Reduction of Exposure, Inflammation, and Oxidative Stress Following at Least 2 Years of Switching to THS Use Compared to Cigarette Smoking

Study Overview
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Brief Summary
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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, to demonstrate beneficial effects of switching from cigarettes to THS.

Detailed Description
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The purpose of this study is primarily to demonstrate beneficial effects of switching from cigarette smoking to THS use for at least 2 years compared to cigarette smoking in a real-life condition on both inflammation and oxidative stress status as a proxy for further long-term harm in healthy subjects, using the well-established and fit-to-purpose measures of WBC and 8-epi-PGF2α, respectively, as indicators of the status of these pathways. The study aims also at demonstrating additional benefits on other mechanistic pathways along with inflammation and oxidative stress by the means of additional biomarkers of potential harm (BoPH) and to assess association with functional benefits that are expected to be responsive to the extent of exposure to harmful and potentially harmful constituents (HPHCs).

Official Title
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A Cross-sectional, Multi-regional Study to Demonstrate Reduction in Exposure to Key Toxicants, Oxidative Stress, and Inflammation Following at Least 2 Years of Tobacco Heating System (THS) Use Compared to Cigarette Smoking

Conditions
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Inflammation, Oxidative Stress, Smoking, Smoking Abstinence

Intervention / Treatment
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* Other: THS use
* Other: Cigarette smoking
* Other: Smoking abstinence


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Cigarette<br>Current cigarette smokers | Other: Cigarette smoking<br>* N/A: No intervention was assigned.<br>|
| THS<br>THS users with a minimum of 2 years of THS use | Other: THS use<br>* N/A: No intervention was assigned.<br>|
| SA<br>Former cigarette smokers with minimum of 2 years of smoking abstinence | Other: Smoking abstinence<br>* N/A: No intervention was assigned.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Carboxyhemoglobin (COHb) in blood | Carboxyhemoglobin (COHb) is assayed from whole blood. Expressed as % of saturation of hemoglobin. | Measured when subject visits study site on day 1. | 
| Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (total NNAL) in urine | Concentrations of total NNAL measured in urine and expressed as concentration adjusted for creatinine (pg/mg creat). | Measured when subject visits study site on day 1. | 
| White Blood Cell total count (WBC) in blood | Total count in blood (GI/L). Mean values are provided. | Measured when subject visits study site on day 1. | 
| 8-epi-Prostaglandin-F2α (8-epi-PGF2α) in urine | Concentrations of 8-epi-PGF2α measured in urine and expressed as concentration adjusted for creatinine (pg/mg creat). | Measured when subject visits study site on day 1. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| High-Density Lipoprotein Cholesterol (HDL-C) | Concentrations of HDL-C (mg/dL) measured in serum. | Measured when subject visits study site on day 1. | 
| soluble Intercellular Adhesion Molecule-1 (sICAM-1) | Concentrations of sICAM-1 (ng/mL) measured in serum. | Measured when subject visits study site on day 1. | 
| 11-dehydrothromboxane B2 (11-DTX-B2) | Concentrations of 11-DTX-B2 measured in urine and expressed as concentration adjusted for creatinine (pg/mg creat). | Measured when subject visits study site on day 1. | 
| Augmentation Index (AIx) | 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. | Measured when subject visits study site on day 1. | 
| Forced Expiratory Volume in 1 second (FEV1) %predicted, post-bronchodilator (post-BD) | FEV1 post-bronchodilator and expressed as percentage predicted (FEV1 %pred). | Measured when subject visits study site on day 1. |