Metabolic Syndrome in Diabetic Smokers Using Cigarettes & Combustion-Free Nicotine Delivery Systems

A Randomised Controlled International Multicentre Study Evaluating Changes in Metabolic Syndrome in Smokers With Type 2 Diabetes Mellitus After Switching From Tobacco Cigarettes to Combustion-Free Nicotine Delivery Systems: DIASMOKE Study

Very little is known about the impact of combustion-free nicotine delivery systems (C-F NDS) on cardiovascular risk factors in T2DM patients who smoke. Data from clinical studies to identify any potential reduction in individuals' risk, relative to the risk of continued smoking, are needed.

This study aims to test the hypothesis that avoiding exposure to cigarette smoke toxicants may translate to measurable improvement in cardiovascular risk factors and functional parameters when T2DM patients who smoke switch to using C-F NDS compared with T2DM patients who continue to smoke conventional tobacco products.

The investigators propose a prospective 2-year multicenter randomized controlled trial (RCT) to evaluate changes in cardiovascular risk factors and functional parameters in diabetic smokers using C-F NDS and compared to those continuing cigarette smoking.

This is a multicenter, controlled study utilizing a randomized switching design for cigarette smoking and C-F NDS use. The study will take place in one site in each of five countries. Three countries have so far agreed to participate: UK, Italy, Poland. An amendment will be submitted to the REC once the final two countries are signed up.

A volunteer population of adult smokers with T2DM will be recruited. Smokers will be randomized (1:2 ratio) to either continue to smoke their own cigarette brand (Study Arm A) or use C-F NDS (Study Arm B). The intended minimum number of participants in each arm by the end of the study is 147.

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 RCT.

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

Duration:

This will be a prospective 2-year study conducted in the ambulatory setting. Participants will attend a total of 5 clinic visits at Screening, Day 1 (Visit 1), Day 90 (+/-5 days) (Visit 2), Day 180 (+/-7 days) (Visit 3), Day 360 (+/-7 days) (Visit 4), and Day 720 (+/-7 days) (Visit 5).

Participants will undergo screening within 28 days prior to Day 1. Eligible participants will be enrolled and randomized on Day 1.

Study Arms and Randomization Plan Participants who were eligible and consent to take part will be randomized to either continuing smoking their own cigarette brand (Arm A) or switching to using C-F NDS (Arm B).

The randomization sequence will be computer generated, with an allocation ratio of 1:2 (Arm A: Arm B) to compensate for an estimated 50% success rate (defined as combined smoking abstinence rate + >80% smoking reduction rate) in the long term (more details in the section about Sample Size Calculation). 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 Smokers will continue to smoke their usual brand of cigarette until randomization on Day 1. After randomization, participants in Arms A and B will be asked to use only their assigned products ad libitum for the whole duration of the study (for more info/details - see below).

Participants in Arm A will continue smoking their own cigarette brand as usual. Participants in Arm B will trial and familiarize with their allocated products to select the C-F NDS of their preference. They will be trained and counseled on the chosen C-F NDS; participants will also have the option to try and choose among a selection of either 3 e-liquids or 3 tobacco sticks (depending on the C-F NDS they have chosen). Participants wishing to use a heated tobacco device will receive one 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 wishing to use a vaping product will receive one vaping kit and a full 1 week supply of e-liquids of their choice (they will receive 4, 10 ml refill containers). Free products will be supplied at each subsequent visit throughout the whole duration of the study

Product Monitoring and Compliance A prospective evaluation of cigarette consumption will be carried out throughout the study (see below). Cigarette use will be self-reported and recorded in the eCRF/ automated eDiary-SMS system (+ APP tracker).

Participants in Arm B will be instructed on the importance of using exclusively their C-F NDS and to abstain from smoking. Participants will be asked to report any non-compliance via the automated eDiary-SMS system (+ APP tracker), and will be informed that compliance assessments will be conducted throughout the study. Non-compliance will be documented.

Justification for Study Design

Participants in this study will be a minimum of 23 years of age. This is based on:

• The legal age to obtain tobacco products is 18 years
• Participants will be required to have a smoking history of at least 5 years To investigate the effects of abstaining from smoking by switching in smokers with T2DM, a population of patients who are intending to make the switch to N-C NDS will be recruited. By the end of the study, it is estimated that a high proportion (approx. 50%) 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 80% smoking reduction). To account for this, the C-F NDS population will be oversampled and a 1:2 randomization ratio scheme (i.e. for every patient randomized in the continue-to-smoke population, two will be randomized in the C-F NDS population) will be adopted.

Treatment blinding This is an unblinded study. 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.

Unblinded data will be seen and analysed by the Trial Statistician for the purposes of the Data Monitoring and Ethics Committee (DMEC) meetings. All other trial staff who has access to outcome data will remain blinded until prespecified data analyses will be completed. Prespecified data analyses will be conducted blind to treatment allocation.

Inclusion Criteria:

Participants will be required to satisfy all of the following criteria at the screening visit, unless otherwise stated:

• Participants will be: 1.1. over 23 years of age

• T2DM Patients will have: 2.1. body mass index (BMI) between 17.6 and 34.5 kg/m2, inclusive 2.2. body weight exceeding 50 kg (males) or 40 kg (females) 2.3 6.0<HbA1C<12 3.2. completion of proforma (CRF) 3.3. lab assessment as outlined in the CRF

• Participants will be willing to refrain from eating/drinking prior to screening and Check-in at each study visit.
• Participants will be regular smokers of at least 10 cigarettes/day (max 30 cigarette/day)
• Participants will have smoked for at least five consecutive years prior to screening.
• Participants must have a saliva cotinine level > 10 ng/mL or an exhaled breath CO (eCO) level > 7 ppm at screening.
• Participants in Arm A who continue to smoke will be willing to use their own brand/type cigarettes.
• Participants in Arms B will be willing to use the study products (THP product or e-cigarette) provided to them during the study.

Exclusion Criteria:

Participants will be excluded at the screening visit based on the following criteria:

• Female participants who are pregnant or breastfeeding. This will be confirmed at screening and at visit 1. Any female subject who becomes pregnant during this study will be withdrawn.
• Participants with a history of recent acute decompensation of their disease requiring treatment within 4 weeks prior to visit 1.
• Participants who have a significant history of alcoholism or drug/chemical abuse within 24 months prior to screening, as determined by the investigator.
• Participants who are still participating in another clinical study (e.g. attending follow-up visits) or who have participated in a clinical study involving administration of an investigational drug (new chemical entity) in the past 3 months prior to first product use.
• Participants who have, or who have a history of, any clinically-significant neurological, gastrointestinal, renal, hepatic, cardiovascular, psychiatric, respiratory, metabolic, endocrine, haematological or other major disorder that, in the opinion of the investigator or their appropriately qualified designee, would jeopardise the safety of the subject or impact on the validity of the study results.
• Participants who regularly use any nicotine (e.g. e-cigarettes, NRT) or tobacco product (e.g. HTPs, oral smokeless) other than their own cigarettes within 14 days of screening.

At screening and prior to enrolment, all patients will be offered a locally available free smoking cessation program as per local guidelines. Those who express the intention of booking for the cessation program together with those who, at screening, are planning to quit smoking in the next 6 months, will not be recruited in the study. Patients taking part in the study will be informed that they are free to quit smoking and withdraw from the study at any time. Any subject who decides to quit smoking will be directed to local stop smoking services.

Withdrawal Criteria:

Patients may be withdrawn from the study prematurely for the following reasons:

1. subject experiences a severe adverse event (SAE). The appropriate SAE electronic Case Report Form (eCRF) page must be completed.

2. If any deviations occur during the conduct of the study, which cannot be corrected. All protocol deviations will be fully documented and considered for their effect on study objectives. Deviations that could lead to subject discontinuation from the study include:

   • deviations which could affect subject's safety (e.g. illness requiring treatment[s]) which in the clinical judgement of the investigator might invalidate the study by interfering with the allocated test product or the willingness of the subject to comply with the study activities.
   • deviations involving the use of any nicotine/tobacco products other than the intended conventional cigarettes (in Arm A) or (in Arm B).

3. If the subject is uncooperative, including non-attendance. In these cases, efforts should have been made by the investigator to ascertain the reason and to ensure the subject's attendance as soon as possible.

4. Subject's personal request: the subject could decide, at any moment of the study, to stop his/her participation.

5. Female participant becoming pregnant.