Inflammation, Oxidative Stress, Smoking, Smoking Abstinence
Conditions
Brief summary
This is a cross-sectional 3-group study with subjects enrolled and matched by region (Asia, Europe), age, sex, and average daily product consumption over the last 2 years as self-reported. The study will be conducted as a multi-center and multi-regional study.
Detailed description
The primary purpose of this study was to demonstrate the beneficial effects of switching from cigarette smoking to THS use for at least two years, compared to continued cigarette smoking, in real-life conditions. This was assessed by examining both inflammation and oxidative stress status as proxies for long-term harm in healthy subjects, using well-established and fit-for-purpose measures of WBC and 8-epi-PGF2α, respectively, as indicators of these pathways. Additionally, the study anticipated observing differences in lipid metabolism (HDL-C), endothelial dysfunction (sICAM-1), platelet activation (11-DTX-B2), arterial stiffness (AIx), and lung function (FEV1 %pred post-BD). The study also aimed to demonstrate additional benefits on other mechanistic pathways related to inflammation and oxidative stress through the use of additional biomarkers of potential harm (BoPH). Furthermore, it sought to assess the association with functional benefits that are expected to respond to the extent of exposure to harmful and potentially harmful constituents (HPHCs).
Interventions
OTHERTHS use
N/A: No intervention was assigned.
OTHERCigarette smoking
N/A: No intervention was assigned.
OTHERSmoking abstinence
N/A: No intervention was assigned.
Sponsors
Philip Morris Products S.A.
Study design
Observational model
COHORT
Time perspective
CROSS_SECTIONAL
Eligibility
Sex/Gender
ALL
Age
30 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
* Subject is able to understand the information provided in the main ICF and has signed the main ICF. * Subject is 30-60 years old. * Subject is healthy based on ECG, spirometry, vital signs, physical examination, medical history and Investigator's assessment. Cigarette smokers: * Has smoked ≥ 10 cigarettes/day on average (no brand restriction) over the past 2 years prior to screening. * Has smoked ≥ 10 cigarettes/day on average (no brand restriction) for at least 10 years. * Has not used other tobacco and nicotine products apart from cigarettes on a daily basis over the past 2 years prior to screening. * Smoking status will be verified by urinary cotinine test (≥ 200 ng/mL) and CO breath test (≥ 10 ppm (1)). THS users: * Has used ≥ 10 HeatSticks/day on average over the past 2 years prior to screening. * Has smoked ≥ 10 cigarettes/day on average (no brand restriction) for at least 8 years prior to switching to THS. * Has smoked \< 30 cigarettes/month and used other tobacco products or e-cigarettes \< daily over the past 2 years prior to screening. * Product use will be verified by urinary cotinine test (≥ 200 ng/mL) and CO breath test (\< 10 ppm). Former cigarette smokers: * Has not smoked cigarettes or used any tobacco or nicotine-containing products on a daily basis over the past 2 years prior to screening. * Has smoked ≥ 10 cigarettes/day on average (no brand restriction) for at least 8 years prior to stopping smoking. * Smoking status will be verified by urinary cotinine test (\< 100 ng/mL) and CO breath test (\< 10 ppm).
Exclusion criteria
* As per the judgment of the Investigator, the subject cannot participate in the study for any reason (e.g., medical, psychiatric and/or social reason). The Investigator should specifically evaluate the subject's eligibility considering COVID-19 risk factors and local situation. * The subject is legally incompetent or physically/mentally incapable of giving consent (e.g., emergency situation, under guardianship, in a social or sanitary establishment, prisoner or involuntarily incarcerated). * The subject has/had clinically relevant diseases (including but not limited to gastrointestinal, renal, hepatic, neurological, hematological, endocrine, oncological, urological, immunological, pulmonary, and cardiovascular disease) or conditions that in the opinion of the investigator would jeopardize the safety of the subject or affect the validity of the study results. * The subject has abnormal findings on physical examination, ECG, vital signs, spirometry or in the medical history, deemed clinically significant by investigators. * The subject has/had within 30 days prior to screening a body temperature \>37.5°C or an acute illness (e.g., upper-respiratory-tract infection, viral infection, etc.…) or the subject is confirmed or suspected active COVID-19 infection (based on the signs and symptoms observed at the time of assessment) at screening. * The subject has used any prescribed or over-the-counter systemic medication with an impact on WBC or 8-epi-PGF2α within 5 half-lives of the medication prior to enrollment in the study (please refer to Appendix B). * Subject has high blood pressure (hypertension), defined as \> 139 mmHg systolic and/or \> 89 mmHg diastolic or is currently treated with medication controlling high blood pressure. * The subject has (FEV1/FVC) \< 0.7 and FEV1 \< 80% predicted value at post-bronchodilator (BD) spirometry. * The subject has (FEV1/FVC) \< 0.75 (pre-BD) and reversibility in FEV1 (that is both \> 12% and \> 200 mL from pre- to post-BD values). * The subject has a history of allergic reactions to salbutamol. * The subject has a body mass index (BMI) \< 18.5 or ≥ 30 kg/m2. * The subject has positive alcohol and/or drug screening test results. * The subject has donated or received whole blood or blood products within 3 months prior to V1. * The subject has been previously screened for this study. * The subject is a current or former employee of the tobacco or e-cigarettes industry or of their first-degree relatives (parent, sibling, and child). * The subject is an employee of the investigational site or any other parties involved in the study or of their first-degree relatives (parent, sibling, and child). * The subject has participated in a clinical study within 3 months prior to V1. * For women only: the subject is pregnant (does have a positive pregnancy test) or breast-feeding.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Carboxyhemoglobin (COHb) in Blood | Measured when subject visits study site on day 1. | Carboxyhemoglobin (COHb) is assayed from whole blood. Expressed as percentage of the total hemoglobin saturated with carbon monoxide. |
| Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL) in Urine | Measured when subject visits study site on day 1. | Concentrations of total NNAL measured in urine and expressed as concentration adjusted for creatinine (pg/mg creatinine). |
| White Blood Cell Total Count (WBC) in Blood | Measured when subject visits study site on day 1. | Total count in blood (10\^9 cells/ L). Mean values are provided. |
| 8-epi-Prostaglandin-F2α (8-epi-PGF2α) in Urine | Measured when subject visits study site on day 1. | Concentrations of 8-epi-PGF2α measured in urine and expressed as concentration adjusted for creatinine (pg/mg creatinine). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| High-Density Lipoprotein Cholesterol (HDL-C) | Measured when subject visits study site on day 1. | Concentrations of HDL-C (mmol/L) measured in serum. |
| Soluble Intercellular Adhesion Molecule-1 (sICAM-1) | Measured when subject visits study site on day 1. | Concentrations of sICAM-1 (ng/mL) measured in plasma. |
| 11-dehydrothromboxane B2 (11-DTX-B2) | Measured when subject visits study site on day 1. | Concentrations of 11-DTX-B2 measured in urine and expressed as concentration adjusted for creatinine (pg/mg creatinine). |
| Augmentation Index (AIx) | Measured when subject visits study site on day 1. | The augmentation index (AIx) is a measure of systemic arterial stiffness, and is defined as the ratio of augmentation (Δ P) to central pulse pressure and expressed as percent. AIx = (ΔP/PP) x 100, where P = pressure and PP = Pulse Pressure. Lower AIx values indicate healthier, more flexible arteries and better cardiovascular outcomes, while higher AIx values reflect greater arterial stiffness and worse outcomes. AIx assessments were conducted using a SphygmoCor XCEL device or similar according to the manufacturer's instructions. |
| Forced Expiratory Volume in 1 Second (FEV1) %Predicted, Post-bronchodilator (Post-BD) | Measured when subject visits study site on day 1. | FEV1 post-bronchodilator and expressed as percentage predicted (FEV1 %pred). |
Countries
Bulgaria, Czechia, Germany, Greece, Japan, Poland
Contacts
STUDY_CHAIRChristelle Haziza, PhD
Philip Morris Products S.A.
Participant flow
Recruitment details
A total of 300 triplets were planned for enrollment (a triplet was defined as one Current Smoker, one THS User, and one Former Smoker - enrolled and matched). A maximum of 330 subjects per group was planned for enrollment - a 10% buffer was intended to ease triplet completion and manage mismatched subjects.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Continuous | 43.1 years STANDARD_DEVIATION 7.65 |
| Average Daily Product Consumption 10 to 19 cig/day or 10 to 19 heatsticks/day | 204 Participants |
| Average Daily Product Consumption >19 cig/day or >19 heatsticks/day | 93 Participants |
| BMI | 24.3 kg/m² STANDARD_DEVIATION 3.07 |
| Race/Ethnicity, Customized Asian - Japanese | 139 Participants |
| Race/Ethnicity, Customized Asian - Non-Japanese | 7 Participants |
| Race/Ethnicity, Customized Black | 2 Participants |
| Race/Ethnicity, Customized Multiple | 4 Participants |
| Race/Ethnicity, Customized White | 156 Participants |
| Sex: Female, Male Female | 119 Participants |
| Sex: Female, Male Male | 177 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 322 | 0 / 329 | 0 / 323 |
| other Total, other adverse events | 0 / 322 | 0 / 329 | 0 / 323 |
| serious Total, serious adverse events | 0 / 322 | 0 / 329 | 0 / 323 |
Outcome results
None listed