Nicotine Regulation for Tobacco Use Disorder

(RDEC Trial)

Recruiting at 1 trial location

Overseen By Jennifer Tidey, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of Vermont

Disqualifiers: Pregnancy, Under 21, Health conditions, 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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 12 weeks

308 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine how reducing nicotine in cigarettes affects dual users of cigarettes and e-cigarettes. Researchers are testing whether lowering nicotine levels in cigarettes can reduce smoking and if nicotine levels in e-cigarettes influence this effect. Participants will try different combinations of cigarettes and e-cigarettes with varying nicotine levels. The trial seeks adults who regularly use tobacco and can read and understand English. As a Phase 2 trial, this research measures the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important findings.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that cigarettes with very low nicotine content (VLNC) can help exclusive cigarette smokers reduce their smoking and dependence. These findings come from carefully controlled studies. However, these studies did not include individuals who use both cigarettes and e-cigarettes, leaving uncertainty about how these "dual users" would respond to nicotine restrictions.

Other studies have found that e-cigarettes with higher nicotine levels are more effective at replacing regular cigarettes for dual users. There is concern that reducing nicotine in e-cigarettes might make them less appealing as a replacement, potentially altering smoking habits.

This study examines the safety of regulating nicotine by assessing how different nicotine levels in cigarettes and e-cigarettes affect adult dual users. As a Phase 2 trial, it evaluates the safety of the treatment, though it is not yet fully confirmed. Generally, Phase 2 trials suggest some level of safety because the treatments have passed initial tests for human use, but more information is needed to confirm long-term safety and effectiveness.

Why are researchers excited about this trial's treatments?

Researchers are excited about the nicotine regulation treatments for tobacco use disorder because they take a fresh approach by combining research cigarettes and e-cigarettes in various configurations. Unlike traditional methods such as nicotine replacement therapy (NRT), these experimental treatments aim to fine-tune nicotine delivery in a controlled way, which could offer a more personalized approach to reducing tobacco dependence. This method could provide better control over nicotine intake, potentially leading to more effective and tailored support for those looking to quit smoking. Additionally, the use of research e-cigarettes might offer an appealing alternative for individuals who struggle with traditional cessation methods, possibly increasing success rates.

What evidence suggests that this trial's treatments could be effective for tobacco use disorder?

This trial will explore various combinations of research cigarettes and e-cigarettes to assess their impact on tobacco use disorder. Research has shown that cigarettes with very low nicotine content (VLNC) can help people smoke less and feel less addicted. Studies have found that adults who smoke only cigarettes tend to smoke less and feel less dependent when switching to VLNC cigarettes. For individuals who use both cigarettes and e-cigarettes, the nicotine content in e-cigarettes can influence the effectiveness of this switch. E-cigarettes with higher nicotine levels are more successful at replacing regular cigarettes than those with lower nicotine levels. This suggests that if cigarettes have less nicotine and e-cigarettes have more, dual users might be more likely to switch completely to e-cigarettes. Participants in this trial will be assigned to different arms to test these combinations. ^{1 2 3 4 5}

Who Is on the Research Team?

Elias Klemperer, PhD

Principal Investigator

University of Vermont

Are You a Good Fit for This Trial?

This trial is for adult smokers who regularly use both e-cigarettes and traditional cigarettes. Participants should be dual users to understand how varying nicotine levels in these products impact their smoking habits and dependence.

Inclusion Criteria

Regular use of tobacco

Speak, comprehend, and read English well enough to complete study procedures

I am 21 years old or older.

Exclusion Criteria

Pregnant, trying to become pregnant, or nursing

Health conditions that could undermine ability to complete the study

I am younger than 21 years old.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are assigned to one of four groups to receive either normal or very low nicotine cigarettes and high or low nicotine e-cigarettes for 12 weeks

12 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment, including measures of cigarettes per day, cigarette dependence, and toxicant exposure

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Nicotine Regulation

Trial Overview The study tests the effects of changing nicotine content in cigarettes and e-cigarettes on smoking behavior. It's a double-blind trial with four groups: normal/high nicotine, normal/low, very low/high, and very low/low combinations.

How Is the Trial Designed?

Group I: RC 2 + REC 2 Experimental Treatment 2 Interventions

Research cigarettes #2 + research e-cigarettes #2

Group II: RC 2 + REC 1 Experimental Treatment 2 Interventions

Research cigarettes #2 plus research cigarettes #1

Group III: RC 1 + REC 2 Experimental Treatment 2 Interventions

Research cigarettes #1 plus research e-cigarettes #2

Group IV: RC 1 + REC 1 Experimental Treatment 2 Interventions

Research cigarettes #1 plus research e-cigarettes #1

Nicotine Regulation is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Nicotine Replacement Therapy for:

• Smoking cessation
• Nicotine addiction

Approved in United States as Nicotine Limitation for:

• Smoking cessation
• Tobacco-related harm reduction

Approved in Canada as Nicotine Regulation Standard for:

• Smoking cessation
• Nicotine addiction management

Who Is Running the Clinical Trial?

University of Vermont

Lead Sponsor

Trials

283

Recruited

3,747,000+

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]

In a review of 28 clinical trials involving 7,120 participants, only 10.5% experienced a significant increase in cotinine levels (>50% above baseline) while using nicotine replacement therapy (NRT), indicating that high nicotine exposure is relatively uncommon.

Adverse events related to nicotine overdose, such as nausea, vomiting, and palpitations, were reported infrequently (0.2% to 0.5% of subjects), supporting the overall safety of NRT for smoking cessation or reduction.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Symptoms of nicotine toxicity in subjects achieving high cotinine levels during nicotine replacement therapy. Tonstad, S., Gustavsson, G., Kruse, E., et al.[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]

Reducing nicotine levels in cigarettes could significantly lower tobacco-related health issues, and this approach is supported by regulatory frameworks like the U.S. Family Smoking Prevention and Tobacco Control Act.

Key research gaps were identified, such as determining the optimal nicotine dose for reducing smoking, understanding the role of other tobacco constituents, and assessing potential unintended consequences of nicotine reduction strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotine reduction: strategic research plan. Hatsukami, DK., Benowitz, NL., Donny, E., et al.[2021]

The 'Reduce to Stop' method of Nicotine Replacement Therapy (NRT) helps smokers gradually decrease their cigarette intake while using nicotine preparations, making it a promising option for those not ready to quit completely.

Clinical research shows that this approach not only effectively reduces smoking but also boosts motivation to quit, leading to higher chances of completely giving up smoking.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Alternative method of smoking cessation--reduce to stop]. Florek, E., Piekoszewski, W.[2015]

There are significant regulatory differences across countries regarding the use of Nicotine Replacement Therapy (NRT) for smoking reduction, influenced by varying attitudes towards smoking and nicotine's perceived risks.

To promote the acceptance of NRT as a smoking reduction aid, collaboration among the pharmaceutical industry, clinicians, and researchers is essential, along with addressing safety concerns and providing new evidence to regulatory authorities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Addressing regulatory barriers to licensing nicotine products for smoking reduction. West, R.[2019]

In a study involving 504 smokers, the nicotine patch was found to be the least unpleasant option among various nicotine replacement therapies (NRT), suggesting it may have a lower abuse liability compared to gum, spray, and inhaler.

At the 15-week mark, users of the nicotine patch reported no feelings of dependence, while continued use of NRT was linked to the rate of nicotine delivery, with the patch delivering the lowest amount of nicotine compared to other forms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of the abuse liability and dependence potential of nicotine patch, gum, spray and inhaler. West, R., Hajek, P., Foulds, J., et al.[2022]

Bupropion and nicotine are effective pharmacotherapies for managing tobacco dependency syndrome, often requiring a combination of both for optimal results.

High-dose nicotine therapy can lead to an 80% abstinence rate during treatment, but long-term maintenance of abstinence is challenging due to lasting changes in brain structure and function caused by chronic tobacco use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Smoking cessation. Techniques and benefits. Lillington, GA., Leonard, CT., Sachs, DP.[2019]

In a study of 4,072 current smokers, hospitalization increased the likelihood of receiving a prescription for Nicotine Replacement Therapy (NRT), with an odds ratio of 1.68, indicating a significant association.

Despite this association, only 5% of smokers received an NRT prescription during their hospitalization or at discharge, highlighting a missed opportunity for healthcare providers to promote smoking cessation during hospital stays.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Is hospitalization a missed opportunity to intervene on tobacco cessation? Nielsen, EM., Zhang, J., Marsden, J., et al.[2023]

In a study of 100 smokers, the new nicotine mouth spray was preferred by 54 participants over nicotine gum and inhalers, indicating a strong preference for this delivery method.

While the mouth spray showed comparable efficacy in helping smokers quit, it was associated with a higher rate of local adverse effects, suggesting that reducing the dose might improve safety and compliance.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A nicotine mouth spray for smoking cessation: a pilot study of preference, safety and efficacy. Bolliger, CT., van Biljon, X., Axelsson, A.[2015]

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]

A study of 366 quit attempters using nicotine replacement therapy (NRT) found that many users discontinue treatment prematurely, primarily due to resuming smoking (34%) and experiencing side effects (17%).

Factors such as poverty, age, and minority status were linked to higher rates of discontinuation, suggesting that tailored interventions could improve compliance and enhance the effectiveness of NRT in helping smokers quit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Discontinuation of nicotine replacement therapy among smoking-cessation attempters. Burns, EK., Levinson, AH.[2022]

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]

High-dose transdermal nicotine-replacement therapy (NRT) at doses of 42 mg or more daily appears to be safe, with most trials reporting no serious adverse events, although a dose-response relationship for adverse events was noted.

While high-dose NRT showed a numerically higher abstinence rate in most trials, none achieved statistically significant differences in final abstinence rates, indicating that more extensive studies are needed to confirm its efficacy and identify suitable patient populations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose transdermal nicotine replacement for tobacco cessation. Brokowski, L., Chen, J., Tanner, S.[2019]

Citations

1. ncbi.nlm.nih.gov ncbi.nlm.nih.gov/books/NBK493148/

Nicotine Replacement Therapy - StatPearls - NCBI Bookshelf NRTs are designed to replicate the nicotine response typically experienced through smoking, thereby helping individuals manage cravings and withdrawal symptoms.

2. academic.oup.com academic.oup.com/ntr/article/27/10/1695/8129442

Effectiveness of Nicotine Replacement Therapy and ... This study portrays the effectiveness of combining behavioral intervention (BI) with nicotine replacement therapy (NRT) in promoting cessation of tobacco use ...

3. frontiersin.org frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2025.1525510/full

Nicotine replacement therapy as a smoking cessation tool ... Results: NRT demonstrated limited success in long-term smoking cessation among adolescents, with low cessation rates that often declined post- ...

4. tobaccopreventioncessation.com tobaccopreventioncessation.com/The-effectiveness-of-nicotine-replacement-therapy-on-oral-smokeless-tobacco-cessation,208023,0,2.html

The effectiveness of nicotine replacement therapy on oral ... These two studies found that the high dose of NRT was associated with increased OST abstinence rate as a result of a greater reduction in ...

5. clinicaltrials.gov clinicaltrials.gov/study/NCT02148445

Smoking Cessation Versus Long-term Nicotine ... The investigators believe that GMT with long-term NRT will reduce overall exposure to cigarette smoke, reduce harm related to smoking, and ultimately lead to ...