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Reduced Exposure Study in Smokers Using THS 2.2 With 5 Days in a Confinement 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: NCT01959932
Recruitment Status : Completed
First Posted : October 10, 2013
Results First Posted : October 13, 2016
Last Update Posted : March 12, 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: Tobacco Heating System (THS 2.2)
Other: Smoking abstinence (SA)
Other: Conventional cigarette (CC)
Enrollment 169
Recruitment Details

Study initiated (first subject screened): 29 June 2013

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

Pre-assignment Details

Enrolled and randomized population = 160 subjects

  • 80 subjects in THS 2.2
  • 41 subjects in CC
  • 39 subjects in SA

Number of subjects enrolled but NOT randomized (who tried the THS 2.2 at Day -2) = 9

Arm/Group Title Tobacco Heating System (THS 2.2) Conventional Cigarette (CC) Smoking Abstinence (SA)
Hide Arm/Group Description Ad libitum use of THS 2.2 for 5 days in confinement Ad libitum use of subject's own preferred brand of CC for 5 days in confinement Abstinence from smoking for 5 days in confinement
Period Title: Overall Study
Started 80 41 39
Completed 79 41 39
Not Completed 1 0 0
Reason Not Completed
Withdrawal by Subject             1             0             0
Arm/Group Title Tobacco Heating System (THS 2.2) Conventional Cigarette (CC) Smoking Abstinence (SA) Total
Hide Arm/Group Description Ad libitum use of THS 2.2 for 5 days in confinement Ad libitum use of subject's own preferred brand of CC for 5 days in confinement Abstinence from smoking for 5 days in confinement Total of all reporting groups
Overall Number of Baseline Participants 80 41 39 160
Hide Baseline Analysis Population Description
The study population consisted of all the randomized subjects who had at least 1 post randomization product use experience (THS 2.2 or CC arms), and 1 valid biomarker of exposure (BoExp) measurement. 160 randomized subjects: 80 in THS 2.2, 41 in CC and 39 in SA 159 completers: 1 subject (THS 2.2 arm) voluntarily withdrew on Day 3
Age, Customized  
Mean (Standard Deviation)
Unit of measure:  Years
Between 21 and 65 years Number Analyzed 80 participants 41 participants 39 participants 160 participants
35.4  (9.40) 32.6  (10.06) 33.6  (11.51) 34.3  (10.12)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 80 participants 41 participants 39 participants 160 participants
Female
41
  51.2%
20
  48.8%
19
  48.7%
80
  50.0%
Male
39
  48.8%
21
  51.2%
20
  51.3%
80
  50.0%
Daily CC 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 41 21 19 81
> 19 cig/day 39 20 20 79
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 full analysis set (FAS) population.

The FAS consisted of all the randomized subjects who had at least 1 post randomization product use experience (if randomized to THS 2.2 or CC) and had at least 1 valid biomarker of exposure (BoExp) measurement (THS 2.2, CC, SA arms).

Arm/Group Title Tobacco Heating System (THS 2.2) Conventional Cigarette (CC) Smoking Abstinence (SA)
Hide Arm/Group Description:
Ad libitum use of THS 2.2 for 5 days in confinement
Ad libitum use of subject's own preferred brand of CC for 5 days in confinement
Abstinence from smoking for 5 days in confinement
Overall Number of Participants Analyzed 79 41 39
Least Squares Mean (95% Confidence Interval)
Unit of Measure: pg/mg creat
194.05
(173.23 to 217.38)
2314.37
(1975.39 to 2711.52)
168.01
(142.88 to 197.55)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tobacco Heating System (THS 2.2), Conventional Cigarette (CC)
Comments

The hypothesis to be tested is that the geometric mean level on Day 5 of the biomarker of exposure for THS 2.2 is lower relative to CC.

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 THS 2.2 and CC 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 8.38
Confidence Interval (2-Sided) 95%
6.89 to 10.20
Estimation Comments LS mean ratio THS 2.2:CC
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 means are provided as descriptive statistics.

Time Frame 5 days
Hide Outcome Measure Data
Hide Analysis Population Description

The analysis was performed on the full analysis set (FAS) population.

The FAS consisted of all the randomized subjects who had at least 1 post randomization product use experience (if randomized to THS 2.2 or CC) and had at least 1 valid BoExp measurement (THS 2.2, CC, SA arms).

Arm/Group Title Tobacco Heating System (THS 2.2) Conventional Cigarette (CC) Smoking Abstinence (SA)
Hide Arm/Group Description:
Ad libitum use of THS 2.2 for 5 days in confinement
Ad libitum use of subject's own preferred brand of CC for 5 days in confinement
Abstinence from smoking for 5 days in confinement
Overall Number of Participants Analyzed 79 41 39
Least Squares Mean (95% Confidence Interval)
Unit of Measure: ng/mg creat
398.87
(376.74 to 422.30)
958.03
(884.99 to 1037.09)
242.56
(223.64 to 263.09)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tobacco Heating System (THS 2.2), Conventional Cigarette (CC)
Comments

The hypothesis to be tested is that the geometric mean level on Day 5 of the biomarker of exposure for THS 2.2 is lower relative to CC.

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 THS 2.2 and CC 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 41.63
Confidence Interval (2-Sided) 95%
37.75 to 45.91
Estimation Comments LS mean ratio THS 2.2:CC
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 means are provided as descriptive statistics.

Time Frame 5 days
Hide Outcome Measure Data
Hide Analysis Population Description

The analysis was performed on the full analysis set (FAS) population.

The FAS consisted of all the randomized subjects who had at least 1 post randomization product use experience (if randomized to THS 2.2 or CC) and had at least 1 valid BoExp measurement (THS 2.2, CC, SA arms).

Arm/Group Title Tobacco Heating System (THS 2.2) Conventional Cigarette (CC) Smoking Abstinence (SA)
Hide Arm/Group Description:
Ad libitum use of THS 2.2 for 5 days in confinement
Ad libitum use of subject's own preferred brand of CC for 5 days in confinement
Abstinence from smoking for 5 days in confinement
Overall Number of Participants Analyzed 79 41 39
Least Squares Mean (95% Confidence Interval)
Unit of Measure: pg/mg creat
164.51
(151.82 to 178.25)
2748.16
(2457.56 to 3073.13)
153.66
(137.03 to 172.31)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tobacco Heating System (THS 2.2), Conventional Cigarette (CC)
Comments

The hypothesis to be tested is that the geometric mean level on Day 5 of the biomarker of exposure for THS 2.2 is lower relative to CC.

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 THS 2.2 and CC 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 5.99
Confidence Interval (2-Sided) 95%
5.21 to 6.87
Estimation Comments LS mean ratio THS 2.2:CC
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 full analysis set (FAS) population.

The FAS consisted of all the randomized subjects who had at least 1 post randomization product use experience (if randomized to THS 2.2 or CC) and had at least 1 valid BoExp measurement (THS 2.2, CC, SA arms).

Arm/Group Title Tobacco Heating System (THS 2.2) Conventional Cigarette (CC) Smoking Abstinence (SA)
Hide Arm/Group Description:
Ad libitum use of THS 2.2 for 5 days in confinement
Ad libitum use of subject's own preferred brand of CC for 5 days in confinement
Abstinence from smoking for 5 days in confinement
Overall Number of Participants Analyzed 79 41 39
Least Squares Mean (95% Confidence Interval)
Unit of Measure: % of saturation of hemoglobin
1.06
(1.02 to 1.11)
4.53
(4.29 to 4.77)
0.98
(0.93 to 1.04)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Tobacco Heating System (THS 2.2), Conventional Cigarette (CC)
Comments

The hypothesis to be tested is that the geometric mean level on Day 5 of the biomarker of exposure for THS 2.2 is lower relative to CC.

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 THS 2.2 and CC 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 23.45
Confidence Interval (2-Sided) 95%
22.00 to 24.99
Estimation Comments LS mean ratio THS 2.2:CC
Time Frame From the informed consent form (ICF) signature until the end of the safety follow-up period (7 days after discharge of the subject).
Adverse Event Reporting Description The safety was assessed in the safety population, consisting of 169 subjects: 160 randomized subjects (80 in THS 2.2, 41 in CC and 39 in SA) and 9 subjects exposed to THS 2.2 from the product trial on Day -2 but not randomized.
 
Arm/Group Title Tobacco Heating System (THS 2.2) Smoking Abstinence (SA) Conventional Cigarette (CC) Enrolled But Not Randomized
Hide Arm/Group Description Ad libitum use of THS 2.2 for 5 days in confinement Abstinence from smoking for 5 days in confinement Ad libitum use of subject's own preferred brand of CC for 5 days in confinement Subjects who tried the THS 2.2 at Admission (Day -2) but were not randomized in 1 of the 3 arms as they were back-up subjects
All-Cause Mortality
Tobacco Heating System (THS 2.2) Smoking Abstinence (SA) Conventional Cigarette (CC) Enrolled But Not Randomized
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--      --/--    
Hide Serious Adverse Events
Tobacco Heating System (THS 2.2) Smoking Abstinence (SA) Conventional Cigarette (CC) Enrolled But Not Randomized
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/80 (0.00%)      0/39 (0.00%)      0/41 (0.00%)      0/9 (0.00%)    
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Tobacco Heating System (THS 2.2) Smoking Abstinence (SA) Conventional Cigarette (CC) Enrolled But Not Randomized
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   44/80 (55.00%)      22/39 (56.41%)      26/41 (63.41%)      9/9 (100.00%)    
Blood and lymphatic system disorders         
Leukocytosis * 1  0/80 (0.00%)  0 0/39 (0.00%)  0 0/41 (0.00%)  0 2/9 (22.22%)  2
Cardiac disorders         
Ventricular extrasystoles * 1  0/80 (0.00%)  0 0/39 (0.00%)  0 0/41 (0.00%)  0 1/9 (11.11%)  1
Ear and labyrinth disorders         
Vertigo * 1  3/80 (3.75%)  3 2/39 (5.13%)  2 0/41 (0.00%)  0 0/9 (0.00%)  0
Gastrointestinal disorders         
Constipation * 1  3/80 (3.75%)  3 0/39 (0.00%)  0 2/41 (4.88%)  2 1/9 (11.11%)  1
Toothache * 1  1/80 (1.25%)  1 0/39 (0.00%)  0 1/41 (2.44%)  1 1/9 (11.11%)  1
Abdominal distension * 1  0/80 (0.00%)  0 2/39 (5.13%)  2 0/41 (0.00%)  0 0/9 (0.00%)  0
General disorders         
Influenza like illness * 1  0/80 (0.00%)  0 3/39 (7.69%)  3 1/41 (2.44%)  1 0/9 (0.00%)  0
Investigations         
Spirometry abnormal * 1  4/80 (5.00%)  4 2/39 (5.13%)  2 3/41 (7.32%)  3 3/9 (33.33%)  3
Lymphocyte count increased * 1  1/80 (1.25%)  1 1/39 (2.56%)  1 0/41 (0.00%)  0 1/9 (11.11%)  1
Metabolism and nutrition disorders         
Hypertriglyceridaemia * 1  3/80 (3.75%)  3 2/39 (5.13%)  2 2/41 (4.88%)  2 0/9 (0.00%)  0
Hyperglycaemia * 1  0/80 (0.00%)  0 1/39 (2.56%)  1 0/41 (0.00%)  0 1/9 (11.11%)  1
Hyperkalaemia * 1  1/80 (1.25%)  1 0/39 (0.00%)  0 0/41 (0.00%)  0 1/9 (11.11%)  1
Musculoskeletal and connective tissue disorders         
Back pain * 1  3/80 (3.75%)  3 3/39 (7.69%)  3 2/41 (4.88%)  3 0/9 (0.00%)  0
Nervous system disorders         
Headache * 1  24/80 (30.00%)  30 13/39 (33.33%)  15 16/41 (39.02%)  19 3/9 (33.33%)  3
Syncope * 1  6/80 (7.50%)  6 0/39 (0.00%)  0 4/41 (9.76%)  4 0/9 (0.00%)  0
Renal and urinary disorders         
Polyuria * 1  6/80 (7.50%)  8 2/39 (5.13%)  2 4/41 (9.76%)  6 0/9 (0.00%)  0
Respiratory, thoracic and mediastinal disorders         
Oropharyngeal pain * 1  7/80 (8.75%)  7 0/39 (0.00%)  0 3/41 (7.32%)  3 0/9 (0.00%)  0
Cough * 1  3/80 (3.75%)  3 0/39 (0.00%)  0 0/41 (0.00%)  0 1/9 (11.11%)  1
Vascular disorders         
Hypertension * 1  1/80 (1.25%)  2 2/39 (5.13%)  5 1/41 (2.44%)  1 2/9 (22.22%)  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: NCT01959932    
Other Study ID Numbers: ZRHR-REXC-03-EU
ZRHR-REXC-03-EU ( Other Identifier: Philip Morris Products S.A. )
First Submitted: October 8, 2013
First Posted: October 10, 2013
Results First Submitted: January 26, 2016
Results First Posted: October 13, 2016
Last Update Posted: March 12, 2020