systematic Assessment	EG0001 events1 affected80 at risk EG0010 events0 affected41 at risk EG0022 events2 affected39 at risk
Headache	Nervous system disorders	MedDRA 16.0	Non-systematic Assessment	EG0004 events4 affected80 at risk EG0011 events1 affected41 at risk EG0024 events3 affected39 at risk
Neutrophil count decreased	Investigations	MedDRA 16.0	Non-systematic Assessment	EG0005 events4 affected80 at risk EG0010 events0 affected41 at risk EG0020 events0 affected39 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 hypothesis to be tested is that the geometric mean level on Day 5 of the biomarker of exposure for mTHS 2.2 is lower relative to mCC. Analysis of the BoExp was conducted on the natural log scale in order to test the following hypothesis (one sided test with 2.5% type I error probability): Null hypothesis (H0): m1≥m2 Alternative hypothesis (H1): m1\	ANCOVA	ANCOVA model on 3-HPMA levels with product, sex, cigarette consumption, and baseline value as covariates.	<0.001	The primary endpoints were tested using a multiple testing procedure to preserve the overall alpha level by simultaneously testing the endpoints using a closed procedure with each test performed at an alpha level of 2.5% one sided.	Geometric LS Mean Ratio	45.77			2-Sided	95	39.22	53.41			Geometric LS mean ratio mTHS 2.2:mCC		Superiority or Other (legacy)

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 hypothesis to be tested is that the geometric mean level on Day 5 of the biomarker of exposure for mTHS 2.2 is lower relative to mCC. Analysis of the BoExp was conducted on the natural log scale in order to test the following hypothesis (one sided test with 2.5% type I error probability): Null hypothesis (H0): m1≥m2 Alternative hypothesis (H1): m1\	ANCOVA	ANCOVA model on S-PMA levels with product, sex, cigarette consumption, and baseline value as covariates.	<0.001	The primary endpoints were tested using a multiple testing procedure to preserve the overall alpha level by simultaneously testing the endpoints using a closed procedure with each test performed at an alpha level of 2.5% one sided.	Geometric LS Mean Ratio	12.58			2-Sided	95	9.54	16.58			Geometric LS mean ratio mTHS 2.2:mCC		Superiority or Other (legacy)

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 hypothesis to be tested is that the geometric mean level on Day 90 of the biomarker of exposure for mTHS 2.2 is lower relative to mCC. Analysis of the BoExp was conducted on the natural log scale in order to test the following hypothesis (one sided test with 2.5% type I error probability): Null hypothesis (H0): m1≥m2 Alternative hypothesis (H1): m1\	ANCOVA	ANCOVA model on Total NNAL levels with product, sex, cigarette consumption, and baseline value as covariates	<0.001	The primary endpoints were tested using a multiple testing procedure to preserve the overall alpha level by simultaneously testing the endpoints using a closed procedure with each test performed at an alpha level of 2.5% one sided.	Geometric LS Mean Ratio	26.41			2-Sided	95	17.31	40.26			Geometric LS mean ratio mTHS 2.2:mCC		Superiority or Other (legacy)

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 hypothesis to be tested is that the geometric mean level on Day 90 of the biomarker of exposure for mTHS 2.2 is lower relative to mCC. Analysis of the BoExp was conducted on the natural log scale in order to test the following hypothesis (one sided test with 2.5% type I error probability): Null hypothesis (H0): m1≥m2 Alternative hypothesis (H1): m1\	ANCOVA	ANCOVA model on COHb levels with product, sex, cigarette consumption, and baseline value as covariates.	<0.001	The primary endpoints were tested using a multiple testing procedure to preserve the overall alpha level by simultaneously testing the endpoints using a closed procedure with each test performed at an alpha level of 2.5% one sided.	Geometric LS Mean Ratio	38.14			2-Sided	95	34.24	42.47			Geometric LS mean ratio mTHS 2.2:mCC		Superiority or Other (legacy)