Combination Nicotine Replacement Therapy + Cytisine + Varenicline for Tobacco Use

(Sun Life RCT Trial)

Overseen By Leah Margetson

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Ottawa Heart Institute Research Corporation

Must not be taking: NRT, Cytisine, Varenicline

Disqualifiers: Pregnant, Breastfeeding, Acute mental illness, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

Duration: 12 weeks

1500 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores adherence to three different smoking cessation products combined with counseling. The products include cytisine (a plant-based smoking cessation aid), nicotine replacement therapy (such as patches and gum), and varenicline (a prescription medication to help quit smoking). Researchers aim to evaluate the effectiveness of a virtual pharmacy in delivering these products to participants. Smokers in Ontario, Canada, who smoke more than five cigarettes a day and wish to quit within the next six months may be suitable for this study. As a Phase 4 trial, the treatment is already FDA-approved and proven effective, and this research seeks to understand its benefits for more patients.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. However, you cannot participate if you have used any of the study medications (NRT, cytisine, varenicline) in the past 7 days.

What is the safety track record for these treatments?

Previous studies have found cytisine to be a safe and effective aid for quitting smoking. It often compares to other treatments and shows similar safety results. Nicotine replacement therapy (NRT) is widely used and has a strong safety record. It helps manage cravings and withdrawal symptoms, making it easier to quit smoking. However, some people may experience mild side effects like skin irritation from patches or mouth irritation from lozenges.

Varenicline, another aid for quitting smoking, is also considered safe but can cause side effects like nausea, trouble sleeping, and unusual dreams. Despite these, it effectively helps people quit smoking over the long term. The FDA has approved all three treatments, indicating they have passed safety checks for use. Those considering joining a trial with these treatments should discuss any concerns or side effects with a healthcare provider. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about these treatments for tobacco use because they combine different methods to tackle nicotine addiction more effectively. While most treatments focus solely on nicotine replacement, this approach incorporates cytisine and varenicline as well, each with unique mechanisms. Cytisine is a plant-based compound that helps reduce withdrawal symptoms by partially activating nicotine receptors, while varenicline blocks nicotine's rewarding effects, making smoking less pleasurable. This combination could offer a more comprehensive and potentially quicker path to quitting smoking compared to standard options like nicotine patches or gum alone.

What evidence suggests that this trial's treatments could be effective for smoking cessation?

This trial will compare the effectiveness of three treatments for quitting smoking: cytisine, nicotine replacement therapy (NRT), and varenicline. Studies have shown that cytisine, one of the treatments in this trial, is more effective than NRT, with noticeable improvements at various times. NRT helps control cravings and withdrawal symptoms, with about 15.2% of people quitting smoking after six months when combined with counseling. Varenicline, the third treatment being tested, is particularly effective, with studies showing a quit rate as high as 45.5%, making it more successful than both NRT and bupropion (another medication for quitting smoking). All these treatments are approved and have been proven to help people quit smoking in different ways. ^{2 3 6 7 8}

Are You a Good Fit for This Trial?

This trial is for Sun Life clients who smoke and are interested in quitting. Participants will receive counseling and tobacco cessation products over a year, with a focus on the first 12 weeks. The study excludes individuals not meeting specific health criteria or those unable to commit to the program's duration.

Inclusion Criteria

I am 18 or older and a client of Sun Life Assurance Company of Canada.

Able to provide informed consent

Living in Ontario, Canada

Exclusion Criteria

Pregnant or breastfeeding individuals

Actively enrolled in another formal smoking cessation program

Other conditions deemed by the study team to interfere with participation or outcomes in the opinion of the study investigator (for example acutely unwell, life expectancy less than 1 year)

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive smoking cessation products and virtual counselling over a 12-week period

12 weeks

Virtual delivery of cessation products and counselling sessions

Follow-up

Participants are monitored for safety, adherence, and smoking cessation status

12 months

Follow-up visits at 1, 3, 6, and 12 months

What Are the Treatments Tested in This Trial?

Interventions

• Cytisine
• Nicotine Replacement Therapy
• Varenicline

Trial Overview The trial tests three smoking cessation methods: Cytisine, Nicotine Replacement Therapy (patch plus gum/lozenge), and Varenicline (Champix). It evaluates their effectiveness when combined with counseling and direct delivery from a virtual pharmacy over 12 weeks.

How Is the Trial Designed?

Group I: Varenicline (Champix) Active Control 1 Intervention

Varenicline - standard dose

Group II: Nicotine Replacement Therapy (Nicotine patch plus NRT gum or lozenge) Active Control 1 Intervention

Nicotine replacement therapy patch (titrated based on cigarettes consumed at baseline) plus short term gum or lozenge (as needed)

Group III: Cytisine Active Control 1 Intervention

Cytisine pills, standard dose

Who Is Running the Clinical Trial?

Ottawa Heart Institute Research Corporation

Lead Sponsor

Trials

200

Recruited

95,800+

Vita Aid Professional Therapeutics

Collaborator

Trials

1

Recruited

1,500+

Sun Life Assurance Company of Canada

Collaborator

Trials

2

Recruited

1,800+

Lumino Health™ Pharmacy

Collaborator

Trials

1

Recruited

1,500+

Published Research Related to This Trial

In a study of 282,429 adult smokers in the UK, varenicline was linked to an increased risk of self-harm and suicide, but it also showed a reduced risk of all-cause death, suggesting a complex relationship with mental health during smoking cessation.

Nicotine replacement therapy (NRT) was associated with a higher risk of myocardial infarction and self-harm, as well as increased mortality from heart-related issues and chronic obstructive pulmonary disease, indicating potential cardiovascular risks during its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Risk of neuropsychiatric and cardiovascular adverse events following treatment with varenicline and nicotine replacement therapy in the UK Clinical Practice Research Datalink: a case-cross-over study. Thomas, KH., Davies, NM., Taylor, AE., et al.[2022]

Cytisine and varenicline are two promising partial agonists of nicotinic acetylcholine receptors that can aid in smoking cessation, with cytisine being a low-cost option that has been used for decades but often overlooked in reviews.

Varenicline has shown greater efficacy than existing smoking cessation treatments, supported by encouraging early human trial results, making both drugs potential alternatives for smokers seeking to quit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotinic receptor partial agonists as novel compounds for the treatment of smoking cessation. Tutka, P.[2019]

Cytisine, a smoking cessation medication used since 1964, has shown a significant increase in the likelihood of successful continuous abstinence from smoking, with a relative risk of 1.74 compared to placebo based on a meta-analysis of eight studies.

The most common adverse reactions associated with cytisine are mild to moderate gastrointestinal symptoms, such as nausea and vomiting, making it a relatively safe option for those looking to quit smoking, especially considering its low cost compared to other cessation medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytisine for nicotine addiction treatment: a review of pharmacology, therapeutics and an update of clinical trial evidence for smoking cessation. Tutka, P., Vinnikov, D., Courtney, RJ., et al.[2020]

This study will evaluate the effectiveness and safety of combining nicotine salt e-cigarettes with cytisine for smoking cessation in 800 daily smokers over a 12-week period, with a primary focus on achieving biochemically verified abstinence at six months.

The trial aims to provide real-world evidence on this combination therapy's impact, which could inform future smoking cessation practices and policies in New Zealand.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of nicotine salt vapes, cytisine, and a combination of these products, for smoking cessation in New Zealand: protocol for a three-arm, pragmatic, community-based randomised controlled trial. Walker, N., Calder, A., Barnes, J., et al.[2023]

Cytisinicline, administered for either 6 or 12 weeks, significantly improved smoking cessation rates compared to placebo, with continuous abstinence rates of 32.6% for the 12-week group versus 7.0% for placebo during weeks 9 to 12.

The treatment was well-tolerated, with only 2.9% of participants discontinuing due to adverse events, and no serious drug-related side effects reported, indicating it is a safe option for aiding smoking cessation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytisinicline for Smoking Cessation: A Randomized Clinical Trial. Rigotti, NA., Benowitz, NL., Prochaska, J., et al.[2023]

Combining varenicline with oral nicotine replacement therapy (NRT) and using smartphone medication reminders led to more days of smoking abstinence compared to using varenicline alone, suggesting that this combination may enhance smoking cessation efforts.

Participants who received smartphone reminders adhered to their varenicline medication more consistently and reported higher usage of NRT, indicating that reminders can improve medication adherence, although combining medications may lead to lower adherence overall.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Varenicline Combined With Oral Nicotine Replacement Therapy and Smartphone-Based Medication Reminders for Smoking Cessation: Feasibility Randomized Controlled Trial. Sifat, M., Hébert, ET., Ahluwalia, JS., et al.[2023]

In a study of 3569 smokers, those using varenicline had a significantly higher sustained abstinence rate (15.2%) compared to those using combination nicotine replacement treatment (cNRT) (10.3%) over a 12-month period, indicating that varenicline may be more effective for long-term smoking cessation.

The study highlights that varenicline's effectiveness was observed in a real-world setting, where participants chose their treatment and received structured support, suggesting that it could be a preferred option for smoking cessation programs.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of Varenicline Versus Combination Nicotine Replacement Therapy for Smoking Cessation: One-Year Outcomes in a Smoking Cessation Clinic in Taiwan. Hsueh, KC., Tang, PL., McRobbie, H.[2021]

Citations

1. tobaccopreventioncessation.com tobaccopreventioncessation.com/On-cytisine-s-safety-efficacy-and-cost-effectiveness-in-smoking-cessation-A-brief,194450,0,2.html

On cytisine's safety, efficacy and cost-effectiveness in ... For the primary outcome and longer abstinence, cytisine is more efficient than placebo and NRT but has less efficacy than varenicline.

2. jamanetwork.com jamanetwork.com/journals/jamainternalmedicine/fullarticle/2832701

Cytisinicline for Smoking Cessation: The ORCA Phase 3 ... Cytisinicline reduced nicotine cravings and was well tolerated. Meaning These results demonstrate the high smoking cessation efficacy and ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11344233/

Public Health Impact of FDA's Request for Additional Safety ... Each 1-year delay in cytisine availability could result in 10 000 fewer life-years gained. New smoking cessation pharmacotherapy options are ...

4. medrxiv.org medrxiv.org/content/10.1101/2025.07.23.25332030v1.full-text

Cytisine for smoking cessation: A systematic review and ... Pooled analysis of seven studies demonstrated that cytisine significantly increased biochemically-verified continuous abstinence at 24 weeks or ...

5. nejm.org nejm.org/doi/full/10.1056/NEJMoa1407764

Cytisine versus Nicotine for Smoking Cessation The effectiveness of cytisine for continuous abstinence was superior to that of nicotine-replacement therapy at 1 week, 2 months, and 6 months.

6. jamanetwork.com jamanetwork.com/journals/jama-health-forum/fullarticle/2822687

Public Health Impact of FDA's Request for Additional Safety ... We estimated that without cytisine, the age-dependent annual probability of quitting and maintaining abstinence for at least 1 year would be 5. ...

7. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/39177985/

Public Health Impact of FDA's Request for Additional Safety ... Each additional year of delay in the availability of cytisine might reduce population-level life expectancy by 10 000 years. The model results ...

8. ncsct.co.uk ncsct.co.uk/library/view/pdf/Cytisine.pdf

Cytisine Cytisine is a safe, effective and cost-effective treatment to aid smoking cessation. It has a mode of action similar to varenicline. It has been used as a ...