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Nicotine Pharmacokinetic Profile and Safety of the Tobacco Heating System 2.2 Menthol (THS 2.2 Menthol)

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: NCT01967719
Recruitment Status : Completed
First Posted : October 23, 2013
Results First Posted : February 7, 2017
Last Update Posted : March 18, 2020
Sponsor:
Information provided by (Responsible Party):
Philip Morris Products S.A.

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: None (Open Label);   Primary Purpose: Other
Condition Smoking
Interventions Other: mTHS 2.2
Other: mCC
Other: NNS
Enrollment 64
Recruitment Details

Study initiated (first subject screened): 02 October 2013

At admission (Day -1), all the subjects performed a product trial (mTHS 2.2 and subsequently NNS).

From enrollment, they were asked to remain abstinent from smoking for at least 24 hours (Day 0) before being randomized on Day 1 into 1 of the 4 sequences.
Pre-assignment Details

Enrolled population = 64 subjects: 2 exposed to mTHS 2.2 and NNS at Admission but not randomized and 62 randomized as described below:

  • Sequence "mTHS 2.2 then mCC": 22 subjects
  • Sequence "mCC then mTHS 2.2": 22 subjects
  • Sequence "mTHS 2.2 then NNS": 9 subjects
  • Sequence "NNS then mTHS 2.2": 9 subjects
Arm/Group Title mTHS 2.2 Then mCC mCC Then mTHS 2.2 mTHS 2.2 Then NNS NNS Then mTHS 2.2
Hide Arm/Group Description

Each subject will follow the below study design:

  • Day 0 = Wash-out (1 day)
  • Day 1 = 1st intervention (single product use of mTHS 2.2)
  • Day 2 = wash-out
  • Day 3 = 2nd intervention (single product use of mCC).

Each subject will follow the below study design:

  • Day 0 = Wash-out (1 day)
  • Day 1 = 1st intervention (single product use of mCC)
  • Day 2 = wash-out
  • Day 3 = 2nd intervention (single product use of mTHS 2.2).

Each subject will follow the below study design:

  • Day 0 = Wash-out (1 day)
  • Day 1 = 1st intervention (single product use of mTHS 2.2)
  • Day 2 = wash-out
  • Day 3 = 2nd intervention (single administration of NNS)

Each subject will follow the below study design:

  • Day 0 = Wash-out (1 day)
  • Day 1 = 1st intervention (single administration of NNS)
  • Day 2 = wash-out
  • Day 3 = 2nd intervention (single product use of mTHS 2.2).
Period Title: Washout Period of 1 Day (Day 0)
Started 22 22 9 9
Completed 22 22 9 9
Not Completed 0 0 0 0
Period Title: First Intervention (Day 1)
Started 22 22 9 9
Completed 22 21 9 8
Not Completed 0 1 0 1
Reason Not Completed
Withdrawal by Subject             0             1             0             1
Period Title: Washout Period of 1 Day (Day 2)
Started 22 21 9 8
Completed 22 21 9 8
Not Completed 0 0 0 0
Period Title: Second Intervention (Day 3)
Started 22 21 9 8
Completed 22 20 9 8
Not Completed 0 1 0 0
Reason Not Completed
Withdrawal by Subject             0             1             0             0
Arm/Group Title Group 1 Group 2 Total
Hide Arm/Group Description

This population comprises the following sequences:

  • Sequence "mTHS 2.2 then mCC"
  • Sequence "mCC then mTHS 2.2"

This population comprises the following sequences:

  • Sequence "mTHS 2.2 then NNS"
  • Sequence "NNS then mTHS 2.2"
 Total of all reporting groups
Overall Number of Baseline Participants 41 17 58
Hide Baseline Analysis Population Description
PK population: all randomized subjects who completed at least 1 of the single-use days, with at least 1 derived PK parameter. 62 randomized subjects : 44 in Group 1, 18 in Group 2. PK population = 58 => 41 in Group 1 (2 withdrawn + 1 excluded due to major protocol deviation), 17 in Group 2 (1 withdrawn).
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 41 participants 17 participants 58 participants
36.7  (9.68) 33.8  (6.93) 35.9  (9.00)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 41 participants 17 participants 58 participants
Female
20
  48.8%
9
  52.9%
29
  50.0%
Male
21
  51.2%
8
  47.1%
29
  50.0%
International Organization for Standardization (ISO) nicotine yield  
Measure Type: Number
Unit of measure:  Participants
 Number Analyzed 41 participants 17 participants 58 participants
≤ 1.0 mg 21 11 32
> 1.0 mg 20 6 26
1.Primary Outcome
Title Maximum Concentration (Cmax) of Nicotine Following Single Use of mTHS 2.2, mCC and NNS
Hide Description

Derived from multiple blood sampling on Day 1 and Day 3 (1 blood sampling pre-product use and multiple blood sampling over 24 hours post-product use).

Geometric Least Squares (geometric LS) means are provided.
Time Frame 3 days
Hide Outcome Measure Data
Hide Analysis Population Description
Pharmacokinetics (PK) populations consisted of all the randomized subjects who completed at least 1 of the single use days (Days 1 or 3), and for whom at least 1 PK parameter could be derived. Subjects with major protocol deviations that impacted the evaluability of the results were excluded from the PK populations.
Arm/Group Title mTHS 2.2 - Group 1 mCC - Group 1 mTHS 2.2 - Group 2 NNS - Group 2
Hide Arm/Group Description:

The geometric least squares mean presented below takes into consideration the data of the subjects who were randomized in the following sequences:

  • Sequence "mTHS 2.2 then mCC"
  • Sequence "mCC then mTHS 2.2"

The geometric least squares mean presented below takes into consideration the data of the subjects who were randomized in the following sequences:

  • Sequence "mTHS 2.2 then mCC"
  • Sequence "mCC then mTHS 2.2"

The geometric least squares mean presented below takes into consideration the data of the subjects who were randomized in the following sequences:

  • Sequence "mTHS 2.2 then NNS"
  • Sequence "NNS then mTHS 2.2"

The geometric least squares mean presented below takes into consideration the data of the subjects who were randomized in the following sequences:

  • Sequence "mTHS 2.2 then NNS"
  • Sequence "NNS then mTHS 2.2"
Overall Number of Participants Analyzed 41 41 17 17
Least Squares Mean (95% Confidence Interval)
Unit of Measure: ng/mL
7.40
(6.21 to 8.82)
13.08
(10.99 to 15.58)
8.40
(6.17 to 11.43)
3.23
(2.37 to 4.40)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection mTHS 2.2 - Group 1, mCC - Group 1
Comments The objective of this study was to determine the point estimate and precision of the nicotine bioavailability (ratio of mTHS 2.2:mCC) for Cmax, therefore, there was no statistical hypothesis to be tested for this objective.
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments The model included terms for sequence, subject nested within sequence, period, and product as fixed effect factors.
Method of Estimation Estimation Parameter Geometric LS Mean Ratio
Estimated Value 56.57
Confidence Interval (2-Sided) 95%
44.21 to 72.39
Estimation Comments LS mean ratio (mTHS 2.2 - Group 1:mCC - Group 1)
2.Primary Outcome
Title Area Under the Plasma Nicotine Concentration-Time Curve From Time Zero (Pre-product Use) to Last Time Point [AUC(0-last)] Following Single Use of mTHS 2.2, mCC and NNS
Hide Description

Derived from multiple blood sampling on Day 1 and Day 3 (1 blood sampling pre-product use and multiple blood sampling over 24 hours post-product use).

Geometric Least Squares means are provided.
Time Frame 3 days
Hide Outcome Measure Data
Hide Analysis Population Description
PK populations consisted of all the randomized subjects who completed at least 1 of the single use days (Days 1 or 3), and for whom at least 1 PK parameter could be derived. Subjects with major protocol deviations that impacted the evaluability of the results were excluded from the PK populations.
Arm/Group Title mTHS 2.2 - Group 1 mCC - Group 1 mTHS 2.2 - Group 2 NNS - Group 2
Hide Arm/Group Description:

The geometric least squares mean presented below takes into consideration the data of the subjects who were randomized in the following sequences:

  • Sequence "mTHS 2.2 then mCC"
  • Sequence "mCC then mTHS 2.2".

The geometric least squares mean presented below takes into consideration the data of the subjects who were randomized in the following sequences:

  • Sequence "mTHS 2.2 then mCC"
  • Sequence "mCC then mTHS 2.2"

The geometric least squares mean presented below takes into consideration the data of the subjects who were randomized in the following sequences:

  • Sequence "mTHS 2.2 then NNS"
  • Sequence "NNS then mTHS 2.2"

The geometric least squares mean presented below takes into consideration the data of the subjects who were randomized in the following sequences:

  • Sequence "mTHS 2.2 then NNS"
  • Sequence "NNS then mTHS 2.2"
Overall Number of Participants Analyzed 41 41 17 17
Least Squares Mean (95% Confidence Interval)
Unit of Measure: h*ng/mL
16.53
(13.84 to 19.74)
29.71
(24.88 to 35.47)
15.59
(10.80 to 22.49)
8.72
(6.04 to 12.58)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection mTHS 2.2 - Group 1, mCC - Group 1
Comments The objective of this study was to determine the point estimate and precision of the nicotine bioavailability (ratio of mTHS 2.2:mCC) for AUC(0-last), therefore, there was no statistical hypothesis to be tested for this objective.
Type of Statistical Test Superiority or Other (legacy)
Comments [Not Specified]
Statistical Test of Hypothesis P-Value [Not Specified]
Comments [Not Specified]
Method ANOVA
Comments The model included terms for sequence, subject nested within sequence, period, and product as fixed effect factors.
Method of Estimation Estimation Parameter Geometric LS Mean Ratio
Estimated Value 55.64
Confidence Interval (2-Sided) 95%
43.30 to 71.50
Estimation Comments LS mean ratio (mTHS 2.2 - Group 1:mCC - Group 1)
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 64 subjects: 62 randomized subjects (44 in Group 1, 18 in Group 2) and 2 subjects exposed to mTHS 2.2 and NNS from the product trials on Day -1 but not randomized.
 
Arm/Group Title Group 1 Group 2 Enrolled But Not Randomized
Hide Arm/Group Description

This population comprises the following sequences:

  • Sequence "mTHS 2.2 then mCC"
  • Sequence "mCC then mTHS 2.2"

This population comprises the following sequences:

  • Sequence "mTHS 2.2 then NNS"
  • Sequence "NNS then mTHS 2.2"
 Subjects who tried the mTHS 2.2 at Admission (Day -1) but were not randomized in 1 of the 2 groups as they were back-up subjects
All-Cause Mortality
Group 1 Group 2 Enrolled But Not Randomized
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--      --/--    
Hide Serious Adverse Events
Group 1 Group 2 Enrolled But Not Randomized
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/44 (0.00%)      0/18 (0.00%)      0/2 (0.00%)    
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Group 1 Group 2 Enrolled But Not Randomized
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   12/44 (27.27%)      5/18 (27.78%)      0/2 (0.00%)    
Eye disorders       
Eye pruritus * 1  0/44 (0.00%)  0 1/18 (5.56%)  1 0/2 (0.00%)  0
Ocular hyperaemia * 1  0/44 (0.00%)  0 1/18 (5.56%)  1 0/2 (0.00%)  0
Gastrointestinal disorders       
Vomiting * 1  2/44 (4.55%)  2 1/18 (5.56%)  1 0/2 (0.00%)  0
Nausea * 1  1/44 (2.27%)  1 1/18 (5.56%)  1 0/2 (0.00%)  0
Toothache * 1  0/44 (0.00%)  0 1/18 (5.56%)  1 0/2 (0.00%)  0
Infections and infestations       
Upper respiratory tract infection * 1  0/44 (0.00%)  0 1/18 (5.56%)  1 0/2 (0.00%)  0
Nervous system disorders       
Headache * 1  7/44 (15.91%)  7 0/18 (0.00%)  0 0/2 (0.00%)  0
Dizziness * 1  1/44 (2.27%)  1 1/18 (5.56%)  1 0/2 (0.00%)  0
Respiratory, thoracic and mediastinal disorders       
Nasal congestion * 1  2/44 (4.55%)  2 1/18 (5.56%)  1 0/2 (0.00%)  0
Skin and subcutaneous tissue disorders       
Rash * 1  1/44 (2.27%)  1 1/18 (5.56%)  1 0/2 (0.00%)  0
*
Indicates events were collected by non-systematic assessment
1
Term from vocabulary, MedDRA (16.0)
[Not Specified]
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: NCT01967719    
Other Study ID Numbers: ZRHM-PK-06-US
ZRHM-PK-06-US ( Other Identifier: Philip Morris Products S.A. )
First Submitted: October 18, 2013
First Posted: October 23, 2013
Results First Submitted: February 5, 2016
Results First Posted: February 7, 2017
Last Update Posted: March 18, 2020