Evaluation of Biological and Functional Changes in Healthy Smokers After Switching to THS 2.2 for 26 Weeks

Sponsor
Philip Morris Products S.A. (Industry)
Overall Status
Completed
CT.gov ID
NCT02396381
Collaborator
(none)
1,039
19
2
28.7
54.7
1.9

Study Details

Study Description

Brief Summary

The aim of the study is to demonstrate clinical, biological and functional health changes in smokers switching to the candidate modified risk tobacco product: Tobacco Heating System 2.2 (THS 2.2) as compared to smokers continuing smoking their conventional cigarettes (CC) over a 26-week period.

To characterize the study as successful, at least 5 clinical risk endpoints should move in the direction of smoking cessation and these results would be statistically significant. The main analysis will be defined a priori (using the Hailperin-Ruger approach) and will be made between THS 2.2 use and CC use as "per actual product used" and product use categories.

Condition or Disease Intervention/Treatment Phase
  • Other: THS 2.2
  • Other: CC
N/A

Detailed Description

The clinical, biological and functional endpoints to be measured in this study ("smoker's health profile") may characterize the modification of risk of smoking-related diseases.

Clinical risk endpoint to be assessed are selected based on a) their association to smoking-related diseases b) their association to smoking status, c) their reversibility upon smoking cessation, and d) their suitability to be measured with valid and robust methods in clinical studies.

The biological markers, functional markers and biomarkers of exposure (BoExp) with the strongest scientific evidence will constitute the 'smoker's health profile' and will be measured as the primary objective of the study.

Additional endpoints involved in the mechanistic of smoking-related diseases will be studied to provide additional scientific evidence to strengthen the primary objective.

The study will provide a perspective of product usage in a "real world setting" where smoking CC in addition to THS 2.2 may be expected.

Study Design

Study Type:
Interventional
Actual Enrollment :
1039 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Other
Official Title:
A Randomized, Controlled, 2-arm Parallel Group, Multi-center Study, to Evaluate Biological and Functional Changes in Healthy Smokers Switching to Tobacco Heating System 2.2 (THS 2.2) Compared to Continuing Smoking Conventional Cigarettes for 26 Weeks in an Ambulatory Setting
Actual Study Start Date :
Mar 12, 2015
Actual Primary Completion Date :
Sep 13, 2016
Actual Study Completion Date :
Aug 1, 2017

Arms and Interventions

Arm Intervention/Treatment
Experimental: THS 2.2

Ad libitum use of THS 2.2

Other: THS 2.2
Ad libitum use of THS 2.2 in an ambulatory setting for 26 weeks

Active Comparator: CC

Ad libitum use of CC

Other: CC
Ad libitum use of CC in an ambulatory setting for 26 weeks

Outcome Measures

Primary Outcome Measures

  1. Levels of High Density Lipoprotein C (HDL-C). [26 Weeks]

    Concentrations measured in serum. Geometric Least Squares means are provided as descriptive statistics.

  2. Levels of White Blood Cells (WBC). [26 Weeks]

    Concentrations measured in blood. Geometric Least Squares means are provided as descriptive statistics.

  3. Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1). [26 Weeks]

    FEV1 post-bronchodilator and expressed as percentage predicted (FEV1 %pred). Geometric Least Squares means are provided as descriptive statistics.

  4. Concentrations of Soluble Intercellular Adhesion Molecule 1 (sICAM-1). [26 Weeks]

    Concentrations measured in serum. Geometric Least Squares means are provided as descriptive statistics.

  5. Concentrations of 11-dehydrothromboxane B2 (11-DTXB2). [26 Weeks]

    Concentrations measured in urine and expressed as concentration adjusted for creatinine. Geometric Least Squares means are provided as descriptive statistics.

  6. Concentrations of 8-epi-prostaglandin F2α (8-epi-PGF2α). [26 Weeks]

    Concentrations measured in urine and expressed as concentration adjusted for creatinine. Geometric Least Squares means are provided as descriptive statistics.

  7. Concentrations of Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL). [26 Weeks]

    Concentrations measured in urine and expressed as concentration adjusted for creatinine. Geometric Least Squares means are provided as descriptive statistics.

  8. Percent Change From Baseline of Carboxyhemoglobin (COHb) [26 Weeks]

    Carboxyhemoglobin (COHb) is assayed from whole blood. Geometric Least Squares means are provided as descriptive statistics. Expressed as % of saturation of hemoglobin.

Eligibility Criteria

Criteria

Ages Eligible for Study:
30 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
Yes
Inclusion Criteria:
  • Current healthy smoker as judged by the Principal Investigator(s) or designee(s)

  • Minimum age: 30 years old

  • Have smoked for the last 10 years

  • Have smoked more than 10 non menthol CC/day on average (no brand restriction) over the past year

Exclusion Criteria:
  • Clinically relevant medical conditions that in the opinion of the investigators would jeopardize the safety of the participant.

  • Subject who has (FEV1/FVC) < 0.7 and FEV1 < 80% predicted value at post-bronchodilator spirometry

  • Subject with asthma condition (post-bronchodilator FEV1/FVC < 0.75 and reversibility in FEV1 ≥ 12% and > 200 mL from pre- to post-bronchodilator values)

  • Subject who took or is taking concomitant medication which may have an impact on the "smoker's heath profile"

  • Female subject is pregnant or breast feeding.

  • Female subject who does not agree to use an acceptable method of effective contraception.

Contacts and Locations

Locations

Site City State Country Postal Code
1 Celerion Arizona Tempe Arizona United States 85283
2 Clinical Research West Florida Clearwater Florida United States 33765
3 Covance, Inc Daytona Beach Florida United States 32117
4 Compass Research Orlando Florida United States 32806
5 Clinical Research West Florida Tampa Florida United States 33603
6 Compass Research The Villages Florida United States 32162
7 Central Kentucky Research Associate Lexington Kentucky United States 40509
8 Celerion Lincoln Lincoln Nebraska United States 68502
9 PMG Research of Cary Cary North Carolina United States 27518
10 PMG Research of Charlotte Charlotte North Carolina United States 28209
11 PMG Research of Raleigh Raleigh North Carolina United States 27609
12 PMG Research of Wilmington Wilmington North Carolina United States 28401
13 Midwest Clinical Research Center Dayton Ohio United States 45417
14 PMG Research of Bristol Bristol Tennessee United States 37620
15 NOCCR Knoxville Tennessee United States 37920
16 Benchmark Austin Texas United States 78705
17 Benchmark Fort Worth Texas United States 76135
18 Benchmark San Angelo Texas United States 76904
19 National Clinical Research Richmond Virginia United States 23294

Sponsors and Collaborators

  • Philip Morris Products S.A.

Investigators

  • Study Chair: Christelle Haziza, PhD, Philip Morris Products S.A.
  • Principal Investigator: Danielle Armas, MD, Celerion Arizona
  • Principal Investigator: Leonard Dunn, MD, Clinical Research West Florida
  • Principal Investigator: Hugh Coleman, MD, Covance
  • Principal Investigator: George Stoica, MD, Compass Research
  • Principal Investigator: Mark Adams, MD, Central Kentucky Research Associate
  • Principal Investigator: Peter Davidson, MD, Celerion Lincoln
  • Principal Investigator: John Rubino, MD, PMG Research of Raleigh
  • Principal Investigator: George Raad, MD, PMG Research of Charlotte
  • Principal Investigator: Kevin Cannon, MD, PMG Research of Wilmington
  • Principal Investigator: Derek Schroder, MD, PMG Research of Cary
  • Principal Investigator: Stephanie Powell, MD, PMG Research of Bristol
  • Principal Investigator: William Smith, MD, NOCCR
  • Principal Investigator: Darrell Herrington, MD, Benchmark
  • Principal Investigator: Laurence Chu, MD, Benchmark
  • Principal Investigator: William Seger, MD, Benchmark
  • Principal Investigator: Lon Lynn, MD, Clinical Research West Florida
  • Principal Investigator: David Subich, MD, Compass Research
  • Principal Investigator: Isabel Kuhare-Arcure, MD, Midwest Clinical Research
  • Principal Investigator: Keith Scott, MD, National Clinical Research

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Philip Morris Products S.A.
ClinicalTrials.gov Identifier:
NCT02396381
Other Study ID Numbers:
  • ZRHR-ERS-09-US
  • ZRHR-ERS-09-US
First Posted:
Mar 24, 2015
Last Update Posted:
Aug 21, 2019
Last Verified:
Aug 1, 2019
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Philip Morris Products S.A.

Study Results

Participant Flow

Recruitment Details
Pre-assignment Detail Following randomization of 984 subjects, from 1039 enrolled subjects, one clinical site was terminated from this study due to non-GCP compliance. The safety population of 1012 subjects included all enrolled subjects except 27 subjects from the terminated site.
Arm/Group Title THS 2.2 Group CC Group
Arm/Group Description Randomized to Ad libitum use of THS 2.2 in an ambulatory setting for 26 weeks Randomized to Ad libitum use of CC in an ambulatory setting for 26 weeks
Period Title: Overall Study
STARTED 488 496
Full Analysis Set - As Exposed (FAS-EX) 414 443
COMPLETED 381 422
NOT COMPLETED 107 74

Baseline Characteristics

Arm/Group Title THS 2.2 Use CC Use Dual Use Other Use Total
Arm/Group Description ≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on >50% of days in the analysis period. ≥1 THS 2.2 or CC use, and <1% THS 2.2 use over the entire analysis period and <1% THS 2.2 use on ≥ 50% of days in the analysis period. ≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 <70% over the analysis period, or THS 2.2-use and CC-use categories do not apply to 50% of these days. Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns between consecutive analysis periods. Total of all reporting groups
Overall Participants 245 428 142 42 857
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
44.2
(9.64)
45.2
(9.55)
43.8
(9.77)
44.2
(8.14)
44.6
(9.55)
Sex: Female, Male (Count of Participants)
Female
94
38.4%
182
42.5%
63
44.4%
14
33.3%
353
41.2%
Male
151
61.6%
246
57.5%
79
55.6%
28
66.7%
504
58.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino
17
6.9%
28
6.5%
7
4.9%
1
2.4%
53
6.2%
Not Hispanic or Latino
228
93.1%
400
93.5%
135
95.1%
41
97.6%
804
93.8%
Unknown or Not Reported
0
0%
0
0%
0
0%
0
0%
0
0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
2
0.8%
2
0.5%
2
1.4%
0
0%
6
0.7%
Asian
2
0.8%
5
1.2%
0
0%
1
2.4%
8
0.9%
Native Hawaiian or Other Pacific Islander
1
0.4%
2
0.5%
0
0%
0
0%
3
0.4%
Black or African American
42
17.1%
74
17.3%
25
17.6%
10
23.8%
151
17.6%
White
195
79.6%
341
79.7%
113
79.6%
30
71.4%
679
79.2%
More than one race
0
0%
0
0%
0
0%
0
0%
0
0%
Unknown or Not Reported
3
1.2%
4
0.9%
2
1.4%
1
2.4%
10
1.2%
BMI (kg/m2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m2]
26.9
(3.99)
27.1
(4.13)
26.9
(4.35)
26.9
(5.12)
27.0
(4.18)

Outcome Measures

1. Primary Outcome
Title Levels of High Density Lipoprotein C (HDL-C).
Description Concentrations measured in serum. Geometric Least Squares means are provided as descriptive statistics.
Time Frame 26 Weeks

Outcome Measure Data

Analysis Population Description
Full Analysis Set - As Exposed (FAS-EX)
Arm/Group Title THS 2.2 Use CC Use Dual Use Other Use
Arm/Group Description ≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on >50% of days in the analysis period. ≥1 THS 2.2 or CC use, and <1% THS 2.2 use over the entire analysis period and <1% THS 2.2 use on ≥ 50% of days in the analysis period. ≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 <70% over the analysis period, or THS 2.2-use and CC-use categories do not apply to 50% of these days. Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns between consecutive analysis periods.
Measure Participants 245 428 142 42
Geometric Mean (95% Confidence Interval) [mg/dL]
54.1
50.9
56.3
52.8
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection THS 2.2 Use, CC Use
Comments The analysis will test if the mean level of HDL-C for THS-use is greater than for CC-use. The following hypothesis will be evaluated: H0: XTHS - XCC ≤ 0.0 HA: XTHS - XCC > 0.0 where XTHS and XCC are the adjusted means of THS-use and CC-use, respectively. H0 is rejected with a type I error α = 1.5625% (one-sided test).
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value <0.001
Comments
Method Hailperin-Rüger
Comments p-value less than 1.5625% would be considered statistically significant, following test multiplicity adjustment using the Hailperin-Rüger approach
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 3.09
Confidence Interval (2-Sided) 96.875%
1.10 to 5.09
Parameter Dispersion Type:
Value:
Estimation Comments
2. Primary Outcome
Title Levels of White Blood Cells (WBC).
Description Concentrations measured in blood. Geometric Least Squares means are provided as descriptive statistics.
Time Frame 26 Weeks

Outcome Measure Data

Analysis Population Description
Full Analysis Set - As Exposed (FAS-EX)
Arm/Group Title THS 2.2 Use CC Use Dual Use Other Use
Arm/Group Description ≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on >50% of days in the analysis period. ≥1 THS 2.2 or CC use, and <1% THS 2.2 use over the entire analysis period and <1% THS 2.2 use on ≥ 50% of days in the analysis period. ≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 <70% over the analysis period, or THS 2.2-use and CC-use categories do not apply to 50% of these days. Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns between consecutive analysis periods.
Measure Participants 245 428 142 42
Geometric Mean (95% Confidence Interval) [GI/L]
6.98
7.48
7.41
8.71
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection THS 2.2 Use, CC Use
Comments The analysis will test if the mean level of WBC for THS-use is lower than for CC-use. The following hypothesis will be evaluated: H0: XTHS - XCC ≥ 0.0 HA: XTHS - XCC < 0.0 where XTHS and XCC are the adjusted means of THS-use and CC-use, respectively. H0 is rejected with a type I error α = 1.5625% (one-sided test).
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.001
Comments
Method Hailperin-Rüger
Comments p-value less than 1.5625% would be considered statistically significant, following test multiplicity adjustment using the Hailperin-Rüger approach
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value -0.420
Confidence Interval (2-Sided) 96.875%
-0.717 to -0.123
Parameter Dispersion Type:
Value:
Estimation Comments
3. Primary Outcome
Title Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1).
Description FEV1 post-bronchodilator and expressed as percentage predicted (FEV1 %pred). Geometric Least Squares means are provided as descriptive statistics.
Time Frame 26 Weeks

Outcome Measure Data

Analysis Population Description
Full Analysis Set - As Exposed (FAS-EX)
Arm/Group Title THS 2.2 Use CC Use Dual Use Other Use
Arm/Group Description ≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on >50% of days in the analysis period. ≥1 THS 2.2 or CC use, and <1% THS 2.2 use over the entire analysis period and <1% THS 2.2 use on ≥ 50% of days in the analysis period. ≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 <70% over the analysis period, or THS 2.2-use and CC-use categories do not apply to 50% of these days. Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns between consecutive analysis periods.
Measure Participants 245 428 142 42
Geometric Mean (95% Confidence Interval) [Percent of predicted FEV1]
95.4
93.4
93.7
94.3
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection THS 2.2 Use, CC Use
Comments The analysis will test if the mean level of FEV1 for THS-use is greater than for CC-use. The following hypothesis will be evaluated: H0: XTHS - XCC ≤ 0.0 HA: XTHS - XCC > 0.0 where XTHS and XCC are the adjusted means of THS-use and CC-use, respectively. H0 is rejected with a type I error α = 1.5625% (one-sided test).
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.008
Comments
Method Hailperin-Rüger
Comments p-value less than 1.5625% would be considered statistically significant, following test multiplicity adjustment using the Hailperin-Rüger approach
Method of Estimation Estimation Parameter LS Mean Difference
Estimated Value 1.28
Confidence Interval (2-Sided) 96.875%
0.145 to 2.42
Parameter Dispersion Type:
Value:
Estimation Comments
4. Primary Outcome
Title Concentrations of Soluble Intercellular Adhesion Molecule 1 (sICAM-1).
Description Concentrations measured in serum. Geometric Least Squares means are provided as descriptive statistics.
Time Frame 26 Weeks

Outcome Measure Data

Analysis Population Description
Full Analysis Set - As Exposed (FAS-EX)
Arm/Group Title THS 2.2 Use CC Use Dual Use Other Use
Arm/Group Description ≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on >50% of days in the analysis period. ≥1 THS 2.2 or CC use, and <1% THS 2.2 use over the entire analysis period and <1% THS 2.2 use on ≥ 50% of days in the analysis period. ≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 <70% over the analysis period, or THS 2.2-use and CC-use categories do not apply to 50% of these days. Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns between consecutive analysis periods.
Measure Participants 245 428 142 42
Geometric Mean (95% Confidence Interval) [ng/mL]
252
266
270
273
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection THS 2.2 Use, CC Use
Comments The analysis of sICAM-1 will test if the mean level of this clinical risk endpoint for THS-use is lower relative to CC-use. The following hypothesis will be evaluated: H0: XTHS / XCC ≥ 1.0 HA: XTHS / XCC < 1.0 where XTHS and XCC are the adjusted geometrical means of THS-use and CC-use, respectively. H0 is rejected with a type I error α = 1.5625% (one-sided test).
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.030
Comments
Method Hailperin-Rüger
Comments p-value less than 1.5625% would be considered statistically significant, following test multiplicity adjustment using the Hailperin-Rüger approach
Method of Estimation Estimation Parameter % Reduction
Estimated Value 2.86
Confidence Interval (2-Sided) 96.875%
-0.426 to 6.04
Parameter Dispersion Type:
Value:
Estimation Comments Derived as 1 - LS Mean Ratio (THS / CC)
5. Primary Outcome
Title Concentrations of 11-dehydrothromboxane B2 (11-DTXB2).
Description Concentrations measured in urine and expressed as concentration adjusted for creatinine. Geometric Least Squares means are provided as descriptive statistics.
Time Frame 26 Weeks

Outcome Measure Data

Analysis Population Description
Full Analysis Set - As Exposed (FAS-EX)
Arm/Group Title THS 2.2 Use CC Use Dual Use Other Use
Arm/Group Description ≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on >50% of days in the analysis period. ≥1 THS 2.2 or CC use, and <1% THS 2.2 use over the entire analysis period and <1% THS 2.2 use on ≥ 50% of days in the analysis period. ≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 <70% over the analysis period, or THS 2.2-use and CC-use categories do not apply to 50% of these days. Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns between consecutive analysis periods.
Measure Participants 245 428 142 42
Geometric Mean (95% Confidence Interval) [pg/mg creat]
496
523
532
626
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection THS 2.2 Use, CC Use
Comments The analysis of 11-DTX-B2 will test if the mean level of this clinical risk endpoint for THS-use is lower relative to CC-use. The following hypothesis will be evaluated: H0: XTHS / XCC ≥ 1.0 HA: XTHS / XCC < 1.0 where XTHS and XCC are the adjusted geometrical means of THS-use and CC-use, respectively. H0 is rejected with a type I error α = 1.5625% (one-sided test).
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.193
Comments
Method Hailperin-Rüger
Comments p-value less than 1.5625% would be considered statistically significant, following test multiplicity adjustment using the Hailperin-Rüger approach
Method of Estimation Estimation Parameter % Reduction
Estimated Value 4.74
Confidence Interval (2-Sided) 96.875%
-7.5 to 15.6
Parameter Dispersion Type:
Value:
Estimation Comments Derived as 1 - LS Mean Ratio (THS / CC)
6. Primary Outcome
Title Concentrations of 8-epi-prostaglandin F2α (8-epi-PGF2α).
Description Concentrations measured in urine and expressed as concentration adjusted for creatinine. Geometric Least Squares means are provided as descriptive statistics.
Time Frame 26 Weeks

Outcome Measure Data

Analysis Population Description
Full Analysis Set - As Exposed (FAS-EX)
Arm/Group Title THS 2.2 Use CC Use Dual Use Other Use
Arm/Group Description ≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on >50% of days in the analysis period. ≥1 THS 2.2 or CC use, and <1% THS 2.2 use over the entire analysis period and <1% THS 2.2 use on ≥ 50% of days in the analysis period. ≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 <70% over the analysis period, or THS 2.2-use and CC-use categories do not apply to 50% of these days. Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns between consecutive analysis periods.
Measure Participants 245 428 142 42
Geometric Mean (95% Confidence Interval) [pg/mg creat]
321
351
347
335
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection THS 2.2 Use, CC Use
Comments The analysis of 8-epi-PGF2α will test if the mean level of this clinical risk endpoint for THS-use is lower relative to CC-use. The following hypothesis will be evaluated: H0: XTHS / XCC ≥ 1.0 HA: XTHS / XCC < 1.0 where XTHS and XCC are the adjusted geometrical means of THS-use and CC-use, respectively. H0 is rejected with a type I error α = 1.5625% (one-sided test).
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value 0.018
Comments
Method Hailperin-Rüger
Comments p-value less than 1.5625% would be considered statistically significant, following test multiplicity adjustment using the Hailperin-Rüger approach
Method of Estimation Estimation Parameter % Reduction
Estimated Value 6.80
Confidence Interval (2-Sided) 96.875%
-0.216 to 13.3
Parameter Dispersion Type:
Value:
Estimation Comments Derived as 1 - LS Mean Ratio (THS / CC)
7. Primary Outcome
Title Concentrations of Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL).
Description Concentrations measured in urine and expressed as concentration adjusted for creatinine. Geometric Least Squares means are provided as descriptive statistics.
Time Frame 26 Weeks

Outcome Measure Data

Analysis Population Description
Full Analysis Set - As Exposed (FAS-EX)
Arm/Group Title THS 2.2 Use CC Use Dual Use Other Use
Arm/Group Description ≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on >50% of days in the analysis period. ≥1 THS 2.2 or CC use, and <1% THS 2.2 use over the entire analysis period and <1% THS 2.2 use on ≥ 50% of days in the analysis period. ≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 <70% over the analysis period, or THS 2.2-use and CC-use categories do not apply to 50% of these days. Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns between consecutive analysis periods.
Measure Participants 245 428 142 42
Geometric Mean (95% Confidence Interval) [pg/mg creat]
144
282
286
342
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection THS 2.2 Use, CC Use
Comments The analysis of Total NNAL will test if the mean level of this clinical risk endpoint for THS-use is lower relative to CC-use. The following hypothesis will be evaluated: H0: XTHS / XCC ≥ 1.0 HA: XTHS / XCC < 1.0 where XTHS and XCC are the adjusted geometrical means of THS-use and CC-use, respectively. H0 is rejected with a type I error α = 1.5625% (one-sided test).
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value <0.001
Comments
Method Hailperin-Rüger
Comments p-value less than 1.5625% would be considered statistically significant, following test multiplicity adjustment using the Hailperin-Rüger approach
Method of Estimation Estimation Parameter % Reduction
Estimated Value 43.5
Confidence Interval (2-Sided) 96.875%
33.7 to 51.9
Parameter Dispersion Type:
Value:
Estimation Comments Derived as 1 - LS Mean Ratio (THS / CC)
8. Primary Outcome
Title Percent Change From Baseline of Carboxyhemoglobin (COHb)
Description Carboxyhemoglobin (COHb) is assayed from whole blood. Geometric Least Squares means are provided as descriptive statistics. Expressed as % of saturation of hemoglobin.
Time Frame 26 Weeks

Outcome Measure Data

Analysis Population Description
Full Analysis Set - As Exposed (FAS-EX)
Arm/Group Title THS 2.2 Use CC Use Dual Use Other Use
Arm/Group Description ≥1 THS 2.2 or CC, and ≥70% THS 2.2 use over the analysis period, and ≥70% THS 2.2 use on >50% of days in the analysis period. ≥1 THS 2.2 or CC use, and <1% THS 2.2 use over the entire analysis period and <1% THS 2.2 use on ≥ 50% of days in the analysis period. ≥ 1 THS 2.2 or CC and, 1% ≤THS 2.2 <70% over the analysis period, or THS 2.2-use and CC-use categories do not apply to 50% of these days. Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns between consecutive analysis periods.
Measure Participants 245 428 142 42
Geometric Mean (95% Confidence Interval) [percentage change from baseline]
2.84
4.38
4.23
5.59
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection THS 2.2 Use, CC Use
Comments The analysis will test if the mean level of COHb for THS-use is lower relative to CC-use. The following hypothesis will be evaluated: H0: XTHS / XCC ≥ 1.0 HA: XTHS / XCC < 1.0 where XTHS and XCC are the adjusted geometrical means of THS-use and CC-use. H0 is rejected with a type I error α = 1.5625% (one-sided test).
Type of Statistical Test Superiority
Comments
Statistical Test of Hypothesis p-Value <0.001
Comments
Method Hailperin-Rüger
Comments p-value less than 1.5625% would be considered statistically significant, following test multiplicity adjustment using the Hailperin-Rüger approach
Method of Estimation Estimation Parameter % Reduction
Estimated Value 32.2
Confidence Interval (2-Sided) 96.875%
24.5 to 39
Parameter Dispersion Type:
Value:
Estimation Comments Derived as 1 - LS Mean Ratio (THS / CC)

Adverse Events

Time Frame The entire study duration per subject was between 32 to 38 weeks, including a Screening period of up to 42 days prior to enrollment, a 6 to 10-day run-in period prior to randomization, followed by a 26 week randomized exposure period. The end of study for a subject was defined as the check-out or the date of early termination of the subject plus the 28 day Safety Follow-up period, unless the subject was lost to follow-up.
Adverse Event Reporting Description
Arm/Group Title THS 2.2 Group CC Group Product Test
Arm/Group Description Randomized to Ad libitum use of THS 2.2 in an ambulatory setting for 26 weeks Randomized to Ad libitum use of CC in an ambulatory setting for 26 weeks Enrolled subjects who participated in a product test, but were not randomized.
All Cause Mortality
THS 2.2 Group CC Group Product Test
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 2/477 (0.4%) 0/483 (0%) 0/52 (0%)
Serious Adverse Events
THS 2.2 Group CC Group Product Test
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 6/477 (1.3%) 7/483 (1.4%) 0/52 (0%)
Infections and infestations
Pneumonia mycoplasmal 1/477 (0.2%) 1 0/483 (0%) 0 0/52 (0%) 0
Cellulitis 0/477 (0%) 0 1/483 (0.2%) 1 0/52 (0%) 0
Pyelonephritis acute, with Urosepsis and Nephrolithiasis 0/477 (0%) 0 1/483 (0.2%) 3 0/52 (0%) 0
Tooth Infection 0/477 (0%) 0 1/483 (0.2%) 1 0/52 (0%) 0
Injury, poisoning and procedural complications
Head injury with seizure 1/477 (0.2%) 2 0/483 (0%) 0 0/52 (0%) 0
Laceration 1/477 (0.2%) 1 0/483 (0%) 0 0/52 (0%) 0
Musculoskeletal and connective tissue disorders
Vertebral osteophyte with Cervical myelopathy 0/477 (0%) 0 1/483 (0.2%) 2 0/52 (0%) 0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Papillary thyroid cancer 0/477 (0%) 0 1/483 (0.2%) 1 0/52 (0%) 0
Metastases to small intestine with anaemia 1/477 (0.2%) 2 0/483 (0%) 0 0/52 (0%) 0
Psychiatric disorders
Completed suicide 1/477 (0.2%) 1 0/483 (0%) 0 0/52 (0%) 0
Suicidal ideation 0/477 (0%) 0 1/483 (0.2%) 1 0/52 (0%) 0
Alcohol abuse 1/477 (0.2%) 1 0/483 (0%) 0 0/52 (0%) 0
Adjustment disorder with depressed mood and bereavement 0/477 (0%) 0 1/483 (0.2%) 2 0/52 (0%) 0
Other (Not Including Serious) Adverse Events
THS 2.2 Group CC Group Product Test
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 23/477 (4.8%) 29/483 (6%) 0/52 (0%)
Infections and infestations
Upper respiratory tract infection 23/477 (4.8%) 26 29/483 (6%) 33 0/52 (0%) 0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

We confirm we have the contractual provisions in place which specify 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

Name/Title Christelle Haziza
Organization Philip Morris Products S.A.
Phone +41 58 242 11 11
Email ClinicalTrials.PMI@pmi.com
Responsible Party:
Philip Morris Products S.A.
ClinicalTrials.gov Identifier:
NCT02396381
Other Study ID Numbers:
  • ZRHR-ERS-09-US
  • ZRHR-ERS-09-US
First Posted:
Mar 24, 2015
Last Update Posted:
Aug 21, 2019
Last Verified:
Aug 1, 2019