E-cigarettes vs Nicotine Pouches for Smoking Cessation

Overseen By Krysten W Bold, PhD

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Yale University

Must not be taking: NRT, Bupropion, Varenicline

Disqualifiers: Pregnancy, Breastfeeding, Medical, Psychiatric, others

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

Compensation: Varies

Number of Visits: 6

Duration: 4 weeks

256 Participants Needed

Trial Summary

What is the purpose of this trial?

The study will recruit an anticipated 256 adults who currently smoke cigarettes and report a willingness to try switching to alternative, non-combustible products. Participants will be randomized to receive either e-cigarettes or nicotine pouches for a duration of 4 weeks and to 1 of 4 possible regulatory scenarios within products where flavor availability is either menthol and tobacco/unflavored available or tobacco/unflavored only available, and nicotine concentration is either higher (5% e-cig, 6mg pouch) or lower (2.4% e-cig, 3mg pouch). Participants will return for bi-weekly research visits (in person or remote videocall) to complete measures for study aims. Participants will complete a final follow-up at Week 6 to assess maintenance of cigarette reduction and willingness to continue using products once they are no longer provided. The investigators expect to observe which products and constituents lead to greater smoking reduction.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications, but you cannot be using smoking cessation medications like nicotine replacement therapy, bupropion, or varenicline.

What data supports the effectiveness of the treatment E-cigarettes and Nicotine Pouches for smoking cessation?

Research suggests that e-cigarettes can be effective for helping people quit smoking by providing nicotine and mimicking the act of smoking. Nicotine pouches, like ZYN, are considered a lower-risk alternative to smoking, with a toxicant profile similar to Swedish snus, which is known to be less harmful than smoking. ^{1 2 3 4 5}

Is there any safety information available for e-cigarettes and nicotine pouches?

Research suggests that nicotine pouches like Zyn may be a lower-risk alternative to smoking, with a toxicant profile similar to Swedish snus, which is known to be less harmful than smoking. However, there is limited research on their safety, and more studies are needed to fully understand their potential harms and benefits. ^{1 2 6 7 8}

How do e-cigarettes and nicotine pouches differ from other treatments for smoking cessation?

E-cigarettes and nicotine pouches are unique smoking cessation aids because they provide both nicotine and a behavioral substitute for smoking, unlike traditional nicotine replacement therapies (NRTs) that only deliver nicotine. Nicotine pouches are tobacco-free and offer a reduced-risk alternative to cigarettes, similar to Swedish snus, with potentially lower health risks. ^{1 2 4 9 10}

Research Team

Krysten Bold, PhD

Principal Investigator

Yale University

Lisa Fucito, PhD

Principal Investigator

Yale University

Eligibility Criteria

Adults over 21 who currently smoke cigarettes and are willing to try e-cigarettes or nicotine pouches. They must speak English, not be planning to quit smoking or use cessation drugs in the next month, and cannot be pregnant, breastfeeding, using other cessation services, or have a serious medical condition or allergy to propylene glycol.

Inclusion Criteria

I am over 21 years old.

English literate

You are actively smoking cigarettes, as confirmed by biochemistry.

Exclusion Criteria

Currently pregnant or breastfeeding

Known hypersensitivity to propylene glycol.

I am currently using help or medication to quit smoking.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants are randomized to receive either e-cigarettes or nicotine pouches for 4 weeks, with bi-weekly research visits to complete study measures

4 weeks

5 visits (in-person or remote videocall)

Follow-up

Participants complete a final follow-up at Week 6 to assess maintenance of cigarette reduction and willingness to continue using products

2 weeks

1 visit (in-person or remote videocall)

Treatment Details

Interventions

• E-cigarettes
• Nicotine pouches

Trial Overview The trial is testing if switching smokers from cigarettes to either e-cigarettes with varying nicotine levels and flavors (tobacco only or menthol) or flavored tobacco pouches with different nicotine strengths can reduce cigarette smoking over a period of 4 weeks.

Participant Groups

Group I: Nicotine Pouches Experimental Treatment 4 Interventions

Adults who smoke cigarettes will be randomized to receive nicotine pouches for a duration of 4 weeks and to 1 of 4 possible regulatory scenarios within products where flavor availability is either menthol and tobacco/unflavored available or tobacco/unflavored only available, and nicotine concentration is either higher (6mg pouch) or lower (3mg pouch). Participants will return for bi-weekly research visits (in person or remote videocall) to complete measures for study aims. They will complete a final follow-up at Week 6 to assess maintenance of cigarette reduction and willingness to continue using products once they are no longer provided.

Group II: E-cigarettes Experimental Treatment 4 Interventions

Adults who smoke cigarettes will be randomized to receive e-cigarettes for a duration of 4 weeks and to 1 of 4 possible regulatory scenarios within products where flavor availability is either menthol and tobacco/unflavored available or tobacco/unflavored only available, and nicotine concentration is either higher (5% e-cig) or lower (2.4% e-cig). Participants will return for bi-weekly research visits (in person or remote videocall) to complete measures for study aims. They will complete a final follow-up at Week 6 to assess maintenance of cigarette reduction and willingness to continue using products once they are no longer provided.

E-cigarettes is already approved in European Union, United States, Canada, Japan, United Kingdom for the following indications:

Approved in European Union as E-cigarettes for:

• Smoking cessation aid

Approved in United States as E-cigarettes for:

• No therapeutic indications approved; regulated as tobacco products

Approved in Canada as E-cigarettes for:

• Smoking cessation aid under prescription

Approved in Japan as E-cigarettes for:

• Prescription-only for smoking cessation

Approved in United Kingdom as E-cigarettes for:

• Smoking cessation aid under prescription

Who Is Running the Clinical Trial?

Yale University

Lead Sponsor

Trials

1,963

Recruited

3,046,000+

National Institute on Drug Abuse (NIDA)

Collaborator

Trials

2,658

Recruited

3,409,000+

Findings from Research

ZYN nicotine pouches contain no nitrosamines or polycyclic aromatic hydrocarbons (PAHs), indicating a potentially lower risk profile compared to traditional tobacco products, which often contain harmful constituents.

The levels of harmful and potentially harmful constituents (HPHCs) in ZYN were found to be similar to those in nicotine replacement therapy (NRT) products, suggesting that ZYN may be a safer alternative for nicotine delivery compared to moist snuff, which had significantly higher levels of harmful compounds.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Harmful and potentially harmful constituents (HPHCs) in two novel nicotine pouch products in comparison with regular smokeless tobacco products and pharmaceutical nicotine replacement therapy products (NRTs). Back, S., Masser, AE., Rutqvist, LE., et al.[2023]

Introducing the nicotine pouch ZYN in the US in 2000 could potentially lead to 249 fewer deaths among a simulated cohort of 100,000 smokers by 2050, translating to approximately 700,000 fewer deaths nationwide.

The model suggests that even with conservative estimates of ZYN's reduced risk compared to smoking, switching to ZYN could significantly lower product-related mortality, highlighting its potential as a safer alternative for smokers not intending to quit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Estimating the public health impact had tobacco-free nicotine pouches been introduced into the US in 2000. Lee, PN., Fry, JS., Ljung, T.[2022]

E-cigarettes have been shown to significantly reduce the desire to smoke and the number of cigarettes smoked per day in small clinical studies, suggesting they may help modify smoking habits.

While e-cigarettes may have fewer adverse effects compared to nicotine patches and can aid in short-term smoking reduction, there is limited evidence for their long-term effectiveness in achieving sustained smoking cessation beyond 6 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of electronic cigarettes for smoking cessation. Orr, KK., Asal, NJ.[2018]

Nicotine e-cigarettes were found to be more effective for smoking cessation compared to licensed nicotine replacement therapies (NRT), with participants using e-cigarettes being 49% more likely to remain abstinent from smoking than those using NRT.

The review included 7 e-cigarette trials with a total of 5,674 participants and 9 NRT trials with 6,080 participants, but many e-cigarette studies had a moderate to high risk of bias, indicating a need for more rigorous research to confirm these findings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A systematic review of randomized controlled trials and network meta-analysis of e-cigarettes for smoking cessation. Chan, GCK., Stjepanović, D., Lim, C., et al.[2023]

The E3 trial is a comprehensive study involving 376 participants over 12 weeks, aimed at evaluating the effectiveness of nicotine e-cigarettes compared to non-nicotine e-cigarettes and no e-cigarettes for smoking cessation, with follow-ups extending to 52 weeks.

This trial will provide crucial data on the efficacy and safety of e-cigarettes as a smoking cessation tool, helping inform healthcare professionals and regulators about their potential role in helping smokers quit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Randomized Controlled Trial Evaluating the Efficacy of E-Cigarette Use for Smoking Cessation in the General Population: E3 Trial Design. Hébert-Losier, A., Filion, KB., Windle, SB., et al.[2022]

The study found that Zyn Chill, marketed as 'Flavour-Ban Approved', activates the TRPM8 receptor, providing a cooling sensation, despite being advertised as unflavoured, indicating misleading marketing practices.

Chemical analysis revealed that Zyn Chill contains WS-3, a synthetic cooling agent, while mint-flavoured ONPs contain both WS-3 and mint flavourants, suggesting that these products still have flavoring agents that could appeal to consumers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthetic cooling agent in oral nicotine pouch products marketed as 'Flavour-Ban Approved'. Jabba, SV., Erythropel, HC., Woodrow, JG., et al.[2023]

Nicotine pouches, a new product category, are being marketed with minimal research and regulatory oversight, highlighting significant gaps in understanding their potential harms and benefits.

The commentary suggests a comprehensive assessment approach to inform regulatory policies, aiming to enhance public health outcomes while reducing unintended negative effects associated with nicotine pouch use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The New Nicotine Pouch Category: A Tobacco Harm Reduction Tool? Patwardhan, S., Fagerström, K.[2023]

The study found that 'Flavor-Ban Approved' Zyn-'Chill' nicotine pouches activate the TRPM8 receptor, which is responsible for the cooling sensation, indicating they still provide a cooling effect despite being marketed as free of flavor additives.

Chemical analysis revealed that Zyn-'Chill' contains WS-3, a synthetic cooling agent, which enhances its appeal while having lower irritant effects compared to traditional mint-flavored pouches, suggesting that the label 'Flavor-Ban Approved' may be misleading.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Synthetic Cooling Agent in Oral Nicotine Pouch Products Marketed as "Flavor-Ban Approved". Jabba, SV., Erythropel, HC., Woodrow, JG., et al.[2023]

A study analyzing data from the 2014 Eurobarometer survey across 28 European Union countries found that regular use of nicotine e-cigarettes is linked to lower odds of being a former smoker, suggesting that e-cigarettes may inhibit smoking cessation rather than assist it.

Among current smokers, those who used e-cigarettes consumed a similar or slightly higher number of cigarettes daily compared to those who did not use e-cigarettes, indicating that e-cigarette use may not effectively reduce overall cigarette consumption.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

E-cigarettes Associated With Depressed Smoking Cessation: A Cross-sectional Study of 28 European Union Countries. Kulik, MC., Lisha, NE., Glantz, SA.[2022]

In a study involving 30 adult smokers, 6-mg oral nicotine pouches (ONPs) delivered more nicotine to the bloodstream at 30 minutes compared to both 3-mg ONPs and cigarettes, suggesting they can be effective for nicotine delivery.

However, neither concentration of ONPs provided as much relief from cravings at 5 minutes as cigarettes did, indicating that while ONPs may be less harmful, they might not satisfy cravings as effectively, which could influence their potential for misuse.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Evaluating the effects of nicotine concentration on the appeal and nicotine delivery of oral nicotine pouches among rural and Appalachian adults who smoke cigarettes: A randomized cross-over study. Keller-Hamilton, B., Alalwan, MA., Curran, H., et al.[2023]

References

1. Switzerland pubmed.ncbi.nlm.nih.gov

Harmful and potentially harmful constituents (HPHCs) in two novel nicotine pouch products in comparison with regular smokeless tobacco products and pharmaceutical nicotine replacement therapy products (NRTs). [2023]

2. England pubmed.ncbi.nlm.nih.gov

Estimating the public health impact had tobacco-free nicotine pouches been introduced into the US in 2000. [2022]

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

Efficacy of electronic cigarettes for smoking cessation. [2018]

4. England pubmed.ncbi.nlm.nih.gov

A systematic review of randomized controlled trials and network meta-analysis of e-cigarettes for smoking cessation. [2023]

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

A Randomized Controlled Trial Evaluating the Efficacy of E-Cigarette Use for Smoking Cessation in the General Population: E3 Trial Design. [2022]

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

Synthetic cooling agent in oral nicotine pouch products marketed as 'Flavour-Ban Approved'. [2023]

7. England pubmed.ncbi.nlm.nih.gov

The New Nicotine Pouch Category: A Tobacco Harm Reduction Tool? [2023]

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

Synthetic Cooling Agent in Oral Nicotine Pouch Products Marketed as "Flavor-Ban Approved". [2023]

9. Netherlands pubmed.ncbi.nlm.nih.gov

E-cigarettes Associated With Depressed Smoking Cessation: A Cross-sectional Study of 28 European Union Countries. [2022]

10. England pubmed.ncbi.nlm.nih.gov

Evaluating the effects of nicotine concentration on the appeal and nicotine delivery of oral nicotine pouches among rural and Appalachian adults who smoke cigarettes: A randomized cross-over study. [2023]