The Abuse Liability of a Novel Heated Tobacco Product (IQOS) and Its Feasibility as a Menthol Cigarette Substitute

Study Overview
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Brief Summary
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This project examines the influence of flavor availability on switching to an MRTP known as IQOS, part of the Heated Tobacco Product (HTP) class, among menthol smokers using clinical lab and naturalistic evaluations of abuse liability. Results will help federal regulators predict the public health impact on menthol cigarette smokers of policies restricting access to menthol-flavored HTPs.

Detailed Description
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The public health success of FDA's proposed ban on menthol cigarettes hinges upon whether menthol smokers who are unable to quit smoking switch to non-menthol cigarettes (no public health gain) or to potentially lower harm alternatives like heated tobacco products (HTP). In 2019, FDA authorized an HTP called IQOS and its tobacco- and menthol-flavored HeatSticks (HS) as a modified risk tobacco product (MRTP). One issue relevant to FDA's future action regarding IQOS will be whether and how certain flavors may help adult cigarette smokers reduce cigarette use and switch to potentially less harmful products (FDA, 2018). Understanding the potential for HTPs like IQOS to reduce the health burden of cigarettes requires targeted research investigating the extent to which flavor availability is important for menthol smokers to switch to HTPs. For one tobacco product to substitute for another, their abuse liabilities should be congruent. Validated clinical lab methods exist for comparing tobacco product abuse liability by characterizing their nicotine delivery profiles (via plasma nicotine and puff topography) and reinforcing efficacy (via subjective and behavioral measures). Naturalistic assessment can validate clinical lab results regarding use patterns and product substitution. The current study involves a two-arm, two-week, parallel group trial. The first week is an own brand (OB) menthol cigarette baseline, during which tobacco use will be assessed daily using ecological momentary assessment (EMA). On Monday and Friday, participants will complete clinical lab sessions that involve using OB cigarettes and responding to subjective measures and an Experimental Tobacco Marketplace (ETM) task that assesses willingness to substitute menthol cigarettes with an array of tobacco products including IQOS. During the next week, participants will be randomized to receive IQOS-menthol (n=25) or IQOS-tobacco (n=25); EMA and clinical lab visits will be repeated. Aim 1 assesses IQOS' abuse liability in a clinical lab setting. Outcomes include plasma nicotine levels, puffing behavior, responses about subjective effects, and product substitution from the ETM task. Aim 2 measures tobacco use patterns in naturalistic settings where participants will report daily OB and IQOS use outcomes via EMA. The overarching hypothesis is that, relative to OB, IQOS-menthol's abuse liability profile will differ less than IQOS-tobacco's, suggesting that menthol smokers will be more likely to substitute an HTP for combustible menthol cigarettes when a menthol-flavored HTP is available. Results will deepen our understanding of the public health impact of HTPs and policies that might restrict access to menthol-flavored MRTPs.

Official Title
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Effects of Heated Tobacco Product Flavor on Tobacco Use Behavior and Abuse Liability Among Menthol Cigarette Smokers

Conditions
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Tobacco Use

Intervention / Treatment
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* Device: Tobacco product administration and assessment


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy adults (aged 21 and older) Daily menthol cigarette smokers Exhaled Carbon Monoxide (CO) reading of > 5 PPM at in-person screening (to confirm smoking status) A 'positive' cotinine cassette result to verify nicotine use at the in-person screening. Participants must be willing to provide informed consent and abstain from nicotine/tobacco for ≥8 hours prior to each lab session. Participants must have access to a computer/smartphone and be willing to receive and respond to daily surveys Able to read and write in English Exclusion Criteria: Daily use of any tobacco products other than cigarettes Self-reported history of chronic medical or psychiatric conditions Women will be excluded if they test positive for pregnancy (by urinalysis) or self-report breastfeeding. Some details of the study inclusion and exclusion criteria are omitted at this time, to preserve scientific integrity. Full inclusion and exclusion criteria will be posted following study completion.

Ages Eligible for Study
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Minimum Age: 21 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Tobacco-Flavored IQOS<br>Tobacco - where menthol smokers will only have access to tobacco-flavored HeatSticks to use in the IQOS 2.4 Tobacco Heating System | Device: Tobacco product administration and assessment<br>* Participants are first instructed to smoke their usual brand of menthol cigarettes normally for the next 7 days and avoid using any other tobacco products. After this baseline week, participants are randomized to 1 of 2 HTP flavor conditions (tobacco-flavored HeatSticks or Fresh Menthol-flavored HeatSticks), with equal probability and provided with a supply of their condition specific HTP and asked to use it in place of their usual menthol cigarettes for the next week. Participants use their own brand menthol cigarettes and assigned HTP both at home (naturalistic use) and in the clinical laboratory (two visits/week).<br>|
| Experimental: Menthol-Flavored IQOS<br>Menthol - where menthol smokers will only have access to menthol-flavored HeatSticks to use in the IQOS 2.4 Tobacco Heating System | Device: Tobacco product administration and assessment<br>* Participants are first instructed to smoke their usual brand of menthol cigarettes normally for the next 7 days and avoid using any other tobacco products. After this baseline week, participants are randomized to 1 of 2 HTP flavor conditions (tobacco-flavored HeatSticks or Fresh Menthol-flavored HeatSticks), with equal probability and provided with a supply of their condition specific HTP and asked to use it in place of their usual menthol cigarettes for the next week. Participants use their own brand menthol cigarettes and assigned HTP both at home (naturalistic use) and in the clinical laboratory (two visits/week).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Average Daily Cigarette Use | Number of cigarettes consumed per day, collected via daily text/email survey, averaged over consumption for Tues-Thurs of each week. Outcome will compare the change in cigarette consumption from the baseline week (OB menthol cigarette use) to the intervention week (IQOS use) between the two study arms. | Week 1 (baseline) to Week 2 (intervention) | 
| Willingness to Substitute from Cigarettes to HTPs | Participants will complete the Experimental Tobacco Marketplace Task - which asks participants to allocate a hypothetical budget across a large menu of products. Reported demand for tobacco products is used to determine substitution between IQOS and cigarettes. Purchasing decisions are not reinforced. Outcome will compare the cross-price elasticity (CPE) of IQOS with respect to menthol cigarettes among those with access to IQOS-menthol and IQOS-Tobacco (IQOS-M group) compared to those with access to IQOS-tobacco only (IQOS-T group). | Week 2, Friday Clinical Lab visit | 
| Plasma Nicotine Delivery | Change in the plasma nicotine levels from before to after a standardized 10-puff (30-sec interpuff interval) bout with IQOS in the participant's assigned flavor. Outcome will compare the average plasma nicotine boost (the change in plasma nicotine levels from before to after the standardized puffing bout) across two study arms as well as compared to own-brand menthol cigarettes. | Week 2, Friday Clinical Lab visit (10 puff bout period) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cigarette Craving Suppression | We will compare the degree of cigarette craving will be assessed before and after a 10-puff use bout of IQOS. Cigarette craving will be assessed before and after a standardized puffing bout using the Questionnaire of Smoking Urges (QSU), which features 7-point likert-like scales. The reduction in urges to smoke item from the QSU will be used in this assessment. The average cigarette craving suppression score will be compared across the two experimental IQOS groups. | Week 2, Friday Clinical Lab Visit (10 puff bout period) | 
| Puff Topography (Puff Duration) | Average duration per puff during a standardized 10-puff (30-sec interpuff interval) bout with IQOS in assigned flavor. Puff duration will be measured using a validated puff topography instrument that attaches to the IQOS device. Outcome will compare the average puff duration across two study arms. | Week 2, Friday Clinical Lab visit (10 puff bout period) | 
| Plasma Menthol Delivery | Change in the plasma menthol-glucuronide levels from before to after a standardized 10-puff (30-sec interpuff interval) bout with IQOS in the participant's assigned flavor. Outcome will compare the average plasma menthol-glucuronide boost (the change in plasma menthol-glucuronide levels from before to after the standardized puffing bout) across two study arms as well as compared to own-brand menthol cigarettes. | Week 2, Friday Clinical Lab visit (10 puff bout period) | 
| Average daily IQOS Usage | Number of IQOS HeatSticks used each day will be assessed during the study. We will compare the number of Heatsticks used per day, on average (from Tues-Thurs of intervention week), between the two study arms. | Week 2 (intervention week), Tuesday-Thursday | 
| Percentage of total tobacco consumption that is IQOS | The number of IQOS HeatSticks used per day on average, divided by the sum of the number of cigarettes and IQOS HeatSicks consumed per day on average (intervention week, Tues-Thurs). This outcome will compare the percentage of total tobacco consumption (IQOS HeatSticks + Cigarettes) that is from use of IQOS between the two study arms. | Week 2 (intervention week), Tuesday-Thursday | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Heated Tobacco Products, Flavor, Abuse Liability, Tobacco, Cigarettes, Menthol, Experimental Tobacco Marketplace, Nicotine Delivery, Puff Topography, Ecological Momentary Assessment, Modified Risk Tobacco Product, IQOS, Heated Tobacco Products Flavors