E-cigarettes and Nicotine Pouches for Cigarette Smokers

Overseen By Janet Audrain-McGovern, Ph.D.

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: Abramson Cancer Center at Penn Medicine

Must not be taking: Smoking cessation medication

Disqualifiers: Substance abuse, Excessive alcohol, Pregnancy, others

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

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 4

Duration: 6 weeks

200 Participants Needed

Trial Summary

What is the purpose of this trial?

This between-subjects study aims to evaluate whether e-cigarettes (ECIGS) versus oral nicotine pouches (ONPS) more readily substitute for combustible cigarettes among 200 cigarette smokers. After measuring baseline cigarette smoking rate, participants will be randomized to ECIGS or ONPS and be instructed to switch (versus smoking cigarettes) over a 6-week period. Relative reductions in biomarkers of exposure will be measured. ECIG- and ONP-associated subjective reward and the reinforcing value of ECIGS and ONPS relative to combustible cigarettes will be assessed as mechanisms.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are using smoking cessation medication, you will need to stop that to participate.

What data supports the effectiveness of the treatment using E-cigarettes and Nicotine Pouches for cigarette smokers?

Research suggests that oral nicotine pouches, like Zyn, may serve as a low-risk alternative to cigarettes and could motivate smokers to switch from traditional tobacco products. Additionally, vaporized nicotine products have shown potential as smoking cessation aids, particularly among people in substance use treatment. ^{1 2 3 4 5}

Is it safe to use nicotine pouches like Zyn compared to smoking cigarettes?

Research suggests that nicotine pouches like Zyn may be a lower-risk alternative to smoking cigarettes, as they have a toxicant profile similar to Swedish snus, which is known to have much less health impact than smoking. However, there is limited research on their long-term safety, and more studies are needed to fully understand their potential harms and benefits. ^{3 6 7 8 9}

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

E-cigarettes and nicotine pouches are unique because they provide nicotine without the harmful chemicals found in traditional cigarettes, and they come in various flavors and strengths, making them potentially more appealing to smokers who find it hard to quit. Unlike other nicotine replacement therapies, these products do not contain tobacco and are designed to mimic the sensory experience of smoking, which may help smokers transition away from cigarettes. ^{1 3 10 11 12}

Eligibility Criteria

This trial is for persistent cigarette smokers over 21 years old who smoke at least 5 cigarettes daily for the past 6 months, have tried to quit smoking at least five times, and are not using other nicotine forms. Participants must have a breath carbon monoxide level above 10 ppm, plan to stay in the area for six weeks, and be able to give informed consent.

Inclusion Criteria

I can fluently speak, write, and read in English.

I am over 21 and have smoked 5 or more cigarettes daily for the last 6 months.

My carbon monoxide level is above 10 ppm.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 week

1 visit (in-person)

Baseline Assessment

Baseline smoking rate is established during days 1-5, followed by laboratory visits to assess ECIG and ONP-associated subjective reward and reinforcing value

1 week

2 visits (in-person)

Treatment

Participants switch from cigarette smoking to ECIGS or ONPS for a six-week period

6 weeks

Weekly supply visits

Follow-up

Participants are monitored for cigarette consumption and biomarkers of exposure at a 6-month follow-up

19 weeks

1 visit (in-person)

Treatment Details

Interventions

• Alternative Nicotine Delivery Systems

Trial Overview The study compares e-cigarettes (ECIGS) with oral nicotine pouches (ONPS) as alternatives to regular cigarettes among 200 smokers. It's designed to see which substitute reduces harmful biomarkers more effectively over a six-week period while also assessing their satisfaction and preference compared to traditional cigarettes.

Participant Groups

Group I: ONPS Experimental Treatment 1 Intervention

Participants randomized to ONPS will be provided with oral nicotine pouches and be instructed to switch from smoking combustible cigarettes to using only the study-provided nicotine pouches. Participants will be able to choose between Original, Mint, Berry, and Citrus flavored nicotine pouches. They will receive their supply of nicotine pouches in 7-day increments, based on baseline smoking behavior.

Group II: ECIGS Experimental Treatment 1 Intervention

Participants randomized to ECIGS will be provided with an e-cigarette device and be instructed to switch from smoking combustible cigarettes to using only the study-provided e-cigarette device. Participants will be able to choose between Tobacco, Menthol, Watermelon, and Blueberry flavored nicotine pods. They will receive their supply of nicotine pods in 7-day increments, based on baseline smoking behavior.

Alternative Nicotine Delivery Systems is already approved in United States, European Union for the following indications:

Approved in United States as E-cigarettes for:

• Harm reduction for persistent cigarette smokers

Approved in United States as Oral Nicotine Pouches for:

• Harm reduction for persistent cigarette smokers

Approved in European Union as E-cigarettes for:

• Harm reduction for persistent cigarette smokers

Approved in European Union as Oral Nicotine Pouches for:

• Harm reduction for persistent cigarette smokers

Who Is Running the Clinical Trial?

Abramson Cancer Center at Penn Medicine

Lead Sponsor

Trials

425

Recruited

464,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

University of Pennsylvania

Collaborator

Trials

2,118

Recruited

45,270,000+

Findings from Research

Oral Nicotine Pouches (ONPs) are gaining popularity, especially among adolescents and young adults, with over 50% of users preferring flavored options like menthol, fruity, and dessert flavors, which may encourage smokers to switch from cigarettes.

The study identified 152 natural and 228 synthetic ONP products, revealing that while tobacco and menthol flavors dominate natural ONPs, fruity and menthol flavors are most common in synthetic ONPs, raising concerns about potential health risks due to their chemical composition and effects on cellular signaling pathways.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Classification, Perception, and Toxicity of Emerging Flavored Oral Nicotine Pouches. Shaikh, SB., Newton, C., Tung, WC., et al.[2023]

Medicinal nicotine has significantly improved smoking cessation rates over the past 20 years, with various products like patches, gum, and inhalers available to help smokers quit.

Innovative nicotine delivery methods, such as high-dose patches and new forms like drinks and lollipops, are being developed to enhance cessation success and manage withdrawal symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotine delivery systems. Shiffman, S., Fant, RV., Buchhalter, AR., et al.[2015]

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]

In a study involving 63 smokers, both snus and Zonnic were preferred over nicotine gum, showing greater effectiveness in reducing smoking urges and causing fewer side effects.

Participants experienced significant reductions in smoking (33% for gum, 37% for snus, and 42% for Zonnic), indicating that snus and Zonnic could be promising alternatives for nicotine replacement therapy, warranting further research on their long-term effectiveness.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized crossover trial of the acceptability of snus, nicotine gum, and Zonnic therapy for smoking reduction in heavy smokers. Caldwell, B., Burgess, C., Crane, J.[2022]

Vaporised nicotine products (VNPs) can effectively help individuals in alcohol and other drug treatment manage nicotine cravings and mimic the hand-to-mouth action of smoking, making them a promising smoking cessation aid.

However, participants faced challenges such as device maintenance, regulatory limitations, and the difficulty of quitting tobacco while also trying to reduce cannabis use, which could hinder the effectiveness of VNPs in smoking cessation efforts.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Barriers and facilitators to using vaporised nicotine products as smoking cessation aids among people receiving treatment for substance use disorder. Lum, A., Skelton, E., Robinson, M., et al.[2021]

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]

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]

The novel tobacco-free nicotine pouch, ZYN, delivers nicotine effectively, with the 6 mg and 8 mg doses providing similar or faster nicotine absorption compared to traditional smokeless products like General snus and Longhorn moist snuff.

ZYN products showed a higher extraction fraction of nicotine (50-59%) compared to General snus (32%) and Longhorn moist snuff (19%), indicating a more efficient delivery of nicotine without significant adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic Comparison of a Novel Non-tobacco-Based Nicotine Pouch (ZYN) With Conventional, Tobacco-Based Swedish Snus and American Moist Snuff. Lunell, E., Fagerström, K., Hughes, J., et al.[2021]

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]

In a study involving 40 adult smokers, the JUUL2 prototype with 18 mg/mL nicotine delivered more nicotine than the JUUL 59 mg/mL, suggesting it could be more effective in helping smokers switch from combustible cigarettes.

The JUUL2 prototype 40 mg/mL was found to be more aversive than other products, indicating it may need adjustments to be appealing for adult smokers, while the JUUL products generally provided greater satisfaction and craving reduction compared to the IQOS heated tobacco product.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetic and subjective assessment of prototype JUUL2 electronic nicotine delivery system in two nicotine concentrations, JUUL system, IQOS, and combustible cigarette. Goldenson, NI., Augustson, EM., Chen, J., et al.[2022]

A study analyzing nicotine pouch advertising from January 2019 to September 2021 found that Zyn and Velo dominated the market, accounting for 44.4% and 52.8% of 286 unique ads, respectively, with a total expenditure of nearly $24.8 million, primarily on radio and television.

The advertising themes heavily emphasized 'freedom' and 'flavour', with Zyn focusing on brand identity and Velo on innovation, highlighting the need for regulatory oversight to understand the impact of these marketing strategies on consumers, especially young people.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotine pouch marketing strategies in the USA: an analysis of Zyn, On! and Velo. Duan, Z., Henriksen, L., Vallone, D., et al.[2022]

In a study involving adult smokers, nicotine pouches (NPs) showed lower peak nicotine levels (Cmax) and longer time to peak (tmax) compared to traditional cigarettes, indicating a slower nicotine delivery.

Participants reported lower cravings for cigarettes when using NPs, suggesting that these products may have a lower abuse potential and could serve as a safer alternative for smokers looking to switch from cigarettes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nicotine pharmacokinetics and subjective response among adult smokers using different flavors of on!® nicotine pouches compared to combustible cigarettes. Rensch, J., Liu, J., Wang, J., et al.[2021]

References

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

Classification, Perception, and Toxicity of Emerging Flavored Oral Nicotine Pouches. [2023]

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

Nicotine delivery systems. [2015]

3. 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]

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

Randomized crossover trial of the acceptability of snus, nicotine gum, and Zonnic therapy for smoking reduction in heavy smokers. [2022]

5. England pubmed.ncbi.nlm.nih.gov

Barriers and facilitators to using vaporised nicotine products as smoking cessation aids among people receiving treatment for substance use disorder. [2021]

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

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

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

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

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

Pharmacokinetic Comparison of a Novel Non-tobacco-Based Nicotine Pouch (ZYN) With Conventional, Tobacco-Based Swedish Snus and American Moist Snuff. [2021]

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

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

10. Germany pubmed.ncbi.nlm.nih.gov

Pharmacokinetic and subjective assessment of prototype JUUL2 electronic nicotine delivery system in two nicotine concentrations, JUUL system, IQOS, and combustible cigarette. [2022]

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

Nicotine pouch marketing strategies in the USA: an analysis of Zyn, On! and Velo. [2022]

12. Germany pubmed.ncbi.nlm.nih.gov

Nicotine pharmacokinetics and subjective response among adult smokers using different flavors of on!® nicotine pouches compared to combustible cigarettes. [2021]