Exploratory THS 2.1 Biomarkers of Exposure Study

Study Overview
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Brief Summary
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The goal of this exploratory study is to evaluate the effect of a candidate modified risk tobacco product (MRTP), THS 2.1, on selected biomarkers of exposure to harmful and potentially harmful smoke constituents (HPHCs), compared to conventional cigarettes (CC). The subjective effects (urge to smoke and withdrawal symptoms) which are related to the use of this product will be explored. Initial information on safety and on some biological effects when using THS 2.1 will be collected. Human Smoking Topography (HST) will be explored.

Detailed Description
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This study intends to evaluate the levels of selected biomarkers of exposure to selected HPHC and of cytochrome P450 1A2 (CYP1A2) enzymatic activity, as compared to smokers continuing smoking CC ad libitum, after 5 days of ad libitum use. Additional parameters will be explored, such as: cytochrome P450 2A6 (CYP2A6) enzymatic activity, nicotine pharmacokinetics, product evaluation and safety, marker of platelet function, and HST. After screening, subjects will be admitted to the clinic for 9 days, including the Day of Admission, 2 days of baseline during which all subjects will continue to smoke their usual CC for a 5-day exposure after randomization. After leaving the clinic on the Day of Discharge, the subjects will be followed up for safety over a period of 7 days. All subjects will receive smoking cessation advice at screening, at Day of Admission and at Day of Discharge. This clinical study will be conducted in compliance with International Conference on Harmonisation of technical requirements for registration of pharmaceuticals for human use (ICH Good Clinical Practice), the Declaration of Helsinki as amended in 2008, and the applicable regulatory requirements.

Official Title
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A Single-center, Open-label, Randomized, Controlled, 2-arm Parallel Group Study to Evaluate the Exposure to Selected Smoke Constituents in Smoking, But Otherwise Healthy Subjects Switching From Conventional Cigarettes to the Tobacco Heating System (THS) 2.1

Conditions
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Smoking

Intervention / Treatment
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* Other: Conventional cigarettes (CC)
* Other: THS 2.1


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject has signed an informed consent form before commencement of study procedures Healthy Caucasian aged between 23 to 65 years Subject is a current smoker for at least 3 years (based on self-reporting and biochemically verified), who, for the last 4 weeks, had smoked at least 10 commercially available non-mentholated CC per day, and is not planning to make a quit attempt within the next 3 months Main Exclusion Criteria: As per Investigator judgment, the subject should not participate in the study for any reason (e.g. medical, psychiatric and/or social reason) The subject has a medical condition requiring smoking cessation, or has a clinically relevant disease / condition which could interfere with the study participation and/or study results The subject has participated in a clinical study within 3 months prior to the Screening Visit Pregnant or lactating woman, and for woman of childbearing potential, absence / refusal to use an acceptable method of effective contraception

Ages Eligible for Study
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Minimum Age: 23 Years
Maximum Age: 65 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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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Conventional cigarettes (CC)<br>Smokers are continuing to smoke exclusively their usual own brand of CC, for 5 days, ad libitum, under highly controlled conditions | Other: Conventional cigarettes (CC)<br>* Subjects are randomized in a 1:1 fashion to be assigned either A) continuing CC, or B) switching to THS 2.1<br>|
| Experimental: Tobacco Heating System 2.1 (THS 2.1)<br>Smokers are switching to the exclusive and ad-libitum use of THS 2.1 for 5 days, under highly controlled conditions | Other: THS 2.1<br>* Subjects are randomized in a 1:1 fashion to be assigned either A) continuing CC, or B) switching to THS 2.1<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of carboxyhemoglobin (COHb) levels in blood, and evaluation of excretion of 3-hydroxypropyl mercapturic acid (3-HPMA), monohydroxybutenyl mercapturic acid (MHBMA), and S-phenyl mercapturic acid (S-PMA) in 24-hour urine on switching to THS 2.1 | Biomarkers of exposure to carbon monoxide (CO), acrolein, 1,3-butadiene, and benzene | 5 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Selected secondary biomarkers of exposure to HPHCs | Evaluation of the levels of total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (total NNAL),1-hydroxypyrene , total N-nitrosonornicotine (NNN), 4-aminobiphenyl (4-ABP), 2- aminonaphthalene (2-NA), o-toluidine, nicotine equivalents and 2-cyanoethylmercapturic acid, biomarkers of exposure to the HPHCs 4-(methylnitrosamino)-1- (3-pyridyl)-1-butanone, NNN, 4-ABP, 2-NA, o-toluidine, nicotine and acrylonitrile, respectively, as excreted in urine. | 5 days | 
| CYP1A2 activity and CYP2A6 activity | Evaluation of the CYP1A2 activity, as measured by the plasma caffeine molar metabolic ratio (paraxanthine / caffeine) and in CYP2A6 activity, as measured by nicotine molar metabolic ratio (3-hydroxy-cotinine / cotinine) in plasma and in urine | 5 days | 
| Plasma nicotine | Time course of nicotine plasma concentrations and derived pharmacokinetic parameters | 5 days | 
| 11-dehydro-thromboxane B2 (11-DTX-B2) | To describe the 11-DTX-B2 levels in urine as a marker of platelet function | 5 days | 
| Product use and smoking topography | Monitoring of daily product use and human smoking topography | Up to 5 days | 
| Safety monitoring | Monitoring of adverse events, based on clinical and laboratory evaluation | 8 days + 7 days follow-up | 
| Cough Visual Analog Scale (Cough VAS) | Visual Analog Scale on cough | 7 days | 
| Modified Cigarette Evaluation Questionnaire (MCEQ) | MCEQ measuring subjective effects of smoking | 5 days | 
| Questionnaire on Smoking Urges (brief version) (QSU-brief) | QSU-brief measuring subjective effects of smoking | 5 days | 
| Minnesota Withdrawal Scale-Revised (MNSWS-R) | MNWS-R questionnaire measuring subjective effects of smoking | 5 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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smoking, cigarette, exposure, biomarker, human smoking topography (HST), modified risk tobacco product (MRTP), THS 2.1