Timing of Nicotine Replacement Therapy for Smoking Cessation

(MC-NRT Trial)

Overseen By Laurie A Zawertailo, PhD

Age: 18 - 65

Sex: Female

Trial Phase: Phase 4

Sponsor: Centre for Addiction and Mental Health

Must be taking: Nicotine replacement

Must not be taking: Hormones, Smoking cessation

Disqualifiers: Pregnancy, Cannabis, Tobacco, Psychiatric, 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: Unknown

Duration: 6 weeks

1200 Participants Needed

Trial Summary

What is the purpose of this trial?

Tobacco use is a risk factor for at least 20 types of cancer and remains the leading preventable cause of cancer in Canada. Smoking cessation is an important cancer prevention strategy for the close to 2 million Canadian women who currently smoke. However, findings from controlled trials and real-world clinical settings indicate that women have greater difficulty achieving abstinence following a quit attempt than men. There is some evidence that hormonal levels and fluctuations throughout the menstrual cycle (MC) may contribute to the greater difficulty women experience when trying to quit smoking. In this study, the start of a quit attempt using nicotine replacement therapy (NRT) will be targeted to specific phases of MC. It was hypothesized that starting a quit attempt during the first half of MC (follicular phase) will result in increased quit success compared to starting during the second half of MC (luteal phase) or the usual practice of not targeting quit start date to MC phase.

Will I have to stop taking my current medications?

If you are currently using nicotine replacement therapy or other smoking cessation medications, you will need to stop taking them to participate in this trial. Additionally, if you are using hormonal treatments like progesterone, estrogen, testosterone, or fertility treatments, you will also need to stop.

What data supports the effectiveness of this treatment for smoking cessation?

Research shows that nicotine replacement therapy (NRT), including lozenges, patches, and inhalers, can nearly double the chances of successfully quitting smoking. Additionally, using a combination of NRT methods, like a nicotine inhaler and patch together, may be more effective than using a single method. ^{1 2 3 4 5}

Is nicotine replacement therapy (NRT) safe for humans?

Nicotine replacement therapy (NRT) has an established safety record and is generally considered safe for use in humans, including those with cardiovascular disease, although it should be used correctly to avoid potential adverse effects. ^{5 6 7 8 9}

How is nicotine replacement therapy (NRT) unique for smoking cessation?

Nicotine replacement therapy (NRT) is unique because it offers various forms like gum, patches, lozenges, and inhalers to help reduce withdrawal symptoms by replacing nicotine from cigarettes. This treatment can be tailored to individual needs, potentially improving success rates, and includes novel options like mucoadhesive tablets that release nicotine in a controlled manner. ^{1 2 5 10 11}

Research Team

Laurie Zawertailo, PhD

Principal Investigator

Centre for Addiction and Mental Health

Eligibility Criteria

This trial is for Canadian women who smoke at least 5 cigarettes daily, have regular menstrual cycles without hormonal contraception use in the past 6 months, and are planning to quit smoking soon. They must be willing to try nicotine replacement therapy (patches/gum/lozenge) and not have severe health issues like recent heart attacks or unstable psychiatric conditions.

Inclusion Criteria

I am willing and able to use nicotine patches and gum or lozenges to quit smoking.

I have smoked at least 5 cigarettes daily for the last 6 months.

Stated willingness to comply with all study procedures

Exclusion Criteria

I am currently using hormone or fertility treatments.

I do not have severe heart rhythm problems or worsening chest pain.

I have used hormonal contraceptives in the last 6 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive nicotine replacement therapy (NRT) and behavioral support for 6 weeks, starting on their target quit date (TQD) based on menstrual cycle phase

6 weeks

Online program with app and email support

Follow-up

Participants are monitored for smoking abstinence and quit success at 7 days, end of treatment, and 6 months post-target quit date

6 months

Treatment Details

Interventions

• Nicotine Replacement Therapy Agent
• Timing of nicotine replacement therapy start date

Trial Overview The study tests if timing the start of a quit attempt with nicotine replacement therapy to certain phases of the menstrual cycle affects success rates. It compares starting during the follicular phase versus luteal phase or at any time without considering the cycle.

Participant Groups

Group I: Mid-Luteal Phase Target Quit Date Experimental Treatment 2 Interventions

Participants will start their quit attempts during the mid-luteal phase of their MC (6-8 days pre-onset of menses). Each participant will be provided with a range of appropriate dates based on the information about their menstrual cycle, and they will select a target quit date from the range. Participants will be receiving NRT and will have access to behavioral support for the following 6 weeks.

Group II: Mid-Follicular Phase Target Quit Date Experimental Treatment 2 Interventions

Participants will start their quit attempts during the mid-follicular phase of their MC (6-8 days post-onset of menses). Each participant will be provided with a range of appropriate dates based on the information about their menstrual cycle, and they will select a target quit date from the range. Participants will be receiving NRT and will have access to behavioral support for the following 6 weeks.

Group III: Randomly Selected Target Quit Date (Usual Care) Active Control 1 Intervention

Participants will start their quit attempts within 30 days of their enrollment into the study. They will select their target quit dates without regard for their MC. Participants will be receiving NRT and will have access to behavioral support for the following 6 weeks.

Nicotine Replacement Therapy Agent is already approved in European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Nicotine Replacement Therapy for:

• Smoking cessation

Approved in United States as Nicotine Replacement Therapy for:

• Smoking cessation

Approved in Canada as Nicotine Replacement Therapy for:

• Smoking cessation

Approved in Japan as Nicotine Replacement Therapy for:

• Smoking cessation

Who Is Running the Clinical Trial?

Centre for Addiction and Mental Health

Lead Sponsor

Trials

388

Recruited

84,200+

Canadian Cancer Society (CCS)

Collaborator

Trials

84

Recruited

42,100+

Findings from Research

Nicotinell lozenges, particularly the 1 mg formulation, have been shown to be bioequivalent to 2 mg nicotine gum, providing effective nicotine delivery for smoking cessation, with significant short-term efficacy demonstrated in over 900 smokers.

The lozenges have an excellent safety profile, with only mild and reversible adverse events reported, making them a safe option for smokers seeking to quit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, safety and efficacy from randomized controlled trials of 1 and 2 mg nicotine bitartrate lozenges (Nicotinell). Dautzenberg, B., Nides, M., Kienzler, JL., et al.[2023]

Mucoadhesive nicotine tablets can effectively deliver nicotine in a controlled manner, helping individuals gradually reduce their dependence on smoking.

The best formulation for these tablets was found to be a mixture of Hydroxypropyl Methylcellulose (HPMC 50cps) and Carbopol 934, which provided optimal adhesiveness and a stable release rate of nicotine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Formulation of nicotine mucoadhesive tablet for smoking cessation and evaluation of its pharmaceuticals properties. Bahri-Najafi, R., Rezaei, Z., Peykanpour, M., et al.[2021]

In a study of 400 smokers, using a nicotine inhaler combined with a nicotine patch led to significantly higher smoking cessation rates compared to using the inhaler with a placebo patch, with 60.5% abstinence at 6 weeks versus 47.5%.

The combination therapy not only improved cessation rates but also showed a trend toward better lung function and reduced respiratory symptoms in those who quit smoking, indicating its potential benefits for overall respiratory health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotine inhaler and nicotine patch as a combination therapy for smoking cessation: a randomized, double-blind, placebo-controlled trial. Bohadana, A., Nilsson, F., Rasmussen, T., et al.[2019]

Nicotine replacement therapies (NRTs) significantly increase the chances of quitting smoking, with an overall odds ratio of 1.71 based on a review of 53 trials involving 17,703 patients.

Among different NRT forms, the transdermal patch and inhaled nicotine showed the highest effectiveness, with odds ratios of 2.07 and 3.05 respectively, indicating that these methods may be particularly beneficial for smokers trying to quit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The effectiveness of nicotine replacement therapies in smoking cessation. Silagy, C., Mant, D., Fowler, G., et al.[2019]

The study found that three prototype 4-mg nicotine lozenges produced in India were bioequivalent to the globally marketed Nicorette® 4-mg lozenge, indicating they can effectively deliver similar levels of nicotine to the bloodstream.

All prototype lozenges were well tolerated and had safety profiles comparable to the reference product, suggesting they are a safe alternative for nicotine replacement therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic characterization of three novel 4-mg nicotine lozenges . Sukhija, M., Srivastava, R., Kaushik, A.[2018]

In a study of 33,690 smokers using nicotine replacement therapy (NRT) through the New York State Smokers' Quitline, about 25% reported adverse effects at 2 weeks, which increased to 42% at 3 months, but most effects were mild.

Only a small percentage (4.4%-5.4%) discontinued NRT due to these adverse effects, indicating that NRT is generally safe for users when proper screening is conducted.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Adverse effects with use of nicotine replacement therapy among quitline clients. Ossip, DJ., Abrams, SM., Mahoney, MC., et al.[2015]

Nicotine replacement therapy (NRT) is safe and effective, but it is often used incorrectly; providing clear instructions and adequate dosing is crucial for maximizing its benefits.

Combining different forms of NRT, such as using a nicotine patch with gum or lozenges, and starting the patch two weeks before quitting can significantly improve quit rates and help prevent relapse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Optimising nicotine replacement therapy in clinical practice. Mendelsohn, C.[2018]

A study involving 30 smokers using a 2 mg sublingual nicotine tablet for 3-6 months found that it has a good safety profile, with only mild and transient oral mucosal effects, primarily melanin pigmentation.

After 6 months, most oral lesions observed during treatment resolved, indicating that the sublingual tablet is a safe option for nicotine replacement therapy in smoking cessation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The long-term effect of nicotine on the oral mucosa. Wallström, M., Sand, L., Nilsson, F., et al.[2023]

Cessation of smoking significantly reduces the risk of cardiovascular events, and nicotine replacement therapy (NRT) is an effective tool to help individuals quit smoking.

The article reviews the safety of NRT, concluding that it is safer than continued smoking, even for patients with existing cardiovascular disease, and provides recommendations for its use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotine replacement therapy and cardiovascular disease. Ford, CL., Zlabek, JA.[2023]

Nicotine replacement therapy (NRT) is effective for smoking cessation, but many users do not achieve long-term abstinence, suggesting a need for personalized treatment approaches.

Tailoring NRT to individual smokers' needs and preferences, potentially using genetic profiling, could improve treatment outcomes and safety, addressing the variability in response to standard NRT formulations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tailoring nicotine replacement therapy: rationale and potential approaches. McClure, JB., Swan, GE.[2018]

Nicotine replacement therapy (NRT) significantly increases the chances of quitting smoking, with an odds ratio of 1.72 compared to control, and is effective across various forms including gum, patches, and nasal sprays, regardless of the level of additional support provided.

While all forms of NRT are effective, the study suggests that bupropion may be more effective than NRT alone or in combination, indicating that alternative pharmacotherapies could enhance smoking cessation efforts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotine replacement therapy for smoking cessation. Silagy, C., Mant, D., Fowler, G., et al.[2018]

References

1. England pubmed.ncbi.nlm.nih.gov

Pharmacokinetics, safety and efficacy from randomized controlled trials of 1 and 2 mg nicotine bitartrate lozenges (Nicotinell). [2023]

2. India pubmed.ncbi.nlm.nih.gov

Formulation of nicotine mucoadhesive tablet for smoking cessation and evaluation of its pharmaceuticals properties. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Nicotine inhaler and nicotine patch as a combination therapy for smoking cessation: a randomized, double-blind, placebo-controlled trial. [2019]

4. United States pubmed.ncbi.nlm.nih.gov

The effectiveness of nicotine replacement therapies in smoking cessation. [2019]

5. Germany pubmed.ncbi.nlm.nih.gov

Pharmacokinetic characterization of three novel 4-mg nicotine lozenges . [2018]

6. England pubmed.ncbi.nlm.nih.gov

Adverse effects with use of nicotine replacement therapy among quitline clients. [2015]

7. Australia pubmed.ncbi.nlm.nih.gov

Optimising nicotine replacement therapy in clinical practice. [2018]

8. England pubmed.ncbi.nlm.nih.gov

The long-term effect of nicotine on the oral mucosa. [2023]

9. England pubmed.ncbi.nlm.nih.gov

Nicotine replacement therapy and cardiovascular disease. [2023]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Tailoring nicotine replacement therapy: rationale and potential approaches. [2018]

11. England pubmed.ncbi.nlm.nih.gov

Nicotine replacement therapy for smoking cessation. [2018]