Biomarkers, E-Diaries, & Enrollment: Lessons Learned From An E-cigarette Cessation Trial

By Daniel Cain, vice president, clinical research, and Julie Ball, senior director of clinical operations, Achieve Life Sciences

According to the CDC, in 2022, about 6% of U.S. adults used e-cigarettes, a slight uptick from prior years.¹ This form of smoking contains significant levels of nicotine, making e-cigarettes just as addictive as combustible cigarettes, and may also contain other dangerous chemicals, including acetaldehyde, acrolein, and formaldehyde. While the full health impacts of e-cigarettes have not yet been determined,² these aldehydes may contribute to lung damage and cardiovascular disease.² For example, one JUUL pod contains the same amount of nicotine as 20 combustible cigarettes (equivalent to one pack).³ Similarly, there are about 130-140 puffs in a 500 mg vaping cartridge, and studies have shown that users of e-cigarettes vape about 200 puffs a day.⁴

In this article, we’ll review the considerations, design, implementation, and lessons learned from a clinical trial evaluating a novel nicotine cessation therapy in adults who use e-cigarettes. Key considerations included defining an appropriate study population, deploying tools to evaluate e-cigarette use prior to randomization, and monitoring investigational product compliance while on study; utilizing objective biomarkers to verify participant-reported cessation success and to monitor the potential for participants to revert to using combustible cigarettes while quitting e-cigarettes; and the importance of preparing for faster than anticipated enrollment.

Ready & Willing To Quit — With Help

While many users of e-cigarettes may feel they are not addicted, there are also many who want to quit nicotine altogether. Data from a longitudinal study show that 60% of people who vape would like to quit,⁵ while a survey sponsored by Achieve Life Sciences found that approximately 73% of 508 respondents indicated an intent to quit vaping in the next three to 12 months.⁶ A key challenge for those interested in quitting e-cigarettes is that there are no cessation medications specifically approved for this indication. Nicotine replacement therapy (NRT) and non-nicotine-containing therapies (varenicline and bupropion) are FDA-approved for smoking cessation, but none are approved for nicotine e-cigarette cessation.

In 2022, Achieve Life Sciences initiated a clinical program to evaluate cytisinicline in individuals motivated to quit e-cigarettes. Cytisinicline is a naturally occurring alkaloid that is structurally like nicotine and is believed to reduce nicotine cravings, withdrawal symptoms, and reward and satisfaction associated with nicotine use by targeting nicotine receptors. When nicotine binds to this receptor, it causes dopamine to be released. Cytisinicline acts as a partial agonist, preventing nicotine from binding and releasing dopamine.

E-Diaries Served Dual Role In Screening, Data Collection

Key challenges in designing a clinical trial to assess the safety and efficacy of cytisinicline as a cessation aid for individuals trying to quit e-cigarettes were to define a study population in which efficacy could be measured and identify the relevant baseline characteristics to be captured for analysis. In conjunction with experts in the field, Achieve developed a detailed questionnaire to aid clinical research sites in documenting the smoking and vaping history for each trial participant at baseline. The study population included male and female subjects 18 years and older who vape nicotine e-cigarettes daily and intend to make a quit attempt during the study.

The trial employed a password protected electronic diary (e-diary) accessed via the internet by personal computer, tablet, or phone to record daily nicotine-containing e-cigarette usage in the 28-day screening period prior to study randomization. This e-diary was linked to the study database and has been used by Achieve in previous combustible cigarette studies. Overall acceptance and compliance with timely entries was high, but this tool also served to screen out those few individuals who, for whatever reason, were unable or unwilling to comply with the daily entry ritual since the e-diary was also used to record daily dosing with study medication over the 12-week treatment period. Researchers have confirmed that self-reported measures of e-cigarette frequency are predictive of actual use, but quantifying e-cigarette use in patterns similar to those of combustible cigarettes, which is often the number of cigarettes smoked, is problematic.⁵ Terms such as “number of puffs per day” or “number of times or minutes per day” (one “time” consists of around 15 puffs or lasts around 10 minutes) were considered but thought to be highly variable. Therefore, the study simply asked a participant a binary yes/no question: “Have you vaped in the last 24 hours?”

For those individuals who turned to e-cigarettes when quitting combustible cigarettes, it was important to monitor that they did not restart smoking combustible cigarettes while quitting e-cigarettes or end up becoming dual users. Also, individuals who were smokers before turning to e-cigarettes may have a stronger nicotine dependence when compared to individuals who have never smoked. Therefore, stratifying the randomization for prior smoking history (more than 100 cigarettes in their lifetime) was important to balance the possible impact of previous use of combustible cigarettes across treatment groups.

Relying On Biomarkers For Verification

The trial design included assessments of salivary cotinine levels (a metabolite of nicotine) to measure the amount of nicotine-containing e-cigarette usage and expired carbon monoxide (CO) to detect for any use of combustible cigarettes. This not only provided insight into the efficacy of cytisinicline in reducing e-cigarette use but also identified any potential harm of reverting to combustible cigarettes.

Participants whose expired CO was greater than 10 ppm while on the study were asked if they had smoked any combustible cigarettes since the last visit and, if so, how many cigarettes they had smoked. If the participant responded that they had not smoked any combustible cigarettes since the last visit, they were then asked if they had smoked any cannabis since the last visit, as well as the number of days they smoked cannabis since the last visit.

The final trial design was based on input from multiple key opinion leaders with expertise in addiction medicine and smoking-related health risks, which was critical for achieving the goals of conducting a study with a high likelihood of demonstrating potential benefit in a population of participants with substantial unmet need for new vaping cessation therapy options.

Faster Subject Enrollment: A Boon And A Burden

Given the lack of previous trial experience in this population and selective inclusion criteria, we anticipated that completing enrollment of 150 subjects at five clinical sites would take at least six months. In reality, the enrollment rate was faster than anticipated, and the trial was fully enrolled in four months. One possible reason for this rapid accrual may be that there are indeed many people using e-cigarettes who really are motivated to quit and participation in this trial provided a possible way to achieve that goal. While rapid accrual is always a benefit in reducing the overall time (and therefore costs) needed to complete the trial, it resulted in an extra burden on the clinical sites due to the study design that required weekly visits of all participants in the treatment period as well as keeping up with the volume of data required for collection.

Clinical trial sponsors often develop contingency plans for lower-than-expected enrollment rates, typically employing the activation of additional “rescue” sites. However, our experience with ORCA-V1 underscores the importance of also preparing for more rapid rates as well. Although no site was allowed to randomize more than 45 subjects (30% in total), there was no restriction on the rate of randomization at each site. In the future, a cap on the number of subjects that could be randomized in a week should be considered to steady the flow of participant visits and data collection. Site selection is key in that clinical sites having dedicated data management and subject retention groups as well as a track record of successfully managing high throughput studies are generally better prepared to handle the burdens of rapid enrollment. In addition, more frequent monitoring, both remotely (employing tools available via an electronic data entry/database system) and through on-site visits, along with a well-developed risk-based monitoring plan, is recommended.

Lessons Learned & Looking Ahead

Achieve recently reported promising data from the Phase 2 ORCA-V1 trial demonstrating that participants who received 12 weeks of cytisinicline treatment had 2.6 times higher odds of quitting vaping during the last four weeks of treatment compared with participants who received placebo (p=0.035). In addition, cytisinicline was well-tolerated, and no serious adverse events were reported. Cytisinicline has also shown promise in two Phase 3 trials in participants trying to quit combustible cigarettes, with data from the first trial recently published in the Journal of American Medical Association.⁶

Insights gained from the design and results of ORCA-V1 will inform the design and further clinical evaluation of cytisinicline in individuals trying to quit nicotine containing e-cigarettes. Based on our experience with the ORCA-V1 trial, we intend to continue the use of e-diaries for both participant screening and data collection in future vaping cessation trials, as well as biochemical verification of participant-reported cessation success. We would also consider the faster than anticipated enrollment of ORCA-V1 in determining the number of study sites for future vaping cessation trials and potentially limiting the number of participants that sites could enroll each week. Frequent monitoring, remote and on-site, would be implemented at the study start in order to quickly identify any potential issues around enrollment numbers, enrollment rates, subject retention, and data collection. Sponsors of all clinical trials — regardless of therapy or indication — must do their part to minimize the burden that clinical trial participation may impose on participants and clinical site staff. Without these key constituencies, clinical innovation would grind to a halt, and it is incumbent on all of us to recognize and appreciate their time and commitment to our shared causes.

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About The Authors:

Daniel Cain is a clinical research professional with 40 years’ experience in the health care industry and over 30 years of clinical research and operational leadership experience in the biopharmaceutical and device industries. Dan joined Achieve Life Sciences at its inception in 2018 and has been responsible for oversight of several Phase 1, 2, and 3 studies in smoking cessation, as well as the clinical program for cytisinicline.

Julie Ball is an accomplished clinical operations leader with 30+ years’ experience in the pharmaceutical and CRO industries. When she joined Achieve Life Sciences in 2021, she assumed responsibility for the then-ongoing Phase 3 study (ORCA-2) in smoking cessation for combustible cigarettes. Most recently, she was responsible for directing the now-completed ORCA-V1 study, which is the subject of this article.