Cytisinicline for Smoking and Vaping Cessation

(ORCA-OL Trial)

No longer recruiting at 28 trial locations

Overseen By Alan J Kivitz, MD, CPI

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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the safety of using cytisinicline, a medication, over a year to help people quit smoking or vaping. Researchers aim to determine if taking 3 mg of cytisinicline three times a day is safe for long-term use. Suitable candidates for this trial include those who have previously participated in specific ORCA studies and are current daily smokers or vapers seeking to quit. Participants should be prepared to start the treatment immediately after joining and set a quit date within two weeks. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to the potential availability of a new treatment.

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.

Is there any evidence suggesting that cytisinicline is likely to be safe for humans?

Research shows that cytisinicline is generally safe and well-tolerated. Studies have found it to be a potentially effective and safe option for people who want to quit smoking or vaping. Cytisinicline works by partially activating nicotine receptors in the brain, which helps reduce cravings.

Earlier clinical trials demonstrated that cytisinicline is safe and effective. Participants using the treatment reported only minor side effects, similar to those from other quitting aids. These might include mild symptoms like nausea or trouble sleeping, but they are not severe.

Since this trial is in a later phase, strong evidence supports the safety of cytisinicline. Earlier studies have already provided extensive safety information. Current research aims to confirm that taking 3 mg three times a day for a year is safe for participants. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for smoking cessation?

Unlike the standard smoking cessation treatments like nicotine replacement therapy, varenicline, or bupropion, cytisinicline offers a unique approach by using its active ingredient, cytisine, which has a similar mechanism of action to nicotine. Researchers are excited about cytisinicline because it not only aims to reduce cravings and withdrawal symptoms but also potentially offers fewer side effects compared to existing options. This could make it a more tolerable and appealing choice for those trying to quit smoking or vaping.

What evidence suggests that cytisinicline might be an effective treatment for smoking and vaping cessation?

Research has shown that cytisinicline, the treatment being studied in this trial, can help people quit smoking. Earlier studies found this drug to be safe and more effective than a placebo, which contains no active ingredients, in increasing the chances of quitting smoking. It has also more than doubled the chances of quitting e-cigarettes. While most studies focus on short-term results, evidence consistently supports cytisinicline’s ability to help people stop smoking. This makes it a promising option for those wanting to quit smoking or vaping. ^{3 5 6 7 8}

Who Is on the Research Team?

Julie Ball

Principal Investigator

Achieve Life Sciences, Inc.

Are You a Good Fit for This Trial?

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

Prior participation in the ORCA-2, ORCA-3 or ORCA-V1 clinical studies

Exclusion Criteria

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

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

Clinically significant abnormal screening serum chemistry or hematology values

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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 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]

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]

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]

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]

Citations

1. jamanetwork.com jamanetwork.com/journals/jamainternalmedicine/fullarticle/2832701

Cytisinicline for Smoking Cessation: The ORCA Phase 3 ... The findings of the ORCA phase 3 trial reaffirms the efficacy and tolerability of cytisinicline at both 6- and 12-week treatment for smoking cessation.

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11074928/

Cytisinicline for Vaping Cessation in Adults Using Nicotine E ... Cytisinicline treatment more than doubled the odds of achieving the primary outcome, biochemically confirmed continuous e-cigarette abstinence ...

3. tobaccopreventioncessation.com tobaccopreventioncessation.com/On-cytisine-s-safety-efficacy-and-cost-effectiveness-in-smoking-cessation-A-brief,194450,0,2.html

On cytisine's safety, efficacy and cost-effectiveness in ... Conclusions: Cytisine is a safe, efficient, cheap, and cost-effective smoking cessation aid as compared with placebo and NRT. Although cytisine ...

4. jwatch.org jwatch.org/na58704/2025/05/06/new-medication-smoking-cessation

A New Medication for Smoking Cessation? In a recent phase 3 trial of cytisinicline versus placebo, the drug was well tolerated and effective for smoking cessation (JAMA 2023; 330:152); ...

5. medrxiv.org medrxiv.org/content/10.1101/2025.07.23.25332030v1.full-text

Cytisine for smoking cessation: A systematic review and ... Insufficient data on long-term outcomes: Most studies reported outcomes at 24-26 weeks; longer-term effectiveness remains uncertain. Research ...

6. jamanetwork.com jamanetwork.com/journals/jama-health-forum/fullarticle/2822687

Public Health Impact of FDA's Request for Additional Safety ... Cytisine could have major public health benefits, including lengthening population-level life expectancy; therefore, a timely review of cytisine for approval ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11344233/

Public Health Impact of FDA's Request for Additional Safety ... Cytisine, a plant-based partial agonist of nicotinic acetylcholine receptors, has demonstrated safety and efficacy in several randomized ...

8. tobaccopreventioncessation.com tobaccopreventioncessation.com/Cytisine-for-smoking-cessation-A-40-day-treatment-with-an-induction-period,187556,0,2.html

Cytisine for smoking cessation: A 40-day treatment with an ... The aim of this study is to evaluate the effectiveness and tolerability of a 40-day cytisine treatment with an induction phase and a slower reduction schedule.