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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Smoking; Inflammation; Oxidative Stress; Smoking Abstinence
• Intervention / Treatment: Other: Cigarette smoking; Other: THS use; Other: Smoking abstinence

Detailed Description

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).

• Study Type: Observational
• Enrollment (Actual): 952
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Christelle Haziza, PhD; Phone Number: +41 58 242 11 11; Email: Christelle.Haziza@pmi.com
• Study Contact Backup: Name: S. Michael Ansari; Phone Number: +41 58 242 11 11

Study Locations

• Czechia
  • Praha, Czechia
    • Clintrial s.r.o.
  • Rychnov nad Kněžnou, Czechia
    • Vestra Clinics s.r.o.
• Germany
  • Berlin, Germany
    • emovis GmbH
  • Leipzig, Germany
    • Sibamed GmbH & Co.KG
  • München, Germany
    • Centrum für Diagnostik und Gesundheit, Klinische Forschung und Entwicklung
  • Reinfeld, Germany
    • Praxis Reinfeld Mitte
  • Stuttgart, Germany
    • Hautarzt Stuttgart - Hautarztpraxis Leitz & Kollegen
• Greece
  • Athens, Greece
    • National and Kapodistrian University of Athens, Medical school, Attikon Hospital, 2nd Cardiology Department
• Japan
  • Fukuoka, Japan
    • Hakata Clinic
  • Minami, Japan
    • Nishikumamoto Hospital
  • Tokyo, Japan
    • Sumida Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 28 years to 58 years (Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

The study population was recruited through social media and traditional display advertising. The subjects included current cigarette smokers, current THS users (with a minimum of 2 years THS use), and former cigarette smokers (with a minimum of 2 years of smoking abstinence).

Description

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.

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Cigarette; Current cigarette smokers	Other: Cigarette smoking; N/A: No intervention was assigned.
THS; THS users with a minimum of 2 years of THS use	Other: THS use; N/A: No intervention was assigned.
SA; Former cigarette smokers with minimum of 2 years of smoking abstinence	Other: Smoking abstinence; N/A: No intervention was assigned.

What is the study measuring?

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
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.
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.
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.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Neutrophil to Lymphocyte Ratio (NLR)	Calculated by dividing the number of neutrophils by number of lymphocytes from serum.	Measured when subject visits study site on day 1.
High-sensitivity C-Reactive Protein (hs-CRP)	Concentrations of hs-CRP (mg/dL) measured in serum.	Measured when subject visits study site on day 1.
Homocysteine (HCY)	Concentrations of HCY (μmol/L) measured in plasma.	Measured when subject visits study site on day 1.
Myeloperoxidase (MPO)	Concentrations of MPO (μg/L) measured in serum.	Measured when subject visits study site on day 1.
Triglycerides (TG)	Concentrations of TG (mg/dL) measured in blood.	Measured when subject visits study site on day 1.
Fibrinogen	Concentrations of Fibrinogen (mg/dL) measured in serum.	Measured when subject visits study site on day 1.
Glycated Hemoglobin (HbA1c)	HbA1c measured in whole blood (%).	Measured when subject visits study site on day 1.
Forced Expiratory Volume in 1 second/Forced Vital Capacity (FEV1/FVC) ratio	Measured with and without bronchodilator, absolute and % predicted values, where applicable.	Measured when subject visits study site on day 1.
Nicotine Equivalents (NEQ) in urine (expressed as concentration adjusted to creatinine)	NEQ measured in urine and expressed as concentration adjusted for creatinine.	Measured when subject visits study site on day 1.
2-Cyanoethyl Mercapturic Acid N-Acetyl-S-(2-cyanoethyl)-L-cysteine (2CyEMA)	2CyEMA measured in urine and expressed as concentration adjusted to creatinine.	Measured when subject visits study site on day 1.

Collaborators and Investigators

• Sponsor: Philip Morris Products S.A.
• Investigators: Study Chair: Christelle Haziza, PhD, Philip Morris Products S.A.

Study record dates

Study Major Dates

• Study Start (Actual): June 13, 2022
• Primary Completion (Actual): December 27, 2023
• Study Completion (Estimated): April 15, 2024

Study Registration Dates

• First Submitted: May 17, 2022
• First Submitted That Met QC Criteria: May 17, 2022
• First Posted (Actual): May 23, 2022

Study Record Updates

• Last Update Posted (Estimated): January 23, 2024
• Last Update Submitted That Met QC Criteria: January 22, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Inflammation
• Other Study ID Numbers: P1-RMC-03-INT

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No