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Reduced Exposure Study Using THS 2.2 Menthol With 5 Days in a Confinement Setting Followed by 86 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: NCT01989156
Recruitment Status : Completed
First Posted : November 20, 2013
Results First Posted : April 5, 2017
Last Update Posted : March 24, 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: Menthol Conventional Cigarette (mCC)
Other: Smoking Abstinence (SA)
Enrollment 160
Recruitment Details

Study initiated (first subject screened): 17 December 2013

At admission (Day -2), all the subjects performed a product trial of THS 2.2 Menthol. During the baseline period, they continued to smoke 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

  • 80 subjects in mTHS 2.2
  • 41 subjects in mCC
  • 39 subjects in SA

Number of subjects exposed to the product test = 165

  • Number of subjects enrolled but NOT randomized = 4
  • Number of subjects failed screening = 1
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 86 Days in an Ambulatory Setting 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 Abstinence from smoking for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting
Period Title: Confinement Period (Population at Day 5)
Started 80 41 39
Completed 80 40 34
Not Completed 0 1 5
Reason Not Completed
Withdrawal by Subject             0             1             3
Patient Anxiety             0             0             1
Adverse Event             0             0             1
Period Title: End of Study (Population at Day 90)
Started 80 40 34
Completed 73 35 31
Not Completed 7 5 3
Reason Not Completed
Withdrawal by Subject             2             2             2
Lost to Follow-up             3             2             0
Physician Decision             1             0             1
Moved out of state             1             0             0
Employment Conflict             0             1             0
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 86 Days in an Ambulatory Setting 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 Abstinence from smoking for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting Total of all reporting groups
Overall Number of Baseline Participants 80 41 39 160
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: 80 in mTHS 2.2, 41 in mCC and 39 in SA arms
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 80 participants 41 participants 39 participants 160 participants
39.2  (11.72) 33.7  (10.17) 38.8  (11.42) 37.7  (11.45)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 80 participants 41 participants 39 participants 160 participants
Female
32
  40.0%
17
  41.5%
15
  38.5%
64
  40.0%
Male
48
  60.0%
24
  58.5%
24
  61.5%
96
  60.0%
Daily mCC consumption at screening  
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 80 participants 41 participants 39 participants 160 participants
10 to 19 cig/day 43 21 18 82
> 19 cig/day 36 20 21 77
1.Primary Outcome
Title Concentration of Monohydroxybutenylmercapturic Acid (MHBMA)
Hide Description 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.
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 86 Days in an Ambulatory Setting
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
Abstinence from smoking for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting
Overall Number of Participants Analyzed 65 30 21
Geometric Mean (95% Confidence Interval)
Unit of Measure: pg/mg creat
110.96
(93.49 to 131.68)
882.25
(687.25 to 1132.57)
94.97
(70.67 to 127.61)
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 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<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 <0.001
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 12.58
Confidence Interval (2-Sided) 95%
9.27 to 17.05
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 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.
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 86 Days in an Ambulatory Setting
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
Abstinence from smoking for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting
Overall Number of Participants Analyzed 67 30 21
Geometric Mean (95% Confidence Interval)
Unit of Measure: ng/mg creat
278.13
(254.95 to 303.43)
607.68
(534.34 to 691.09)
152.05
(130.47 to 177.19)
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 <0.001
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 45.77
Confidence Interval (2-Sided) 95%
39.22 to 53.41
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 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.
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 86 Days in an Ambulatory Setting
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
Abstinence from smoking for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting
Overall Number of Participants Analyzed 65 30 21
Geometric Mean (95% Confidence Interval)
Unit of Measure: pg/mg creat
134.11
(114.63 to 156.90)
1065.91
(848.45 to 1339.09)
131.05
(99.78 to 172.13)
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 <0.001
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 12.58
Confidence Interval (2-Sided) 95%
9.54 to 16.58
Estimation Comments Geometric LS mean ratio mTHS 2.2:mCC
4.Primary Outcome
Title Levels of Total 4-(Methylnitrosamino)-1-(3- Pyridyl)-1-butanol (Total NNAL)
Hide Description 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.
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 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 86 Days in an Ambulatory Setting
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
Abstinence from smoking for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting
Overall Number of Participants Analyzed 43 29 9
Geometric Mean (95% Confidence Interval)
Unit of Measure: pg/mg creat
41.05
(31.28 to 53.86)
155.45
(112.46 to 214.88)
54.03
(30 to 97.28)
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 <0.001
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 26.41
Confidence Interval (2-Sided) 95%
17.31 to 40.26
Estimation Comments Geometric LS mean ratio mTHS 2.2:mCC
5.Primary Outcome
Title Levels of Carboxyhemoglobin (COHb)
Hide Description 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.
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 86 Days in an Ambulatory Setting
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
Abstinence from smoking for 5 Days in a Confinement Setting and 86 Days in an Ambulatory Setting
Overall Number of Participants Analyzed 74 34 23
Geometric Mean (95% Confidence Interval)
Unit of Measure: % of saturation of hemoglobin
2.33
(2.19 to 2.48)
6.11
(5.58 to 6.68)
2.39
(2.14 to 2.67)
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 <0.001
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 38.14
Confidence Interval (2-Sided) 95%
34.24 to 42.47
Estimation Comments Geometric LS mean ratio mTHS 2.2:mCC
Time Frame From the informed consent form (ICF) signature until the end of the safety follow-up period, up to 150 days (including a screening period of up to 28 days, an 8-day confinement period followed by an 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 adverse events and serious adverse events reported are for the post-randomization period.

The safety was assessed in the safety population, consisting of 165 subjects: 160 randomized subjects (80 in mTHS 2.2, 41 in mCC and 39 in SA) and 5 subjects exposed to mTHS 2.2 from the product trial on Day -2 but not randomized. After randomization, the Safety Population consisted of 160 subjects with one valid post-randomization safety assessment.
 
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 86 Days in an Ambulatory Setting 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 Abstinence from smoking for 5 Days in a Confinement Setting and 86 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   0/80 (0.00%)      0/41 (0.00%)      0/39 (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   31/80 (38.75%)      12/41 (29.27%)      16/39 (41.03%)    
Infections and infestations       
Upper respiratory tract infection * 1  3/80 (3.75%)  3 4/41 (9.76%)  4 1/39 (2.56%)  1
Injury, poisoning and procedural complications       
Muscle strain * 1  0/80 (0.00%)  0 0/41 (0.00%)  0 2/39 (5.13%)  2
Investigations       
Blood triglycerides increased * 1  2/80 (2.50%)  2 2/41 (4.88%)  3 2/39 (5.13%)  2
Haemoglobin decreased * 1  11/80 (13.75%)  14 4/41 (9.76%)  5 6/39 (15.38%)  8
Lymphocyte count increased * 1  6/80 (7.50%)  7 2/41 (4.88%)  2 1/39 (2.56%)  1
Neutrophil count decreased * 1  4/80 (5.00%)  5 0/41 (0.00%)  0 0/39 (0.00%)  0
Nervous system disorders       
Dizziness * 1  1/80 (1.25%)  1 0/41 (0.00%)  0 2/39 (5.13%)  2
Headache * 1  4/80 (5.00%)  4 1/41 (2.44%)  1 3/39 (7.69%)  4
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA 16.0
Analysis of Primary Outcomes required data from the PP set at Baseline, Day 5 (MHBMA, 3-HPMA, S-PMA, and COHb), and Day 90 (Total NNAL). Differences in the number of participants for each outcome is due to missing data at baseline or at Day5/90.
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 belong 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
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Philip Morris Products S.A.
ClinicalTrials.gov Identifier: NCT01989156    
Other Study ID Numbers: ZRHM-REXA-08-US
ZRHM-REXA-08-US ( Other Identifier: Philip Morris Products S.A. )
First Submitted: November 14, 2013
First Posted: November 20, 2013
Results First Submitted: December 21, 2016
Results First Posted: April 5, 2017
Last Update Posted: March 24, 2020