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Reduced Exposure Study Using THS 2.2 Menthol With 5 Days in a Confinement Setting and 85 Days in an Ambulatory Setting

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01970995
Recruitment Status : Completed
First Posted : October 28, 2013
Results First Posted : February 7, 2017
Last Update Posted : March 23, 2020
Sponsor:
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 Menthol (mTHS 2.2)
Other: Smoking Abstinence (SA)
Other: Menthol Conventional Cigarette (mCC)
Enrollment 160
Recruitment Details

Study initiated (first subject screened): 01 August 2013

At admission (Day -2), all the subjects performed a product trial of the THS 2.2 Menthol. During the baseline period, they continued smoking their single preferred brand of mCC. Then, on Day 0, they were randomized to one of the 3 study arms (mTHS 2.2, mCC or SA) in a 2:1:1 ratio.

Pre-assignment Details

Enrolled and randomized population = 160 subjects

  • 78 subjects in mTHS 2.2
  • 42 subjects in mCC
  • 40 subjects in SA

Number of subjects enrolled but NOT randomized (who tried the mTHS 2.2 at Day -2) = 0

Arm/Group Title THS 2.2 Menthol (mTHS 2.2) Menthol Conventional Cigarette (mCC) Smoking Abstinence (SA)
Hide Arm/Group Description Ad libitum use of THS 2.2 Menthol for 5 days in a confinement setting and 85 days in an ambulatory setting Ad libitum use of subject's own preferred brand of mCC for 5 days in a confinement setting and 85 days in an ambulatory setting Abstinence from smoking for 5 days in a confinement setting and 85 days in an ambulatory setting
Period Title: Confinement Period (Population at Day 5)
Started 78 42 40
Completed 77 41 39
Not Completed 1 1 1
Reason Not Completed
Withdrawal by Subject             1             1             1
Period Title: End of Study (Population at Day 90)
Started 77 41 39
Completed 76 41 38
Not Completed 1 0 1
Reason Not Completed
Withdrawal by Subject             1             0             1
Arm/Group Title THS 2.2 Menthol (mTHS 2.2) Menthol Conventional Cigarette (mCC) Smoking Abstinence (SA) Total
Hide Arm/Group Description Ad libitum use of THS 2.2 Menthol for 5 days in a confinement setting and 85 days in an ambulatory setting Ad libitum use of subject's own preferred brand of mCC for 5 days in a confinement setting and 85 days in an ambulatory setting Abstinence from smoking for 5 days in a confinement setting and 85 days in an ambulatory setting Total of all reporting groups
Overall Number of Baseline Participants 78 42 40 160
Hide Baseline Analysis Population Description
Study population = all randomized subjects who had at least one post randomization product use experience and at least one valid biomarker of exposure measurement. 160 randomized subjects: 78 in mTHS 2.2, 42 in mCC and 40 in SA arms 155 completed, subjects who withdrew: 2 in mTHS 2.2, 1 in mCC and 2 in SA arms
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 78 participants 42 participants 40 participants 160 participants
37.1  (10.58) 37.4  (11.23) 37.0  (9.96) 37.2  (10.54)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 78 participants 42 participants 40 participants 160 participants
Female
33
  42.3%
17
  40.5%
18
  45.0%
68
  42.5%
Male
45
  57.7%
25
  59.5%
22
  55.0%
92
  57.5%
Daily mCC consumption at Screening  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 78 participants 42 participants 40 participants 160 participants
10 to 19 cig/day 40 23 21 84
> 19 cig/day 38 19 19 76
1.Primary Outcome
Title Concentration of Monohydroxybutenyl Mercapturic Acid (MHBMA)
Hide Description

Concentrations measured at Day 5 in urine, adjusted for creatinine.

Geometric Least Squares (LS) means are provided as descriptive statistics.

Time Frame 5 days
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title THS 2.2 Menthol (mTHS 2.2) Menthol Conventional Cigarette (mCC) Smoking Abstinence (SA)
Hide Arm/Group Description:
Ad libitum use of THS 2.2 Menthol for 5 days in a confinement setting and 85 days in an ambulatory setting
Ad libitum use of subject's own preferred brand of mCC for 5 days in a confinement setting and 85 days in an ambulatory setting
Abstinence from smoking for 5 days in a confinement setting and 85 days in an ambulatory setting
Overall Number of Participants Analyzed 76 42 39
Least Squares Mean (95% Confidence Interval)
Unit of Measure: pg/mg creat
83.21
(73.51 to 94.19)
617.04
(521.87 to 729.55)
83.57
(70.32 to 99.32)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection THS 2.2 Menthol (mTHS 2.2), Menthol Conventional Cigarette (mCC)
Comments

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 biomarker 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<m2 Where m1 and m2 are the geometric means of the BoExp levels on Day 5 for mTHS 2.2 and mCC respectively.
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.001
Comments 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.
Method ANCOVA
Comments ANCOVA model on MHBMA levels with product, sex, cigarette consumption, and baseline value as covariates.
Method of Estimation Estimation Parameter Geometric LS Mean Ratio
Estimated Value 13.49
Confidence Interval (2-Sided) 95%
10.96 to 16.60
Estimation Comments Geometric LS mean ratio mTHS 2.2:mCC
2.Primary Outcome
Title Concentration of 3-hydroxypropylmercapturic Acid (3-HPMA)
Hide Description

Concentrations measured at Day 5 in urine, adjusted for creatinine.

Geometric Least Squares (LS) means are provided as descriptive statistics.

Time Frame 5 days
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title THS 2.2 Menthol (mTHS 2.2) Menthol Conventional Cigarette (mCC) Smoking Abstinence (SA)
Hide Arm/Group Description:
Ad libitum use of THS 2.2 Menthol for 5 days in a confinement setting and 85 days in an ambulatory setting
Ad libitum use of subject's own preferred brand of mCC for 5 days in a confinement setting and 85 days in an ambulatory setting
Abstinence from smoking for 5 days in a confinement setting and 85 days in an ambulatory setting
Overall Number of Participants Analyzed 76 42 39
Least Squares Mean (95% Confidence Interval)
Unit of Measure: ng/mg creat
304.56
(283.22 to 327.50)
601.11
(545.07 to 662.91)
183.61
(165.93 to 203.18)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection THS 2.2 Menthol (mTHS 2.2), Menthol Conventional Cigarette (mCC)
Comments

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<m2 Where m1 and m2 are the geometric means of the BoExp levels on Day 5 for mTHS 2.2 and mCC respectively.
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.001
Comments 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.
Method ANCOVA
Comments ANCOVA model on 3-HPMA levels with product, sex, cigarette consumption, and baseline value as covariates.
Method of Estimation Estimation Parameter Geometric LS Mean Ratio
Estimated Value 50.67
Confidence Interval (2-Sided) 95%
44.88 to 57.20
Estimation Comments Geometric LS mean ratio mTHS 2.2:mCC
3.Primary Outcome
Title Concentration of S-phenylmercapturic Acid (S-PMA)
Hide Description

Concentrations measured at Day 5 in urine, adjusted for creatinine.

Geometric Least Squares (LS) means are provided as descriptive statistics.

Time Frame 5 days
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title THS 2.2 Menthol (mTHS 2.2) Menthol Conventional Cigarette (mCC) Smoking Abstinence (SA)
Hide Arm/Group Description:
Ad libitum use of THS 2.2 Menthol for 5 days in a confinement setting and 85 days in an ambulatory setting
Ad libitum use of subject's own preferred brand of mCC for 5 days in a confinement setting and 85 days in an ambulatory setting
Abstinence from smoking for 5 days in a confinement setting and 85 days in an ambulatory setting
Overall Number of Participants Analyzed 76 42 39
Least Squares Mean (95% Confidence Interval)
Unit of Measure: pg/mg creat
119.18
(107.73 to 131.85)
1086.89
(948.47 to 1245.51)
104.83
(91.07 to 120.66)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection THS 2.2 Menthol (mTHS 2.2), Menthol Conventional Cigarette (mCC)
Comments

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<m2 Where m1 and m2 are the geometric means of the BoExp levels on Day 5 for mTHS 2.2 and mCC respectively.
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.001
Comments 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.
Method ANCOVA
Comments ANCOVA model on S-PMA levels with product, sex, cigarette consumption, and baseline value as covariates.
Method of Estimation Estimation Parameter Geometric LS Mean Ratio
Estimated Value 10.97
Confidence Interval (2-Sided) 95%
9.26 to 12.99
Estimation Comments Geometric LS mean ratio mTHS 2.2:mCC
4.Primary Outcome
Title Levels of Carboxyhemoglobin (COHb)
Hide Description

% COHb blood measurements performed in the evening of Day 5, expressed as % of saturation of hemoglobin.

Geometric Least Squares means are provided as descriptive statistics.

Time Frame 5 days
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title THS 2.2 Menthol (mTHS 2.2) Menthol Conventional Cigarette (mCC) Smoking Abstinence (SA)
Hide Arm/Group Description:
Ad libitum use of THS 2.2 Menthol for 5 days in a confinement setting and 85 days in an ambulatory setting
Ad libitum use of subject's own preferred brand of mCC for 5 days in a confinement setting and 85 days in an ambulatory setting
Abstinence from smoking for 5 days in a confinement setting and 85 days in an ambulatory setting
Overall Number of Participants Analyzed 76 42 39
Least Squares Mean (95% Confidence Interval)
Unit of Measure: % of saturation of hemoglobin
2.47
(2.37 to 2.57)
5.49
(5.21 to 5.79)
2.49
(2.35 to 2.63)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection THS 2.2 Menthol (mTHS 2.2), Menthol Conventional Cigarette (mCC)
Comments

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<m2 Where m1 and m2 are the geometric means of the BoExp levels on Day 5 for mTHS 2.2 and mCC respectively.
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.001
Comments 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.
Method ANCOVA
Comments ANCOVA model on COHb levels with product, sex, cigarette consumption, and baseline value as covariates.
Method of Estimation Estimation Parameter Geometric LS Mean Ratio
Estimated Value 44.94
Confidence Interval (2-Sided) 95%
42.11 to 47.97
Estimation Comments Geometric LS mean ratio mTHS 2.2:mCC
5.Primary Outcome
Title Concentration of Total 4-(Methylnitrosamino)-1-(3- Pyridyl)-1-butanol) (Total NNAL)
Hide Description

Concentrations measured at Day 90 in urine, adjusted for creatinine.

Geometric Least Squares (LS) means are provided as descriptive statistics.

Time Frame 90 days
Hide Outcome Measure Data
Hide Analysis Population Description
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 period Day 60 to Day 90.
Arm/Group Title THS 2.2 Menthol (mTHS 2.2) Menthol Conventional Cigarette (mCC) Smoking Abstinence (SA)
Hide Arm/Group Description:
Ad libitum use of THS 2.2 Menthol for 5 days in a confinement setting and 85 days in an ambulatory setting
Ad libitum use of subject's own preferred brand of mCC for 5 days in a confinement setting and 85 days in an ambulatory setting
Abstinence from smoking for 5 days in a confinement setting and 85 days in an ambulatory setting
Overall Number of Participants Analyzed 70 41 37
Least Squares Mean (95% Confidence Interval)
Unit of Measure: pg/mg creat
22.48
(18.82 to 26.84)
96.65
(76.63 to 121.90)
14.90
(11.67 to 19.02)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection THS 2.2 Menthol (mTHS 2.2), Menthol Conventional Cigarette (mCC)
Comments

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<m2 Where m1 and m2 are the geometric means of the BoExp levels on Day 90 for mTHS 2.2 and mCC respectively.
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <.001
Comments 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.
Method ANCOVA
Comments ANCOVA model on Total NNAL levels with product, sex, cigarette consumption, and baseline value as covariates
Method of Estimation Estimation Parameter Geometric LS Mean Ratio
Estimated Value 23.25
Confidence Interval (2-Sided) 95%
17.38 to 31.11
Estimation Comments Geometric LS mean ratio mTHS 2.2:mCC
Time Frame From the informed consent form signature until the end of the safety follow-up period, up to 150 days (including a screening period of up to 28 days, a 9-day confinement period followed by a 85-day ambulatory setting, and by a 28-day safety follow-up period (28 days after discharge of the subject or early discontinuation)).
Adverse Event Reporting Description The safety was assessed in the safety population, consisting of 160 subjects: 160 randomized subjects (78 in mTHS 2.2, 42 in mCC and 40 in SA) and no subject exposed to mTHS 2.2 from the product trial on Day -2 but not randomized.
 
Arm/Group Title THS 2.2 Menthol (mTHS 2.2) Menthol Conventional Cigarette (mCC) Smoking Abstinence (SA)
Hide Arm/Group Description Ad libitum use of THS 2.2 Menthol for 5 days in a confinement setting and 85 days in an ambulatory setting Ad libitum use of subject's own preferred brand of mCC for 5 days in a confinement setting and 85 days in an ambulatory setting Abstinence from smoking for 5 days in a confinement setting and 85 days in an ambulatory setting
All-Cause Mortality
THS 2.2 Menthol (mTHS 2.2) Menthol Conventional Cigarette (mCC) Smoking Abstinence (SA)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--    
Hide Serious Adverse Events
THS 2.2 Menthol (mTHS 2.2) Menthol Conventional Cigarette (mCC) Smoking Abstinence (SA)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/78 (0.00%)      0/42 (0.00%)      0/40 (0.00%)    
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
THS 2.2 Menthol (mTHS 2.2) Menthol Conventional Cigarette (mCC) Smoking Abstinence (SA)
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   16/78 (20.51%)      4/42 (9.52%)      4/40 (10.00%)    
Investigations       
Haemoglobin decreased * 1  11/78 (14.10%)  13 3/42 (7.14%)  5 3/40 (7.50%)  4
Neutrophil count decreased * 1  5/78 (6.41%)  5 1/42 (2.38%)  1 2/40 (5.00%)  2
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA 16.0
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 specifies 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 belongs to the Sponsor.

Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Christelle HAZIZA, PhD
Organization: Philip Morris Products S.A.
Phone: +41 (58) 242 2625
EMail: Christelle.Haziza@pmi.com
Layout table for additonal information
Responsible Party: Philip Morris Products S.A.
ClinicalTrials.gov Identifier: NCT01970995    
Other Study ID Numbers: ZRHM-REXA-07-JP
ZRHM-REXA-07-JP ( Other Identifier: Philip Morris Products S.A. )
First Submitted: October 18, 2013
First Posted: October 28, 2013
Results First Submitted: December 14, 2016
Results First Posted: February 7, 2017
Last Update Posted: March 23, 2020