Reduced Exposure to HPHC in Smokers Switching From Cigarettes to Different Versions of THS

Study Overview
=================
Brief Summary
-----------------
This is a randomized, controlled, open-label, 4 parallel arm study with a stratified randomization by sex (a quota for each sex [females and males] of at least 40% overall). This study aims to demonstrate the reduction of Biomarkers of Exposure (BoExp) to selected Harmful and Potentially Harmful Constituents (HPHC) in smokers switching from cigarettes (CIG) to each of the Tobacco Heating System (THS) variants with different heating technology (Blade device, Induction Mono device, or Induction Mid device, respectively), compared with smokers who continue to smoke CIG. A reduction of exposure to HPHC is expected in CIG smokers when switching completely to THS.

Detailed Description
-----------------
The exposure period in confinement will provide information on exposure reductions achievable in a well-controlled environment with full control on daily THS stick consumption and compared to CIG smoking. The primary hypothesis tested in this study is that BoExp considered for the primary objective will be reduced for each THS variant (Blade device, or Induction Mono device, or Induction Mid device, respectively) in subjects who adhere to switching to THS for 5 days, compared to subjects continuing CIG smoking.

Official Title
-----------------
A Randomized, Controlled, Open-label, 4 Parallel Arms Study to Demonstrate Reductions in Exposure to Selected Harmful and Potentially Harmful Constituents (HPHC) of Cigarette (CIG) Smoke in Healthy Smokers Switching to Different Versions of Tobacco Heating System (THS) Compared to Continuing CIG Smoking, for 5 Days in Confinement

Conditions
-----------------
Smoking, Tobacco Smoking, Tobacco Use

Intervention / Treatment
-----------------
* Other: THS Blade device
* Other: THS Induction Mono device
* Other: THS Induction Mid device
* Other: CIG


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subject has signed the ICF and is able to understand the information provided in the ICF. Subject has been a smoker for ≥3 years prior to the screening visit (smoking cessation attempts during this period, if any, did not last > 6 months in total). Subject has continuously smoked on average ≥10 commercially available regular CIGs/day over the last 4 weeks. Smoking status will be verified based on a urinary cotinine test (cotinine ≥200 ng/mL). Subject is healthy as judged by the Investigator based on available assessments from the screening period (e.g., safety laboratory, spirometry, vital signs, physical examination, ECG, and medical history). Subject does not plan to quit smoking within the next three months. Exclusion Criteria: As per the Investigator's judgment, the subject cannot participate in the study for any reason other than medical (e.g., psychological, social reason). Subject is legally incompetent, or physically or mentally incapable of giving consent (e.g., in emergency situations, under guardianship, prisoners). Subject has a clinically relevant disease which requires medication (including but not limited to gastrointestinal, renal, hepatic, neurological, hematological, endocrine, oncological, urological, immunological, pulmonary, and cardiovascular disease) or any other medical condition (including safety laboratory), which as per the judgment of the Investigator would jeopardize the safety of the subject. Subject experienced within 30 days prior to screening/admission a body temperature >37.5°C or an acute illness (e.g., upper respiratory-tract infection, viral infection, etc.) or the subject has a confirmed or suspected active COVID-19 infection (based on the signs and symptoms observed at the time of assessment) As per the Investigator's judgment, the subject has medical conditions which do or will require a medical intervention (e.g., start of treatment, surgery, hospitalization) during the study participation, which may interfere with the study participation and/or study results. Subject has relevant history of, or current asthma condition or COPD condition, and/or clinically significant findings. Subject has donated blood or received whole blood or blood products within 3 months. BMI < 18.5 kg/m2 or ≥ 32.0 kg/m2. Positive serology test for HIV 1/2, HBV, or HCV. Subject has a positive alcohol breath test and/or has a history of alcohol disorder that could interfere with their participation in the study. The subject has a positive urine drug test. Subject or one of their family members is a current or former employee of the tobacco or e-cigarette industry. Subject or one of their family members is an employee of the investigational site or of any other parties involved in the study. Subject has participated in another clinical study within 3 months. Subject has been previously screened or enrolled in this study. Subject is pregnant (does not have negative pregnancy tests at screening and at admission) or is breastfeeding. For women of childbearing potential only: subject does not agree to use an acceptable method of effective contraception.

Ages Eligible for Study
-----------------
Minimum Age: 21 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: A randomized, controlled, open-label, 4 parallel arms study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: THS Blade device<br>Subjects randomized to this arm will participate in 5 days of ad libitum use, in confinement, of the THS Blade device (using regular THS blade tobacco sticks) between 06:30 AM and 11:00 PM. | Other: THS Blade device<br>* Tobacco Heating System (THS) device with Blade technology for Blade tobacco stick use<br>* Other names: HEETS (blade heated tobacco sticks);|
| Active Comparator: THS Induction Mono device<br>Subjects randomized to this arm will participate in 5 days of ad libitum use, in confinement, of the THS Induction Mono device (using regular THS induction tobacco sticks) between 06:30 AM and 11:00 PM. | Other: THS Induction Mono device<br>* Tobacco Heating System (THS) device with Induction technology (combined Charger-Holder device for Induction tobacco stick use).<br>* Other names: TEREA (induction heated tobacco sticks);|
| Active Comparator: THS Induction Mid device<br>Subjects randomized to this arm will participate in 5 days of ad libitum use, in confinement, of the THS Induction Mid device (using regular THS induction tobacco sticks) between 06:30 AM and 11:00 PM. | Other: THS Induction Mid device<br>* Tobacco Heating System (THS) device with Induction technology (device with Induction stick Holder for Induction tobacco stick use and separate Charger).<br>* Other names: TEREA (induction heated tobacco sticks);|
| Active Comparator: Cigarette<br>Subjects randomized to this arm will participate in 5 days of ad libitum use, in confinement, of the subject's preferred brand of regular (non-mentholated) cigarette between 06:30 AM and 11:00 PM. (Every subject will bring a sufficient number of unopened, single-brand packs of CIG for the entire confinement period.) | Other: CIG<br>* Subject's preferred brand of commercially available regular (non-mentholated) cigarettes. (Cigarettes are not provided by the study sponsor.)<br>* Other names: Cigarette (non-mentholated);|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concentration of 3-hydroxypropylmercapturic Acid (3-HPMA) | Concentrations measured in urine, adjusted for creatinine, at Day 5. Geometric Least Squares means are provided as point estimates of reduction for biomarkers of exposure (BoExp) in smokers switching from CIG to various THS versions (THS Blade device; THS Induction Mono device; THS Induction Mid device) compared to continuing CIG smoking for 5 days. | 5 days | 
| Concentration of 2-cyanoethyl mercapturic acid N-acetyl-S-(2-cyanoethyl)-L-cysteine (2-CyEMA) | Concentrations measured in urine, adjusted for creatinine, at Day 5. Geometric Least Squares means are provided as point estimates of reduction for biomarkers of exposure (BoExp) in smokers switching from CIG to various THS versions (THS Blade device; THS Induction Mono device; THS Induction Mid device) compared to continuing CIG smoking for 5 days. | 5 days | 
| Concentration of Monohydroxybutenyl mercapturic acid (MHBMA) | Concentrations measured in urine, adjusted for creatinine, at Day 5. Geometric Least Squares means are provided as point estimates of reduction for biomarkers of exposure (BoExp) in smokers switching from CIG to various THS versions (THS Blade device; THS Induction Mono device; THS Induction Mid device) compared to continuing CIG smoking for 5 days. | 5 days | 
| Concentration of Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (total NNAL) | Concentrations measured in urine, adjusted for creatinine, at Day 5. Geometric Least Squares means are provided as point estimates of reduction for biomarkers of exposure (BoExp) in smokers switching from CIG to various THS versions (THS Blade device; THS Induction Mono device; THS Induction Mid device) compared to continuing CIG smoking for 5 days. | 5 days | 
| Levels of Carboxyhemoglobin (COHb) | Carboxyhemoglobin (COHb) is assayed from whole blood. Expressed as % of saturation of hemoglobin. Blood measurements performed in the evening of Day 5. Geometric Least Squares means are provided as point estimates of reduction for biomarkers of exposure (BoExp) in smokers switching from CIG to various THS versions (THS Blade device; THS Induction Mono device; THS Induction Mid device) compared to continuing CIG smoking for 5 days. | 5 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Exposure Response, Smoking, Tobacco Heating System, Heated Tobacco