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

Study Title: Reduced Exposure to Harmful and Potentially Harmful Constituents (HPHC) in Smokers Switching From Cigarettes to Different Versions of the Tobacco Heating System (THS)

Who carried out the research? This research was sponsored and funded by Philip Morris Products S.A.

What public involvement there was in the study? Ninety-one healthy, currently smoking, adults participated in this study.

Where and when the study took place? The study was conducted at a clinical trial facility managed by a contract research organization in Belfast, Northern Ireland, from November 4th 2022 to February 4th 2023.

Who participated in the study? Ninety-one healthy male or female adults, aged between 21 and 65 years, participated in this study. All participants were currently smoking. The participants did not plan to quit using tobacco and/or nicotine products within the next 3 months and had smoked continuously for at least the last 3 years prior to joining the study.

Each participant was given full and adequate oral and written information about the nature, purpose, possible risks, and benefits of the study. All participants received information on the risks of smoking, smoking cessation advice and a briefing on the Tobacco Heating System, for example, that its use is not risk-free.

Once each participant had received all the necessary information, and if they agreed to participate, this was documented in an Informed Consent Form with the date, time, and signature of both the participant and the study doctor. Participants were informed that they were free to withdraw from the study at any time.

What treatments or interventions did the participants take/receive? Eighty participants were randomly assigned to one of four study arms: THS Blade device, THS Induction Mono device, THS Induction Mid device, or Cigarette, for five days in a confinement setting.

Participants assigned to one of the THS arms or the Cigarette arm could use their assigned product, as often as they wished, from 6:30 AM to 11:00 PM during the five-day confinement period.

Urine was collected from each participant for analysis, for each 24 hours, from Day -1 (the start of the confinement period) to Day 5 (until discharge at the morning of Day 6).

Participants were also asked to evaluate their experience of using their assigned products, using a product experience questionnaire. The questionnaire assessed the perceived effects experienced by Cigarette smokers switching to the THS Blade device, THS Induction Mono device, or THS Induction Mid device compared to the experience of subjects continuing Cigarette smoking.

What happened during the study? A presentation of THS (without product use) was made to the participants during the Screening visit. All participants received information on the risks of smoking, smoking cessation advice, and a briefing that the use of THS is not risk-free. Eligible participants, fulfilling all criteria for participation, returned to the investigational site for confirmation of eligibility at the Admission visit (Day -2).

On Day -2 (Admission), after eligibility criteria had been verified, subjects had a product test of the THS Blade device and Induction Mono device (with use of up to three THS tobacco sticks per device). All eligible participants were then enrolled and participants willing to continue their participation in the study started their confinement period of seven days.

On Day -1, participants were randomly assigned to one of four arms: THS Blade device, THS Induction Mono device, THS Induction Mid device, or Cigarette. Participants were informed about their randomization arm by the study site staff on Day 1 prior to the start of product use.

The Exposure period in confinement began on Day 1 and consisted of 5 days of at will use of the assigned product in the THS and Cigarette arms. Use of any tobacco/nicotine containing product other than the assigned product was not allowed.

Daily 24-hour urine was collected from Day -1 to Day 5 for HPHC analysis. On Day 1, use of THS or Cigarette smoking in the respective arms was not supposed to start before the end of 24-hour urine collection of Day -1. The 24-hour urine collection period for Day 5 ended in the morning of Day 6 prior to Discharge.

On Day -1 and on Days 1 to 5, participants completed questionnaires to assess the perceived effects experienced after switching to THS, compared to the experience of participants who continued Cigarette smoking.

During the confinement period, adherence to investigational product arm allocation (exclusive use of the assigned THS devices with designated sticks, or Cigarette smoking, respectively) was ensured by strict distribution of the devices, and of each stick/cigarette upon demand of the subject to the study site staff.

Any participant who wanted to attempt to quit using any tobacco or nicotine-containing product at any time during the study (that is, to quit THS use or Cigarette smoking) was encouraged to do so and was to be referred to appropriate medical services. This decision would not affect the participant's financial compensation, and the participant was to be considered as remaining in the study.

The Exposure period to the assigned investigational product (THS or Cigarette) ended at 11:00 PM on Day 5, followed by Discharge on Day 6 after completion of all study procedures. Participants were allowed to smoke Cigarettes or use other tobacco or nicotine-containing products, at their discretion, only after discharge from the study.

After discharge at Day 6 or from the day of an early termination, subjects entered a 3-day Safety follow-up period during which any adverse reactions reported by the participants were collected. The follow-up of adverse reactions ongoing at discharge was conducted by the investigational site.

• THS Blade device (Other), also known as IQOS (THS blade device), HEETS (blade heated tobacco sticks): Tobacco Heating System (THS) device with Blade technology for Blade tobacco stick use
• THS Induction Mono device (Other), also known as IQOS Iluma One (THS induction device), TEREA (induction heated tobacco sticks): Tobacco Heating System (THS) device with Induction technology (combined Charger-Holder device for Induction tobacco stick use).
• THS Induction Mid device (Other), also known as IQOS Iluma (THS induction device), TEREA (induction heated tobacco sticks): Tobacco Heating System (THS) device with Induction technology (device with Induction stick Holder for Induction tobacco stick use and separate Charger).
• CIG (Other), also known as Cigarette (non-mentholated): Subject's preferred brand of commercially available regular (non-mentholated) cigarettes. (Cigarettes are not provided by the study sponsor.)

Primary outcomes

• Concentration of 3-hydroxypropylmercapturic Acid (3-HPMA) [5 days]: Concentrations measured in urine, adjusted for creatinine, at Day 5. Geometric Least Squares means are provided 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.
• Concentration of 2-cyanoethyl Mercapturic Acid N-acetyl-S-(2-cyanoethyl)-L-cysteine (2-CyEMA) [5 days]: Concentrations measured in urine, adjusted for creatinine, at Day 5. Geometric Least Squares means are provided 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.
• Concentration of Monohydroxybutenyl Mercapturic Acid (MHBMA) [5 days]: Concentrations measured in urine, adjusted for creatinine, at Day 5. Geometric Least Squares means are provided 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.
• Concentration of Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL) [5 days]: Concentrations measured in urine, adjusted for creatinine, at Day 5. Geometric Least Squares means are provided 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.
• Levels of Carboxyhemoglobin (COHb) [5 days]: 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 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.

Sex: All, ages: 21 Years to 65 Years, accepts healthy volunteers

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.

Participant flow

Outcome results

• Concentration of 3-hydroxypropylmercapturic Acid (3-HPMA) (Primary), Geometric mean, ng/mg creatinine: Cigarette 786.07 (605.60 to 1020.32); THS Blade Device 674.08 (478.57 to 949.46); THS Induction Mono Device 781.63 (611.65 to 998.85); THS Induction Mid Device 765.28 (579.16 to 1011.21)
• Concentration of 2-cyanoethyl Mercapturic Acid N-acetyl-S-(2-cyanoethyl)-L-cysteine (2-CyEMA) (Primary), Geometric mean, ng/mg creatinine: Cigarette 96.01 (67.06 to 137.46); THS Blade Device 85.66 (57.14 to 128.42); THS Induction Mono Device 107.33 (84.22 to 136.77); THS Induction Mid Device 104.62 (79.50 to 137.68)
• Concentration of Monohydroxybutenyl Mercapturic Acid (MHBMA) (Primary), Geometric mean, ng/mg creatinine: Cigarette 2.08 (1.38 to 3.14); THS Blade Device 2.09 (1.39 to 3.12); THS Induction Mono Device 1.37 (0.77 to 2.43); THS Induction Mid Device 2.64 (1.92 to 3.63)
• Concentration of Total 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (Total NNAL) (Primary), Geometric mean, pg/mg creatinine: Cigarette 115.30 (83.91 to 158.43); THS Blade Device 101.92 (57.26 to 181.43); THS Induction Mono Device 135.02 (96.24 to 189.43); THS Induction Mid Device 150.11 (117.61 to 191.60)
• Levels of Carboxyhemoglobin (COHb) (Primary), Geometric mean, % in blood: Cigarette 5.26 (4.6 to 6.0); THS Blade Device 4.79 (4.0 to 5.8); THS Induction Mono Device 5.17 (4.6 to 5.8); THS Induction Mid Device 5.26 (4.6 to 6.0)

Adverse events

Time frame: Adverse events were collected from the signature of the ICF by each subject until the end of the safety follow-up period, a total duration for each subject of up to 39 days.

Other adverse events by term

• Study Protocol (PDF, 2022-07-15)
• Statistical Analysis Plan (PDF, 2022-10-31)

• Devinda Weeraratne, MD, Principal investigator, Celerion