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

• ClinicalTrials.gov Identifier: NCT05385055
• Recruitment Status: Recruiting
• First Posted: May 23, 2022
• Last Update Posted: December 14, 2022
• Sponsor: Philip Morris Products S.A.
• Information provided by (Responsible Party): Philip Morris Products S.A.

Study Description

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, to demonstrate beneficial effects of switching from cigarettes to THS.

Condition or disease	Intervention/treatment	Phase
Inflammation; Oxidative Stress; Smoking; Smoking Abstinence	Other: THS use; Other: Cigarette smoking; Other: Smoking abstinence	Not Applicable

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 960 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Masking Description: Subjects and Investigators will be unblinded to the subject's group. However, there will be a limited degree of blinding in the data review and data analysis process. In particular, sponsor and contract research organization (CRO) personnel will be blinded to the endpoints tested in the primary objective.
• Primary Purpose: Other
• Official Title: 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
• Actual Study Start Date: June 13, 2022
• Estimated Primary Completion Date: October 2023
• Estimated Study Completion Date: February 2024

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Cigarette; Current cigarette smokers	Other: Cigarette smoking; Subjects (current cigarette smokers) will continue smoking cigarettes in real-life setting
Active Comparator: THS; THS users with a minimum of 2 years of THS use	Other: THS use; Subjects (current THS users) will continue using THS in real-life setting
Active Comparator: SA; Former cigarette smokers with minimum of 2 years of smoking abstinence	Other: Smoking abstinence; Subjects (former cigarette smokers) will continue smoking abstinence (confirmed by cotinine test, with a threshold of < 100 ng/mL)

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. High-Density Lipoprotein Cholesterol (HDL-C) [ Time Frame: Measured when subject visits study site on day 1. ]
   Concentrations (mg/dL) measured in serum. Mean values are provided as descriptive statistics.
2. soluble Intercellular Adhesion Molecule-1 (sICAM-1) [ Time Frame: Measured when subject visits study site on day 1. ]
   Concentrations (ng/mL) measured in serum. Geometric Mean values are provided as descriptive statistics.
3. 11-dehydrothromboxane B2 (11-DTX-B2) [ Time Frame: Measured when subject visits study site on day 1. ]
   Concentrations measured in urine and expressed as concentration adjusted for creatinine (pg/mg creat). Geometric Mean values are provided as descriptive statistics.
4. Augmentation Index (AIx) [ Time Frame: 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.
5. Forced Expiratory Volume in 1 second (FEV1) %predicted, post-bronchodilator (post-BD) [ Time Frame: Measured when subject visits study site on day 1. ]
   FEV1 post-bronchodilator and expressed as percentage predicted (FEV1 %pred). Mean values are provided as descriptive statistics.

Eligibility Criteria

• Ages Eligible for Study: 30 Years to 60 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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.

Contacts and Locations

Contacts

Contact: Christelle Haziza, PhD; +41 58 242 11 11; Christelle.Haziza@pmi.com

Contact: S. Michael Ansari; +41 58 242 11 11

Locations

Czechia

Clintrial s.r.o.; Recruiting

Praha, Czechia

Contact r.gregar@clintrial.cz

Principal Investigator: Roman Gregar, MD

Vestra Clinics s.r.o.; Recruiting

Rychnov nad Kněžnou, Czechia

Contact pazdera@vestraclinics.org

Principal Investigator: Ladislav Pazdera, MD

Germany

emovis GmbH; Recruiting

Berlin, Germany

Contact Luci.Magimaiseelan@emovis.de

Principal Investigator: Luci Magimaiseelan, MD

Sibamed GmbH & Co.KG; Recruiting

Leipzig, Germany

Contact helena@sigal-sms.de

Principal Investigator: Helena Sigal, MD

Centrum für Diagnostik und Gesundheit, Klinische Forschung und Entwicklung; Recruiting

München, Germany

Contact manfred.hartard@sigal-sms.de

Principal Investigator: Manfred Hartard, MD

Praxis Reinfeld Mitte; Recruiting

Reinfeld, Germany

Contact joachim.weimer@sigal-sms.de

Principal Investigator: Joachim Weimer, MD

Hautarzt Stuttgart - Hautarztpraxis Leitz & Kollegen; Recruiting

Stuttgart, Germany

Contact Nicolas.leitz@sigal-sms.de

Principal Investigator: Nicolas Leitz, MD

Greece

National and Kapodistrian University of Athens, Medical school, Attikon Hospital, 2nd Cardiology Department; Recruiting

Athens, Greece

Principal Investigator: John Parissis, MD

Japan

Hakata Clinic; Recruiting

Fukuoka, Japan

Contact Takashi-eto@lta-med.com

Principal Investigator: Takashi Etou, MD

Nishikumamoto Hospital; Recruiting

Minami, Japan

Contact takanori-tanaka@lta-med.com

Principal Investigator: Takanori Tanaka, MD

Sumida Hospital; Recruiting

Tokyo, Japan

Contact takuma-yonemura@lta-med.com

Principal Investigator: Takuma Yonemura, MD

Sponsors and Collaborators

Philip Morris Products S.A.

Investigators

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

More Information

• Responsible Party: Philip Morris Products S.A.
• ClinicalTrials.gov Identifier: NCT05385055
• Other Study ID Numbers: P1-RMC-03-INT
• First Posted: May 23, 2022
• Last Update Posted: December 14, 2022
• Last Verified: July 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Inflammation; Pathologic Processes