Heated Tobacco Products vs Electronic Cigarettes

Study Overview
=================
Brief Summary
-----------------
This is a 12-weeks, open label, non-inferiority trial comparing HTPs vs ECs in terms of efficacy, adoption rate and acceptability, tolerability, and tobacco harm reduction in 220 healthy smokers, not motivated to quit, randomized (1:1) to switch to one of these products. The duration of the study, from the enrollment to the study close out for all the patients at week 24 (follow-up), will be approximately 12 months. Enrollment period will last about 6 months with the support of a multi-channel advertising method. This will include location-based advertising on social networks, advertising in local media, information days organized within the city.

Detailed Description
-----------------
Before the baseline visit, a face to face screening (V0) for pre-eligibility checks will be conducted. Subjects will be asked to practice with the step test for 10-15 minand will be instructed how to collect and store their morning urine before bringing it to the hospital on their Baseline visit (V1). This study will consist of a baseline visit (V1) and 6 follow-up study visits (V2-V7). At baseline (V1), participants will be randomized in two separate study groups. The randomization sequence will be computer generated by using blocks size of 5, with an allocation ratio of 1:1 for each of the study products (IQOS, JustFog-EC). Subjects will use and familiarize with their allocated product, as per randomization. They will be trained and counseled on the use of their allocated study product; oral explanation and practical demonstration will be followed by product trial during which participants will also have the option to try and choose their preferred flavour (either from a selection of 3 e-liquids or 3 tobacco sticks, depending on the allocated arm). Participants randomized in the IQOS arm will receive one iQOS kit and a full 1 week supply of tobacco sticks of their choice (they will receive a number of tobacco sticks/day corresponding to the number of cigarettes smoked at baseline); those randomized in the JustFog-EC arm of the study will receive one JustFog Starter Kit and a full 1 week supply of e-liquids of their choice (they will receive 4, 10 mls refill containers).Free products will be supplied at each subsequent visit throughout the study. No supply of tobacco stick or e-liquid will be given at week-12, but users will be offered to keep using their products to minimize the risk of relapsing back to cigarette smoking. A prospective evaluation of cigarette consumption, adoption rates, acceptability and tolerability will be recorded throughout the study. Visit 2 (V2):This will be scheduled 1 week after V1 (with a tolerance of +/- 3 days). Cigarette/day, eCO, AEs, BP, HR will be measured and product use recorded. Full 1 week supply of the chosen product will be provided. Visit 3 (V3):This will be scheduled 2 weeks after V1 (with a tolerance of +/- 3 days). Cigarette/day, eCO, AEs, BP, HR will be measured and product use recorded. Participants will be instructed on how to collect and store their second urine sample before bringing it to the hospital at V4. Full 2 weeks supply of the chosen product will be provided. Visit 4 (V4):This will be scheduled 4 weeks after V1 (with a tolerance of +/- 3 days). Cigarette/day, eCO, AEs, BP, HR will be measured, questionnaires completed and product use recorded. Step test will be carried out. Second urine sample will be collected, aliquotted and stored. Full 4 weeks supply of the chosen product will be provided. Visit 5 (V5):This will be scheduled 8 weeks after V1 (with a tolerance of +/- 7 days). Cigarette/day, eCO, AEs, BP, HR will be measured, questionnaires completed and product use recorded. Full 4 weeks supply of the chosen product will be provided. Visit 6 (V6):This will be scheduled 12 weeks after V1 (with a tolerance of +/- 7 days). Cigarette/day, eCO, AEs, BP, HR, weight, height will be measured, questionnaires completed and product use recorded. Step test will be carried out. No more products will be dispensed. Follow-up Visit (V7):This final visit will be scheduled 24 weeks after V1 (with a tolerance of +/- 7 days)to review product usage and smoking behavior under naturalistic condition of use. Cigarette/day, eCO, AEs, BP, HR, weight, height will be measured, questionnaires completed and product use recorded. Step test will be carried out. Data will be recorded from every subject on an electronic CRF, provided by a CRO, GCP compliant, 21 CFR Part 11 FDA compliant, listed in AIFA list of operating CRO. Urine samples will be collected at baseline and wk 4, and sent to an external laboratory for analytical assessment of selected Biomarkers of Exposure (BoE). The study will be conducted at the University of Catania, Catania, Italy. Participants Healthy smokers, not motivated to quit, will be randomized in two intervention groups in a 1:1 ratio to compare HTPs vs ECs in terms of reductions in cigarette consumption, adoption rate and acceptability, tolerability, and tobacco harm reduction. Sample size determination (better detailed below, in the relevant section) for no-inferiority testing is based on the assumptions that 1) expected quit rates based on most recent EC literature is about 20-25% and 2) that differences in quit rates between products under investigation should not exceed 10-15% (as per non-inferiority definition). According to these hypotheses the required number of participants per study arm is 104. Hence investigators intend to include 220 participants, 110 per group. Study Products Tested Heated Tobacco Product (HTP):Investigators will use a HTP that does not involve combustion, generating a nicotine-containing aerosol. At the time of writing, IQOS is the only HTP available on the Italian market. IQOS is composed by: 1) a tobacco stick - a novel patent-pending tobacco product with unique processed tobacco made from tobacco powder; 2) an electronic holder into which the tobacco stick is inserted and which heats the tobacco by means of an electronically controlled heating blade; 3) a charger that is used to recharge the holder after each use. Investigators will use the three types of tobacco sticks specifically designed for IQOS(named HEETS) that are currently for sale in the Italian market: Heets Amber, Heets Yellow, and Heets Turquoise. These products are compliant to the EU Tobacco Product Directive. Electronic Cigarette (EC):JustFog Q16 Starter Kit and three types of e-liquid flavours, Puff Riserva Country 16 mg, Puff Riserva Toscana 16 mg, and Puff Artic 16 mg (2 tobacco-flavours and one menthol flavour), were chosen for the study. Products were selected by an Italian expert panel of 3 e-liquid producers and 3 vaping product distributors, moderated by the editor of a popular e-cigarette blog. Experts convened in Verona (Italy) during a major vaping expo event. Through consensus, the expert panel provided specific recommendation on the device(JustFog Q16 Starter Kit is one of the most popular e-cigarette device in Italy due to its good performance and quality, affordable price, and user friendliness especially for beginners) and the choice of e-liquids that could best match the sensorial experience of the iQOS tobacco sticks to be used in a switching study and minimize the local irritant effects of excessive PG/VG ratio. These products are compliant to the EU Tobacco Product Directive.

Official Title
-----------------
Randomized, Non-Inferiority Trial ComparingCigarette Consumption, Adoption Rates, Acceptability, Tolerability, and Tobacco Harm Reduction Potential in Smokers Switching to Heated Tobacco Products or Electronic Cigarettes: Study Protocol

Conditions
-----------------
Smoking, Cigarette

Intervention / Treatment
-----------------
* Device: IQOS
* Device: E-CIG


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Subjects must meet all of the following inclusion criteria to be eligible for enrolment into the study: Able to comply with the study procedures Male or female healthy smokers aged ≥19 Smoking at least 10 cigarettes a day Smoking for at least one year Not currently attempting to quit smoking or wishing to do so in the next 30 days (this will be verified at screening by the answer ''NO'' to both questions ''Do you intend to quit in the next 30 days?'' and ''Are you interested in taking part in one of our smoking cessation programs?'') Female smokers not planning to become pregnant are using an acceptable form of contraception. Exclusion Criteria: The presence of any of the following will exclude a subject from study enrolment: Use of smokeless tobacco, or any other tobacco products (including e-cigarettes, cigars, chewing tobacco, snus, etc.) within the last 3 months, at baseline and during the whole study. Use of nicotine replacement therapy or other smoking cessation therapies within the last 3 months and at baseline. Self-reported pregnancy, planned pregnancy or breastfeeding. Tobacco industry employees and 1st degree relatives will be excluded in order to safeguard independence of the study -

Ages Eligible for Study
-----------------
Minimum Age: 19 Years
Maximum Age: 70 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: IQOS<br>HEAT NOT BURN REDUCED RISK PRODUCT | Device: IQOS<br>* IQOS USE FOR 12 WEEKS<br>|
| Active Comparator: E-CIG<br>ELECTRONIC CIGARETTE REDUCED RISK PRODUCT | Device: E-CIG<br>* ELECTRONIC CIGARETTE FOR 12 WEEKS<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Smoking Cessation | to compare the efficacy of HTP and EC, in terms of quit rates at week 12, by self-reporting abstinence from classic cigarette [validated by an Exhaled breath Carbon monoxide (eCO) measurement ≤10ppm)] | 12 WEEK | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Smoking Reduction | To compare the smoking reduction derived from the use of HTP and EC, intended as a 50% reduction in the number of conventional cigarette/day at week 12, defined through self-reporting; | Week 12 | 
| Adoption Rate | To compare the adoption rate to product use [by collecting (empty) refill bottles and used heathsticks on a daily basis, verified by a study diary filled daily by the subject]; | Week 12 | 
| Acceptability | To compare the acceptability derived from the use of HTP and EC by the modified Cigarette Evaluation Questionnaire (mCEQ). It is a self-administered questionnaire that contains 12 items covering both reinforcing and aversive effects of smoking. The items are rated on a 7-point scale from 1 not at all to 7 extremely The total mCEQ score range from min 12 to max 84. Higher scores for the total mCEQ reflect a better outcome. There are also the following 5 subscales: Smoking Satisfaction (items 1, 2, 12) range of scores min 3 max 21;higher scores mean a better outcome. Psychological Reward (items 4-8), range of scores min 5 max 35; higher scores mean a better outcome. Aversion (items 9 and 10), range of scores min 2 max 14;higher scores mean a worse outcome. Single item score Enjoyment Respiratory Tract Sensations (item 3) range scores min 1 max 7;higher scores mean a better outcome. Single item score Craving Reduction (item 11), higher scores mean a better outcome | Week 12 | 
| Number of Participants With Product-related Adverse Events | To compare number of participants with adverse events derived from the use of HTP and EC as assessed by CTCAE v4.0 | Week 12 | 
| Changes in Biomarkers of Biological Effects (BoBE) | changes in Biomarkers of Biological Effects (BoBE) such as: eCO in the exhaled breath (i.e. eCO), step test values | Week 12 | 
| Reliability | To compare the reliability of HTP and EC, in terms of incidence and kind of malfunctioning events, through self-reporting. | Baseline visit, Week 12 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
smoking, harm reduction, electronic cigarette, heated tobacco product