Smoking
Conditions
Keywords
Candidate modified risk tobacco product, Conventional cigarette, Exposure response, Smoking, Tobacco Heating System
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.
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.
Interventions
Sponsors
Philip Morris Products S.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
30 Years to No maximum
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Levels of High Density Lipoprotein C (HDL-C). | 26 Weeks | Concentrations measured in serum. Geometric Least Squares means are provided as descriptive statistics. |
| Levels of White Blood Cells (WBC). | 26 Weeks | Concentrations measured in blood. Geometric Least Squares means are provided as descriptive statistics. |
| 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. |
| Concentrations of Soluble Intercellular Adhesion Molecule 1 (sICAM-1). | 26 Weeks | Concentrations measured in serum. Geometric Least Squares means are provided as descriptive statistics. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| THS 2.2 Use ≥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. | 245 |
| CC Use ≥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. | 428 |
| Dual Use ≥ 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. | 142 |
| Other Use 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. | 42 |
| Total | 857 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 3 | 2 |
| Overall Study | Could not complete visit | 1 | 0 |
| Overall Study | Lost to Follow-up | 49 | 31 |
| Overall Study | Moved out of town/state | 1 | 3 |
| Overall Study | Non-compliance with study procedures | 1 | 0 |
| Overall Study | Physician Decision | 5 | 5 |
| Overall Study | Possible conflict of interest | 1 | 0 |
| Overall Study | Pregnancy | 2 | 0 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Randomization/Screening Error | 3 | 1 |
| Overall Study | Site terminated by sponsor | 7 | 8 |
| Overall Study | Withdrawal by Subject | 33 | 24 |
Baseline characteristics
| Characteristic | THS 2.2 Use | CC Use | Dual Use | Other Use | Total |
|---|---|---|---|---|---|
| Age, Continuous | 44.2 years STANDARD_DEVIATION 9.64 | 45.2 years STANDARD_DEVIATION 9.55 | 43.8 years STANDARD_DEVIATION 9.77 | 44.2 years STANDARD_DEVIATION 8.14 | 44.6 years STANDARD_DEVIATION 9.55 |
| BMI | 26.9 kg/m2 STANDARD_DEVIATION 3.99 | 27.1 kg/m2 STANDARD_DEVIATION 4.13 | 26.9 kg/m2 STANDARD_DEVIATION 4.35 | 26.9 kg/m2 STANDARD_DEVIATION 5.12 | 27.0 kg/m2 STANDARD_DEVIATION 4.18 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 17 Participants | 28 Participants | 7 Participants | 1 Participants | 53 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 228 Participants | 400 Participants | 135 Participants | 41 Participants | 804 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 2 Participants | 2 Participants | 0 Participants | 6 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 5 Participants | 0 Participants | 1 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 42 Participants | 74 Participants | 25 Participants | 10 Participants | 151 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 2 Participants | 0 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants | 4 Participants | 2 Participants | 1 Participants | 10 Participants |
| Race (NIH/OMB) White | 195 Participants | 341 Participants | 113 Participants | 30 Participants | 679 Participants |
| Sex: Female, Male Female | 94 Participants | 182 Participants | 63 Participants | 14 Participants | 353 Participants |
| Sex: Female, Male Male | 151 Participants | 246 Participants | 79 Participants | 28 Participants | 504 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 477 | 0 / 483 | 0 / 52 |
| other Total, other adverse events | 23 / 477 | 29 / 483 | 0 / 52 |
| serious Total, serious adverse events | 6 / 477 | 7 / 483 | 0 / 52 |
Outcome results
Primary
Concentrations of 11-dehydrothromboxane B2 (11-DTXB2).
Concentrations measured in urine and expressed as concentration adjusted for creatinine. Geometric Least Squares means are provided as descriptive statistics.
Time frame: 26 Weeks
Population: Full Analysis Set - As Exposed (FAS-EX)
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| THS 2.2 Use | Concentrations of 11-dehydrothromboxane B2 (11-DTXB2). | 496 pg/mg creat |
| CC Use | Concentrations of 11-dehydrothromboxane B2 (11-DTXB2). | 523 pg/mg creat |
| Dual Use | Concentrations of 11-dehydrothromboxane B2 (11-DTXB2). | 532 pg/mg creat |
| Other Use | Concentrations of 11-dehydrothromboxane B2 (11-DTXB2). | 626 pg/mg creat |
Comparison: 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).p-value: 0.19396.875% CI: [-7.5, 15.6]Hailperin-Rüger
Primary
Concentrations of 8-epi-prostaglandin F2α (8-epi-PGF2α).
Concentrations measured in urine and expressed as concentration adjusted for creatinine. Geometric Least Squares means are provided as descriptive statistics.
Time frame: 26 Weeks
Population: Full Analysis Set - As Exposed (FAS-EX)
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| THS 2.2 Use | Concentrations of 8-epi-prostaglandin F2α (8-epi-PGF2α). | 321 pg/mg creat |
| CC Use | Concentrations of 8-epi-prostaglandin F2α (8-epi-PGF2α). | 351 pg/mg creat |
| Dual Use | Concentrations of 8-epi-prostaglandin F2α (8-epi-PGF2α). | 347 pg/mg creat |
| Other Use | Concentrations of 8-epi-prostaglandin F2α (8-epi-PGF2α). | 335 pg/mg creat |
Comparison: 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).p-value: 0.01896.875% CI: [-0.216, 13.3]Hailperin-Rüger
Primary
Concentrations of Soluble Intercellular Adhesion Molecule 1 (sICAM-1).
Concentrations measured in serum. Geometric Least Squares means are provided as descriptive statistics.
Time frame: 26 Weeks
Population: Full Analysis Set - As Exposed (FAS-EX)
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| THS 2.2 Use | Concentrations of Soluble Intercellular Adhesion Molecule 1 (sICAM-1). | 252 ng/mL |
| CC Use | Concentrations of Soluble Intercellular Adhesion Molecule 1 (sICAM-1). | 266 ng/mL |
| Dual Use | Concentrations of Soluble Intercellular Adhesion Molecule 1 (sICAM-1). | 270 ng/mL |
| Other Use | Concentrations of Soluble Intercellular Adhesion Molecule 1 (sICAM-1). | 273 ng/mL |
Comparison: 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).p-value: 0.0396.875% CI: [-0.426, 6.04]Hailperin-Rüger
Primary
Concentrations of Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL).
Concentrations measured in urine and expressed as concentration adjusted for creatinine. Geometric Least Squares means are provided as descriptive statistics.
Time frame: 26 Weeks
Population: Full Analysis Set - As Exposed (FAS-EX)
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| THS 2.2 Use | Concentrations of Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL). | 144 pg/mg creat |
| CC Use | Concentrations of Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL). | 282 pg/mg creat |
| Dual Use | Concentrations of Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL). | 286 pg/mg creat |
| Other Use | Concentrations of Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL). | 342 pg/mg creat |
Comparison: 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).p-value: <0.00196.875% CI: [33.7, 51.9]Hailperin-Rüger
Primary
Levels of High Density Lipoprotein C (HDL-C).
Concentrations measured in serum. Geometric Least Squares means are provided as descriptive statistics.
Time frame: 26 Weeks
Population: Full Analysis Set - As Exposed (FAS-EX)
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| THS 2.2 Use | Levels of High Density Lipoprotein C (HDL-C). | 54.1 mg/dL |
| CC Use | Levels of High Density Lipoprotein C (HDL-C). | 50.9 mg/dL |
| Dual Use | Levels of High Density Lipoprotein C (HDL-C). | 56.3 mg/dL |
| Other Use | Levels of High Density Lipoprotein C (HDL-C). | 52.8 mg/dL |
Comparison: 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).p-value: <0.00196.875% CI: [1.1, 5.09]Hailperin-Rüger
Primary
Levels of White Blood Cells (WBC).
Concentrations measured in blood. Geometric Least Squares means are provided as descriptive statistics.
Time frame: 26 Weeks
Population: Full Analysis Set - As Exposed (FAS-EX)
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| THS 2.2 Use | Levels of White Blood Cells (WBC). | 6.98 GI/L |
| CC Use | Levels of White Blood Cells (WBC). | 7.48 GI/L |
| Dual Use | Levels of White Blood Cells (WBC). | 7.41 GI/L |
| Other Use | Levels of White Blood Cells (WBC). | 8.71 GI/L |
Comparison: 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).p-value: 0.00196.875% CI: [-0.717, -0.123]Hailperin-Rüger
Primary
Percent Change From Baseline of Carboxyhemoglobin (COHb)
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
Population: Full Analysis Set - As Exposed (FAS-EX)
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| THS 2.2 Use | Percent Change From Baseline of Carboxyhemoglobin (COHb) | 2.84 percentage change from baseline |
| CC Use | Percent Change From Baseline of Carboxyhemoglobin (COHb) | 4.38 percentage change from baseline |
| Dual Use | Percent Change From Baseline of Carboxyhemoglobin (COHb) | 4.23 percentage change from baseline |
| Other Use | Percent Change From Baseline of Carboxyhemoglobin (COHb) | 5.59 percentage change from baseline |
Comparison: 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).p-value: <0.00196.875% CI: [24.5, 39]Hailperin-Rüger
Primary
Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1).
FEV1 post-bronchodilator and expressed as percentage predicted (FEV1 %pred). Geometric Least Squares means are provided as descriptive statistics.
Time frame: 26 Weeks
Population: Full Analysis Set - As Exposed (FAS-EX)
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| THS 2.2 Use | Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1). | 95.4 Percent of predicted FEV1 |
| CC Use | Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1). | 93.4 Percent of predicted FEV1 |
| Dual Use | Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1). | 93.7 Percent of predicted FEV1 |
| Other Use | Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1). | 94.3 Percent of predicted FEV1 |
Comparison: 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).p-value: 0.00896.875% CI: [0.145, 2.42]Hailperin-Rüger