Cytisinicline for Smoking Cessation

(Cytisinicline Trial)

Overseen By Dylan E Kirsch, PhD

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: University of California, Los Angeles

Must not be taking: Smoking cessation aids, Psychoactive drugs

Disqualifiers: Substance use disorder, Psychotic disorders, Serious medical illness, others

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: 2-3 weeks

64 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial requires that you do not use other smoking cessation aids or psychoactive drugs (except cannabis). If you are using these, you would need to stop before participating.

What data supports the effectiveness of the drug Cytisinicline for smoking cessation?

Research shows that Cytisinicline, a plant-based drug, helps people quit smoking. In a large study, 8.4% of people using Cytisinicline stayed smoke-free for a year, compared to 2.4% of those taking a placebo (a pill with no active drug). ^{1 2 3 4 5}

Is cytisinicline safe for humans?

Cytisinicline (also known as cytisine) has been used for decades in some European countries to help people quit smoking, and it is generally considered safe. However, like any medication, it may have some side effects, and its safety profile is still being evaluated in clinical trials. ^{1 3 6 7 8}

How is the drug cytisinicline different from other smoking cessation treatments?

Cytisinicline is unique because it is a plant-based alkaloid that acts as a partial agonist (a substance that activates a receptor but not to its full potential) at the α4β2 nicotinic acetylcholine receptors, which are involved in nicotine addiction. It has been used in Eastern Europe for decades and is known for its low cost and a specific dosing schedule that involves a downward titration over 25 days. ^{1 3 5 9 10}

What is the purpose of this trial?

This study will randomize 64 non-treatment seeking individuals who smoke cigarettes daily in a double-blind, placebo-controlled laboratory study testing the effects of cytisinicline on the neural substrates of cigarette cue reactivity.

Eligibility Criteria

This trial is for individuals aged 18-65 who smoke at least 10 cigarettes a day and are not looking to quit smoking. They must be willing to provide informed consent.

Inclusion Criteria

Smoke 5 or more combustible cigarettes per day

Not seeking treatment for smoking

Exclusion Criteria

I have thoughts of harming myself or have attempted suicide in the past.

Non-removable ferromagnetic object in body

Claustrophobia

Timeline

Screening

Participants are screened for eligibility to participate in the trial

1 week

Treatment

Participants receive cytisinicline or placebo for 2-to-3 weeks and complete daily diary assessments

2-3 weeks

Cue-exposure task

Participants complete a cigarette cue-exposure task during fMRI to measure BOLD activation

1 day

Follow-up

Participants are monitored for safety and effectiveness after treatment

1 week

Treatment Details

Interventions

• Cytisinicline

Trial Overview The study is testing the effects of Cytisinicline, compared with a placebo, on brain responses to cigarette-related cues in daily smokers who aren't seeking treatment.

Participant Groups

Group I: Cytisinicline Experimental Treatment 1 Intervention

3mg cytisinicline oral capsule 3 times daily for 2-to-3 weeks

Group II: Placebo Placebo Group 1 Intervention

matched to experimental drug

Cytisinicline is already approved in Canada, United Kingdom for the following indications:

Approved in Canada as Cravv for:

• Smoking cessation

Approved in United Kingdom as Cytisine for:

• Smoking cessation

Who Is Running the Clinical Trial?

University of California, Los Angeles

Lead Sponsor

Trials

1,594

Recruited

10,430,000+

Findings from Research

In an open-label trial with 436 smokers, 13.8% achieved continuous abstinence from smoking for 12 months using cytisine (Tabex), indicating its potential effectiveness as a smoking cessation aid.

While 15.5% of participants discontinued cytisine due to minor side effects like gastric disturbances and nausea, these were not serious, suggesting that cytisine has a manageable safety profile for smokers seeking to quit.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An uncontrolled trial of cytisine (Tabex) for smoking cessation. Zatonski, W., Cedzynska, M., Tutka, P., et al.[2018]

Cytisine has been shown to significantly improve smoking cessation rates compared to placebo, with a recent trial of 740 participants reporting 12-month continuous abstinence rates of 8.4% for cytisine versus 2.4% for placebo, indicating a relative risk of 3.4.

A new trial involving 1,310 participants aims to determine if cytisine is at least as effective as nicotine replacement therapy (NRT) for helping smokers quit, which could position cytisine as a low-cost and acceptable alternative for smoking cessation, especially in low- and middle-income countries.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Study protocol for a non-inferiority trial of cytisine versus nicotine replacement therapy in people motivated to stop smoking. Walker, N., Howe, C., Bullen, C., et al.[2021]

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]

In a randomized controlled trial involving 869 heavy smokers, cytisine combined with counseling led to a significant quit rate of 32.1% at 12 months, compared to only 7.3% in the counseling-only group, demonstrating its efficacy as a smoking cessation aid.

While cytisine was effective, it was associated with a higher frequency of self-reported adverse events, particularly gastrointestinal issues, indicating that while it is a promising treatment, monitoring for side effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Cytisine Therapy Improved Smoking Cessation in the Randomized Screening and Multiple Intervention on Lung Epidemics Lung Cancer Screening Trial. Pastorino, U., Ladisa, V., Trussardo, S., et al.[2023]

In a clinical trial with 254 adult smokers, cytisinicline at both 1.5 mg and 3 mg doses significantly reduced the number of cigarettes smoked and increased abstinence rates compared to placebo, with the 3 mg dose showing the highest effectiveness.

The study found that a simplified dosing schedule of taking cytisinicline three times daily (TID) was well-tolerated and led to better continuous abstinence rates from Weeks 5 to 8, prompting further Phase 3 studies for potential market approval in the U.S.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Multicenter, Double-Blind, Randomized, Placebo-Controlled Phase 2b Trial of Cytisinicline in Adult Smokers (The ORCA-1 Trial). Nides, M., Rigotti, NA., Benowitz, N., et al.[2021]

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]

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 and varenicline are both effective in helping smokers quit compared to a placebo, with cytisine showing greater clinical effectiveness and cost-effectiveness based on a systematic review of 23 randomized controlled trials involving 10,610 participants.

Despite cytisine's advantages, there is uncertainty regarding the comparison with varenicline, suggesting that a head-to-head trial between the two treatments would be beneficial for clearer guidance on their relative efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

What is the clinical effectiveness and cost-effectiveness of cytisine compared with varenicline for smoking cessation? A systematic review and economic evaluation. Leaviss, J., Sullivan, W., Ren, S., et al.[2022]

Cytisine significantly improved smoking cessation rates, with 8.4% of participants achieving sustained abstinence after 12 months compared to only 2.4% in the placebo group, based on a study involving 740 adult smokers.

While cytisine was effective, it was associated with a higher incidence of gastrointestinal side effects, indicating that while it is a promising low-cost treatment for smoking cessation, monitoring for adverse effects is important.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Placebo-controlled trial of cytisine for smoking cessation. West, R., Zatonski, W., Cedzynska, M., et al.[2016]

Cytisine, a plant-based smoking cessation medication, was successfully quantified in human plasma and urine using advanced analytical methods, confirming its presence after a single 3 mg oral dose in healthy smokers.

The study found that cytisine is renally excreted unchanged, with no metabolites detected, and importantly, no adverse reactions were reported, indicating a favorable safety profile.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics of cytisine, an α4 β2 nicotinic receptor partial agonist, in healthy smokers following a single dose. Jeong, SH., Newcombe, D., Sheridan, J., et al.[2019]

References

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

An uncontrolled trial of cytisine (Tabex) for smoking cessation. [2018]

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

Study protocol for a non-inferiority trial of cytisine versus nicotine replacement therapy in people motivated to stop smoking. [2021]

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

Cytisinicline for Smoking Cessation: A Randomized Clinical Trial. [2023]

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

Cytisine Therapy Improved Smoking Cessation in the Randomized Screening and Multiple Intervention on Lung Epidemics Lung Cancer Screening Trial. [2023]

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

A Multicenter, Double-Blind, Randomized, Placebo-Controlled Phase 2b Trial of Cytisinicline in Adult Smokers (The ORCA-1 Trial). [2021]

6. England 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. [2020]

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

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

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

What is the clinical effectiveness and cost-effectiveness of cytisine compared with varenicline for smoking cessation? A systematic review and economic evaluation. [2022]

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

Placebo-controlled trial of cytisine for smoking cessation. [2016]

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

Pharmacokinetics of cytisine, an α4 β2 nicotinic receptor partial agonist, in healthy smokers following a single dose. [2019]