Smoking
Conditions
Keywords
Modified risk tobacco product, Conventional cigarette, Exposure response, Smoking, Tobacco Heating System
Brief summary
The objective of the ZRHR-ERS-09-EXT-US study is to further assess the effect of the Tobacco Heating System 2.2 (THS 2.2), a candidate Modified Risk Tobacco Product, compared to conventional cigarettes (CC) on the components of the smokers' health profile for a prolonged period of 26 weeks, providing additional information to the results of the original study ZRHR-ERS-09-US of 26-week exposure (NCT02396381). In total, the ZRHR-ERS-09-EXT-US study will extend the exposure period to 52 weeks.
Detailed description
The ZRHR-ERS-09-EXT-US study is a 26-week extension of the original study ZRHR-ERS-09-US. The subjects in the Full Analysis Set - As Exposed (FAS-EX) included subjects for combined analyses from the original six month study (ZRHR-ERS-09-US ) who did not enter the extension study (ZRHR-ERS-09-EXT-US). This study was conducted as a separate investigation, as a follow-up of the randomized exposure period of the original study, extending the exposure from Week 26 (Visit 10 \[V10\]) to Week 52 (Visit 16 \[V16\]), and using the same sites. Subjects continued to use the product they were randomized to in the original study ZRHR-ERS-09-US (THS 2.2 arm or CC arm).
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
* Subject completed V10 of the original study (ZRHR-ERS-09-US). * The subject is willing to comply to study procedures and to continue to use the product he/she was allocated to during the original study (THS 2.2 or CC) for an additional 26 weeks at V10. * Subject has given written informed consent to enter the 26-week extension study at V10.
Exclusion criteria
* Clinically relevant medical conditions that in the opinion of the investigators would jeopardize the safety of the participant. * As per judgment of the PI(s) or designee(s), the subject cannot participate in the study for any reason (e.g. medical, psychiatric and/or social reason). * Subject has made an attempt to quit using tobacco-containing products (e.g. CC and THS 2.2) during the original study. * 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). | 52 weeks | Concentrations (mg/dL) measured in serum. Mean values are provided as descriptive statistics. |
| Levels of White Blood Cells (WBC). | 52 weeks | Total count in blood (GI/L). Mean values are provided as descriptive statistics. |
| Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1). | 52 weeks | FEV1 post-bronchodilator and expressed as percentage predicted (FEV1 %pred). Mean values are provided as descriptive statistics. |
| Concentrations of Soluble Intercellular Adhesion Molecule 1 (sICAM-1). | 52 weeks | Concentrations (ng/mL) measured in serum. Geometric Mean values are provided as descriptive statistics. |
| Concentrations of 11-dehydrothromboxane B2 (11-DTXB2). | 52 weeks | Concentrations measured in urine and expressed as concentration adjusted for creatinine (pg/mg creat). Geometric Mean values are provided as descriptive statistics. |
| Concentrations of 8-epi-prostaglandin F2α (8-epi-PGF2α). | 52 weeks | Concentrations measured in urine and expressed as concentration adjusted for creatinine (pg/mg creat). Geometric Mean values are provided as descriptive statistics. |
| Concentrations of Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL). | 52 weeks | Concentrations measured in urine and expressed as concentration adjusted for creatinine (pg/mg creat). Geometric Mean values are provided as descriptive statistics. |
| Levels of Carboxyhemoglobin (COHb). | 52 weeks | Carboxyhemoglobin (COHb) is assayed from whole blood. Expressed as % of saturation of hemoglobin. Geometric Mean values are provided as descriptive statistics. |
Countries
United States
Participant flow
Recruitment details
Of the 984 subjects (488 in the THS arm and 496 in the CC arm) who were enrolled and randomized into the original study, NCT02396381, 672 subjects were enrolled into the extension study (309 in the THS arm and 363 in the CC arm).
Pre-assignment details
672 subjects enrolled in the extension study; the 857 subjects in the Full Analysis Set - As Exposed (FAS-EX) included subjects for combined analyses from the original six month study who did not enter the extension study. The analysis was performed according to subjects' exposure over the 12 month period as detailed in Arm/Group (Reporting Groups) table.
Participants by arm
| Arm | Count |
|---|---|
| THS 2.2 Use The THS 2.2 use product use category was defined as THS use of 70% or more over the entire analysis period.
(≥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.) | 230 |
| CC Use The CC use product use category was defined as THS use of less than 1% over the entire 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.) | 424 |
| Dual Use The Dual use product use category was defined as THS use of less than 70% over the entire 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.) | 152 |
| Other Use Other use refers to any other product use over the entire analysis period. (Subjects with missing product use data, subjects using e-cigarettes or other tobacco products, quitters, or subjects who switched across different use patterns.) | 51 |
| Total | 857 |
Baseline characteristics
| Characteristic | THS 2.2 Use | CC Use | Dual Use | Other Use | Total |
|---|---|---|---|---|---|
| Age, Continuous | 43.8 years STANDARD_DEVIATION 9.68 | 45.2 years STANDARD_DEVIATION 9.54 | 44.2 years STANDARD_DEVIATION 9.76 | 44.5 years STANDARD_DEVIATION 8.21 | 44.6 years STANDARD_DEVIATION 9.55 |
| BMI | 27.0 kg/m^2 STANDARD_DEVIATION 4.06 | 27.1 kg/m^2 STANDARD_DEVIATION 4.13 | 26.9 kg/m^2 STANDARD_DEVIATION 4.25 | 26.6 kg/m^2 STANDARD_DEVIATION 4.91 | 27.0 kg/m^2 STANDARD_DEVIATION 4.18 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 17 Participants | 28 Participants | 6 Participants | 2 Participants | 53 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 213 Participants | 396 Participants | 146 Participants | 49 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 | 1 Participants | 2 Participants | 2 Participants | 1 Participants | 6 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 5 Participants | 0 Participants | 1 Participants | 8 Participants |
| Race (NIH/OMB) Black or African American | 41 Participants | 73 Participants | 25 Participants | 12 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 | 182 Participants | 338 Participants | 123 Participants | 36 Participants | 679 Participants |
| Sex: Female, Male Female | 87 Participants | 180 Participants | 67 Participants | 19 Participants | 353 Participants |
| Sex: Female, Male Male | 143 Participants | 244 Participants | 85 Participants | 32 Participants | 504 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 241 | 1 / 434 | 0 / 159 | 1 / 106 |
| other Total, other adverse events | 40 / 241 | 87 / 434 | 26 / 159 | 13 / 106 |
| serious Total, serious adverse events | 12 / 241 | 15 / 434 | 1 / 159 | 1 / 106 |
Outcome results
Primary
Concentrations of 11-dehydrothromboxane B2 (11-DTXB2).
Concentrations measured in urine and expressed as concentration adjusted for creatinine (pg/mg creat). Geometric Mean values are provided as descriptive statistics.
Time frame: 52 weeks
Population: Full Analysis Set - As Exposed Analysis (FAS-EX). Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| THS 2.2 Use | Concentrations of 11-dehydrothromboxane B2 (11-DTXB2). | 582 pg/mg creat |
| CC Use | Concentrations of 11-dehydrothromboxane B2 (11-DTXB2). | 586 pg/mg creat |
| Dual Use | Concentrations of 11-dehydrothromboxane B2 (11-DTXB2). | 595 pg/mg creat |
| Other Use | Concentrations of 11-dehydrothromboxane B2 (11-DTXB2). | 536 pg/mg creat |
Comparison: The analysis will determine the effect of THS 2.2 compared to CC at Month 12 on the components of the smokers' health profile. This study has no formal pre-specified hypotheses associated with the study objectives. Estimates of THS 2.2 effect will be presented by mean of relative reduction of 11-DTXB2 levels between CC and THS 2.2 and related 95% CI.95% CI: [-8.74, 14.3]
Primary
Concentrations of 8-epi-prostaglandin F2α (8-epi-PGF2α).
Concentrations measured in urine and expressed as concentration adjusted for creatinine (pg/mg creat). Geometric Mean values are provided as descriptive statistics.
Time frame: 52 weeks
Population: Full Analysis Set - As Exposed Analysis (FAS-EX). Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| THS 2.2 Use | Concentrations of 8-epi-prostaglandin F2α (8-epi-PGF2α). | 307 pg/mg creat |
| CC Use | Concentrations of 8-epi-prostaglandin F2α (8-epi-PGF2α). | 327 pg/mg creat |
| Dual Use | Concentrations of 8-epi-prostaglandin F2α (8-epi-PGF2α). | 326 pg/mg creat |
| Other Use | Concentrations of 8-epi-prostaglandin F2α (8-epi-PGF2α). | 364 pg/mg creat |
Comparison: The analysis will determine the effect of THS 2.2 compared to CC at Month 12 on the components of the smokers' health profile. This study has no formal pre-specified hypotheses associated with the study objectives. Estimates of THS 2.2 effect will be presented by mean of relative reduction of 8-epi-PGF2α levels between CC and THS 2.2 and related 95% CI.95% CI: [-1.03, 14.7]
Primary
Concentrations of Soluble Intercellular Adhesion Molecule 1 (sICAM-1).
Concentrations (ng/mL) measured in serum. Geometric Mean values are provided as descriptive statistics.
Time frame: 52 weeks
Population: Full Analysis Set - As Exposed Analysis (FAS-EX). Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| THS 2.2 Use | Concentrations of Soluble Intercellular Adhesion Molecule 1 (sICAM-1). | 246 ng/mL |
| CC Use | Concentrations of Soluble Intercellular Adhesion Molecule 1 (sICAM-1). | 258 ng/mL |
| Dual Use | Concentrations of Soluble Intercellular Adhesion Molecule 1 (sICAM-1). | 269 ng/mL |
| Other Use | Concentrations of Soluble Intercellular Adhesion Molecule 1 (sICAM-1). | 255 ng/mL |
Comparison: The analysis will determine the effect of THS 2.2 compared to CC at Month 12 on the components of the smokers' health profile. This study has no formal pre-specified hypotheses associated with the study objectives. Estimates of THS 2.2 effect will be presented by mean of relative reduction of sICAM-1 levels between CC and THS 2.2 and related 95% CI.95% CI: [0.0231, 6.1]
Primary
Concentrations of Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL).
Concentrations measured in urine and expressed as concentration adjusted for creatinine (pg/mg creat). Geometric Mean values are provided as descriptive statistics.
Time frame: 52 weeks
Population: Full Analysis Set - As Exposed Analysis (FAS-EX). Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| THS 2.2 Use | Concentrations of Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL). | 133 pg/mg creat |
| CC Use | Concentrations of Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL). | 269 pg/mg creat |
| Dual Use | Concentrations of Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL). | 253 pg/mg creat |
| Other Use | Concentrations of Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL). | 304 pg/mg creat |
Comparison: The analysis will determine the effect of THS 2.2 compared to CC at Month 12 on the components of the smokers' health profile. This study has no formal pre-specified hypotheses associated with the study objectives. Estimates of THS 2.2 effect will be presented by mean of relative reduction of Total NNAL levels between CC and THS 2.2 and related 95% CI.95% CI: [36.2, 54.8]
Primary
Levels of Carboxyhemoglobin (COHb).
Carboxyhemoglobin (COHb) is assayed from whole blood. Expressed as % of saturation of hemoglobin. Geometric Mean values are provided as descriptive statistics.
Time frame: 52 weeks
Population: Full Analysis Set - As Exposed Analysis (FAS-EX). Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| THS 2.2 Use | Levels of Carboxyhemoglobin (COHb). | 2.59 percent change |
| CC Use | Levels of Carboxyhemoglobin (COHb). | 4.06 percent change |
| Dual Use | Levels of Carboxyhemoglobin (COHb). | 3.92 percent change |
| Other Use | Levels of Carboxyhemoglobin (COHb). | 5.22 percent change |
Comparison: The analysis will determine the effect of THS 2.2 compared to CC at Month 12 on the components of the smokers' health profile. This study has no formal pre-specified hypotheses associated with the study objectives. Estimates of THS 2.2 effect will be presented by mean of relative reduction of COHb levels between CC and THS 2.2 and related 95% CI.95% CI: [23.3, 39.1]
Primary
Levels of High Density Lipoprotein C (HDL-C).
Concentrations (mg/dL) measured in serum. Mean values are provided as descriptive statistics.
Time frame: 52 weeks
Population: Full Analysis Set - As Exposed Analysis (FAS-EX). Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| THS 2.2 Use | Levels of High Density Lipoprotein C (HDL-C). | 52.2 mg/dL |
| CC Use | Levels of High Density Lipoprotein C (HDL-C). | 50.6 mg/dL |
| Dual Use | Levels of High Density Lipoprotein C (HDL-C). | 54.0 mg/dL |
| Other Use | Levels of High Density Lipoprotein C (HDL-C). | 54.7 mg/dL |
Comparison: The analysis will determine the effect of THS 2.2 compared to CC at Month 12 on the components of the smokers' health profile. This study has no formal pre-specified hypotheses associated with the study objectives. Estimates of THS 2.2 effect will be presented by mean of LS Mean difference of HDL-C levels between CC and THS 2.2 and related 95% CI.95% CI: [-0.16, 3.65]
Primary
Levels of White Blood Cells (WBC).
Total count in blood (GI/L). Mean values are provided as descriptive statistics.
Time frame: 52 weeks
Population: Full Analysis Set - As Exposed Analysis (FAS-EX). Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| THS 2.2 Use | Levels of White Blood Cells (WBC). | 6.73 GI/L |
| CC Use | Levels of White Blood Cells (WBC). | 7.31 GI/L |
| Dual Use | Levels of White Blood Cells (WBC). | 7.28 GI/L |
| Other Use | Levels of White Blood Cells (WBC). | 7.57 GI/L |
Comparison: The analysis will determine the effect of THS 2.2 compared to CC at Month 12 on the components of the smokers' health profile. This study has no formal pre-specified hypotheses associated with the study objectives. Estimates of THS 2.2 effect will be presented by mean of LS Mean difference of White Blood Cell counts between CC and THS 2.2 and related 95% CI.95% CI: [-0.694, -0.131]
Primary
Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1).
FEV1 post-bronchodilator and expressed as percentage predicted (FEV1 %pred). Mean values are provided as descriptive statistics.
Time frame: 52 weeks
Population: Full Analysis Set - As Exposed Analysis (FAS-EX). Some participants were excluded from analysis for protocol deviations (including, but not limited to, missing measurements).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| THS 2.2 Use | Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1). | 93.2 Percent of predicted FEV1 |
| CC Use | Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1). | 92.3 Percent of predicted FEV1 |
| Dual Use | Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1). | 91.1 Percent of predicted FEV1 |
| Other Use | Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1). | 95.2 Percent of predicted FEV1 |
Comparison: The analysis will determine the effect of THS 2.2 compared to CC at Month 12 on the components of the smokers' health profile. This study has no formal pre-specified hypotheses associated with the study objectives. Estimates of THS 2.2 effect will be presented by mean of LS Mean difference of FEV1 levels between CC and THS 2.2 and related 95% CI.95% CI: [-0.339, 2.17]