Cytisinicline for Smoking and Vaping Cessation

(ORCA-OL Trial)

Recruiting at 29 trial locations

Overseen By Nancy Rigotti, MD

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Achieve Life Sciences

Must be taking: Cytisinicline

Disqualifiers: Psychosis, Hypertension, Pregnancy, others

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

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

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: 52 weeks

650 Participants Needed

Trial Summary

Do I need to stop my current medications to join the trial?

The trial protocol does not specify whether you need to stop taking your current medications. However, you must be willing to start cytisinicline treatment the day after enrollment.

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

Research shows that Cytisinicline, a plant-based drug, helps people quit smoking by targeting the same brain receptors as nicotine. It has been used in Europe for many years and has shown promise in increasing smoking abstinence rates in several clinical trials. ^{1 2 3 4 5}

Is cytisinicline safe for humans?

Cytisinicline, also known as cytisine, has been used in some European countries for smoking cessation for several decades, and it is generally considered safe for humans. However, there is limited information on its safety compared to modern standards, and more research is needed to fully understand its safety profile. ^{1 5 6 7 8}

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

Cytisinicline is unique because it is a plant-based drug that works by partially activating the same brain receptors as nicotine, helping to reduce cravings and withdrawal symptoms. Unlike some other smoking cessation drugs, it has been used in Eastern Europe for decades and is now being studied for different dosing schedules to improve its effectiveness and tolerability. ^{1 3 5 9 10}

What is the purpose of this trial?

Safety assessment of long-term 3 mg cytisinicline three times daily (TID) exposure for 52 weeks is the main purpose of this study, conducted in the United States.

Research Team

Julie Ball

Principal Investigator

Achieve Life Sciences, Inc.

Eligibility Criteria

This trial is for adults who previously participated in ORCA-2/ORCA-3 or ORCA-V1 studies, currently smoke daily or use nicotine e-cigarettes. They must be willing to try quitting with behavioral support and have certain levels of CO or cotinine. Excluded are those with recent psychosis, severe depression, known cytisinicline sensitivity, abnormal blood tests/ECG results, liver issues, uncontrolled high blood pressure, recent serious heart problems, severe kidney issues, pregnant/breastfeeding women or women not using birth control.

Inclusion Criteria

I smoke cigarettes or use nicotine e-cigarettes daily.

Willing to actively participate in the study's cessation behavioral support provided throughout the study

At Screening, subjects must have expired carbon monoxide (CO) ≥10 ppm if self-reporting as smokers or ≥30 ng/mL cotinine using a point-of-care cotinine oral fluid screening device if self-reporting as users of nicotine containing electronic cigarettes

Exclusion Criteria

Any other reason that the investigator views the subject should not participate or would be unable to fulfill the requirements for the study

Currently psychotic or having had a psychotic event within 3 months prior to screening; currently having suicidal ideation or risk for suicide; or current symptoms of moderate to severe depression at screening

Known hypersensitivity to cytisinicline or any of the excipients

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive 3 mg cytisinicline three times daily for 52 weeks

52 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Cytisinicline

Trial Overview The study is testing the safety of a smoking cessation aid called Cytisinicline taken three times daily for one year. Participants will receive behavioral support to quit smoking/vaping and start treatment the day after enrolling with a set quit date within two weeks.

Participant Groups

Group I: Cytisinicline 3 mg TID Experimental Treatment 1 Intervention

Cytisinicline 3 mg TID for 52 weeks.

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?

Achieve Life Sciences

Lead Sponsor

Trials

36

Recruited

7,800+

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]

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]

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]

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, 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. 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]

3. 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]

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

Cytisinicline increased smoking abstinence at 6 and 12 wk. [2023]

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

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

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. England pubmed.ncbi.nlm.nih.gov

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

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

A Phase I, Double-blind, Randomized, Placebo-controlled, Single Dose-escalation Study to Evaluate the Tolerability, and Safety of Cytisinicline in Adult Smokers. [2023]