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

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ClinicalTrials.gov Identifier: NCT01967706
Recruitment Status : Completed
First Posted : October 23, 2013
Results First Posted : February 2, 2016
Last Update Posted : September 5, 2017
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
Other: mCC
Other: NRT
Enrollment 73
Recruitment Details

Study initiated (first subject screened): 01 August 2013

At admission (Day -1), all the subjects performed a product trial (Tobacco Sticks and subsequently NRT gum).

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 = 73 subjects: 11 exposed to mTHS and NRT at Admission but not randomized and 62 randomized as described below:

  • Sequence "mTHS then mCC": 22 subjects
  • Sequence "mCC then mTHS": 22 subjects
  • Sequence "mTHS then NRT": 9 subjects
  • Sequence "NRT then mTHS": 9 subjects
Arm/Group Title mTHS Then mCC mCC Then mTHS mTHS Then NRT NRT Then mTHS
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)
  • 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).

Each subject will follow the below study design:

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

Each subject will follow the below study design:

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

This population comprises the following sequences:

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

This population comprises the following sequences:

  • Sequence "mTHS then NRT"
  • Sequence "NRT then mTHS"
Total of all reporting groups
Overall Number of Baseline Participants 43 18 61
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. Subjects with major protocol deviations impacting the evaluation of the results were excluded. 62 randomized subjects : 44 in Group 1, 18 in Group 2. 61 completers: 43 in Group 1 (1 withdrawn subject), 18 in Group 2.
Age, Customized  
Mean (Standard Deviation)
Unit of measure:  Years
Between 23 and 65 years Number Analyzed 43 participants 18 participants 61 participants
33.4  (10.03) 30.7  (7.80) 32.6  (9.44)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 43 participants 18 participants 61 participants
Female
20
  46.5%
9
  50.0%
29
  47.5%
Male
23
  53.5%
9
  50.0%
32
  52.5%
International Organization for Standardization (ISO) nicotine level  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 43 participants 18 participants 61 participants
≤ 0.6 mg 25 10 35
> 0.6 to ≤ 1 mg 18 8 26
1.Primary Outcome
Title Maximum Concentration (Cmax) of Nicotine Following Single Use of mTHS, mCC and NRT
Hide Description

T0 = start of single product use.

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 Blood taken 15 minutes prior to T0, 2, 4, 6, 8, 10, 15, 30, 45 minutes, 1, 2, 4, 6, 9, 12, and 24 hours after T0
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 - Group 1 mCC - Group 1 mTHS - Group 2 NRT - 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 then mCC"
  • Sequence "mCC then mTHS"

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

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

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

  • Sequence "mTHS then NRT"
  • Sequence "NRT then mTHS"

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

  • Sequence "mTHS then NRT"
  • Sequence "NRT then mTHS"
Overall Number of Participants Analyzed 43 43 18 18
Least Squares Mean (95% Confidence Interval)
Unit of Measure: ng/mL
10.70
(8.94 to 12.80)
12.09
(10.10 to 14.47)
7.64
(5.39 to 10.81)
7.52
(5.31 to 10.64)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection mTHS - 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:mCC) for Cmax, therefore, there was no statistical hypothesis to be tested for this objective.
Type of Statistical Test Other
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 88.47
Confidence Interval (2-Sided) 95%
68.64 to 114.03
Estimation Comments LS mean ratio (mTHS - Group 1:mCC - Group 1)
2.Primary Outcome
Title Area Under the Plasma Concentration-Time Curve From Time Zero (Pre-product Use) to Last Time Point [AUC(0-last)] Following Single Use of mTHS, mCC and NRT
Hide Description

T0 = start of single product use.

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 Blood taken 15 minutes prior to T0, 2, 4, 6, 8, 10, 15, 30, 45 minutes, 1, 2, 4, 6, 9, 12, and 24 hours after T0
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 - Group 1 mCC - Group 1 mTHS - Group 2 NRT - 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 then mCC"
  • Sequence "mCC then mTHS"

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

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

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

  • Sequence "mTHS then NRT"
  • Sequence "NRT then mTHS"

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

  • Sequence "mTHS then NRT"
  • Sequence "NRT then mTHS"
Overall Number of Participants Analyzed 43 43 18 18
Least Squares Mean (95% Confidence Interval)
Unit of Measure: ng*h/mL
23.99
(20.87 to 27.57)
24.45
(21.27 to 28.10)
15.61
(11.96 to 20.37)
27.94
(21.41 to 36.45)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection mTHS - 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:mCC) for AUC(0-last), therefore, there was no statistical hypothesis to be tested for this objective.
Type of Statistical Test Other
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 98.13
Confidence Interval (2-Sided) 95%
80.61 to 119.46
Estimation Comments LS mean ratio (mTHS - Group 1:mCC - Group 1)
Time Frame From 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 73 subjects: 62 randomized subjects (44 in Group 1, 18 in Group 2) and 11 subjects exposed to mTHS and NRT 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 then mCC"
  • Sequence "mCC then mTHS"

This population comprises the following sequences:

  • Sequence "mTHS then NRT"
  • Sequence "NRT then mTHS"
Subjects who tried the mTHS 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   --/--      --/--      --/--    
Show Serious Adverse Events 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%)      0/11 (0.00%)    
Show Other (Not Including Serious) Adverse Events 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   0/44 (0.00%)      1/18 (5.56%)      0/11 (0.00%)    
Investigations       
Hemoglobin decreased * 1  0/44 (0.00%)  0 1/18 (5.56%)  1 0/11 (0.00%)  0
*
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
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: NCT01967706     History of Changes
Other Study ID Numbers: ZRHM-PK-05-JP
ZRHM-PK-05-JP ( Other Identifier: Philip Morris Products S.A. )
First Submitted: October 18, 2013
First Posted: October 23, 2013
Results First Submitted: June 10, 2015
Results First Posted: February 2, 2016
Last Update Posted: September 5, 2017