Changes in Oral Health in Tobacco Cigarettes Smokers After Switching to Combustion-Free Nicotine Delivery Systems

SMILE is an international, open label, randomized, controlled study of 18 months duration designed to assess whether cigarette smokers switching to combustion free-nicotine delivery systems (C-F NDS) will undergo measurable improvements in oral health parameters and teeth appearance as a consequence of avoiding exposure to cigarette smoke. Five countries have so far agreed to participate: Italy, Moldova, Poland, UK and Indonesia. An amendment will be submitted to the REC once the final two countries are signed up.

A volunteer population of never-smokers and regular smokers of conventional cigarettes with a clinical absence of signs of periodontitis will be recruited. Regular cigarette smokers will be randomized 1:4 ratio either continuing to smoke commercially manufactured conventional cigarettes (Study Arm A) or switching to C-F NDS (Study Arm B). Never Smokers will be assigned to Arm C.The intended minimum number of participants by the end of the study is 460.

Before randomization, all smokers will be reminded of the risks associated with smoking and will be offered a free smoking cessation program according to standard local guidelines and depending on the local availability of antismoking services. Those who decline the invitation will be eligible for recruitment into the study.

Smokers are free to voluntarily quit smoking/C-F NDS and/or withdraw from the study at any time.

Duration:

All participants will attend a total of seven clinics visits: Day -28 to Day -1 - Screening; Day 0 - Enrollment and Randomization (Visit 0); Day 14 (+/-3 days) - Baseline Visit (Visit 1); Day 90 (+/-5 days) - Visit 2; Day 180 (+/-7 days) - Visit 3; Day 360 (+/-10 days) - Visit 4; Day 540 (+/-10 days) - Visit 5.

Each participant will undergo screening within 28 days prior to Visit 0. Eligible participants will be enrolled and randomized on Visit 0. Baseline assessments will be performed at Visit 1, 14 days after Visit 0. The overall duration of study participation for each participant will be a maximum of 568 +/- 10 days.

The randomization sequence will be computer generated, with an allocation ratio of 1:4 (Study Arm A : Study Arm B; Smokers : N-C NDS users) to compensate for an estimated 25% success rate (combined smoking abstinence rate + >90% smoking reduction rate) in the long term. The randomization scheme will be provided to clinical sites via a web-based application set up by the CRO. The staff randomizing the participant will access the web-based application when the participant is with them, entering their participant identification number, date of birth and initials into the program. The allocation will be immediately provided by the program/software.

Product use Regular smokers will continue to smoke their usual brand of conventional cigarette until Baseline on Visit 1. After Visit 1, participants on both Arms A and B will be asked to use only their assigned products ad libitum for the whole duration of the study.

Participants in Arm A will continue smoking their own conventional cigarette brand, as usual.

Participants in Arm B will have the option to try and choose among a selection of either three e-liquids or three tobacco sticks (depending on the C-F NDS they have chosen). They will also be trained and instructed on how to correctly use their chosen C-F NDS. Participants wishing to use a heated tobacco device (HTD) will receive the number of tobacco sticks per day corresponding to the number of cigarettes smoked per day at baseline. Participants wishing to use a vaping product will receive one vaping kit and supply of e-liquids of their choice enough to provide consumption in between supply visits (see Table 2); on average they will receive 4 x 10 ml refill containers per week. Free products will be supplied at each subsequent visit throughout the whole duration of the study.

Participants in Arm C will continue to not smoking or use any form of tobacco or nicotine-containing products.

A prospective monitoring of cigarette consumption, C-F NDS use, and oral hygiene routine will be carried out throughout the study with the tracker APP. Moreover, participants in Arm B will be asked to return all empty, part-used, and unused consumables (tobacco sticks, e-cigarette cartridges, e-liquid refill bottles) at each study visit.

Justification for Study Design

Participants in this study will be a minimum of 18 years of age. This is based on:

• The legal age to obtain tobacco products is 18 years
• The presence of at least 10 natural anterior permanent teeth in total (cuspid to cuspid, lower and upper jaw).

To investigate the effects of abstaining from smoking by switching in smokers with clinical absence of periodontitis, a population of both smokers who are intending to make the switch to N-C NDS and never-smokers will be recruited. By the end of the study, it is estimated that a high proportion (approx. 75%) of patients randomized in the Arm B of the study will not be able to achieve success (defined as either complete smoking abstinence or as at least 90% smoking reduction). To account for this, the C-F NDS population will be over sampled and a 1:4 randomization ratio scheme (i.e. for every patient randomized in the continue-to-smoke population, four will be randomized in the C-F NDS population) will be adopted.

It will not be possible to blind participants to the intervention they will be receiving. It will not be possible to blind trial staff when providing the interventions and collecting data. However, data analyses will be conducted blind to Study Arms allocation. All other trial staff who have access to outcome data will remain blinded until prespecified data analyses will be completed.

Inclusion criteria

• Demonstrate understanding of the study and willingness to participate in the study by providing a signed written informed consent
• Healthy subjects, not taking regular medications for chronic medical conditions
• Adults, age at least 18 years old.
• Presence of at least 10 natural anterior teeth in total (cuspid to cuspid, lower and upper jaw).
• Presence of at least 18 'scorable' teeth with scorable facial and lingual surfaces. Teeth that are grossly carious, orthodontically banded, exhibiting general cervical abrasion and/or enamel abrasion, and third molars will not be included in the tooth count;
• Willingness and ability to comply with the requirements of the study including installing an APP on their digital device, e.g. smart phone or tablet.

For Arms A and B, subject have to be:

• Regular smokers, defined as:

• Smoked for at least five consecutive years prior to Screening.
• Smoked >10 and < 30 cigarettes per day (CPD).
• with an exhaled breath carbon monoxide (CO) level ≥7 ppm at Screening.
• willing to regularly use of any nicotine or tobacco product other than their own conventional cigarettes brand within 14 days prior to Screening.
• willing to change to use of study products or if randomized to Arm A continuing to use their own brand of conventional cigarettes for the whole duration of the study.

For Arm C, subjects have to be:

• Never-smokers, defined as:

• never smoked or who have smoked < 100 cigarettes in their lifetime and none in the 30 days prior to screening.
• with an exhaled breath CO level < 7 ppm at screening.
• willing to not smoke or use any form of tobacco or nicotine-containing products for the whole duration of the study.

Exclusion criteria

• Pregnancy.
• Presence of extensive crown or bridge work, dental implants, and/or rampant decay (per Investigator/Examiner discretion)
• Significant oral soft tissue pathology or any type of gingival overgrowth, other than plaque-induced gingivitis and mild periodontitis (Stage I)
• Moderate to Severe Periodontitis (Stage II, III and IV) based on 2017 World Workshop on the Classification of Periodontal and Peri-Implant Diseases and Conditions, which require:

• Detectable Interdental Clinical Attachment Loss (CAL) ≥ 3 mm at ≥ 2 non-adjacent teeth.
• Buccal or Oral CAL ≥3 mm with pocketing ≥ 5 mm detectable at ≥ 2 teeth.
• Removable dentures or fixed and removable orthodontic appliance (except fixed lingual wires).
• Significant history of alcoholism or drug abuse (other than tobacco/nicotine) within 24 months prior to screening, as determined by the Investigator.
• A course of treatment with any medications or substances (other than tobacco/nicotine) which:

• interfere with the cyclooxygenase pathway (e.g. anti-inflammatory drugs including aspirin and ibuprofen) within 3 days prior to each visit.
• are known to have antibacterial activity (e.g. antibiotics) within 7 days prior to each visit.