Adults who smoked cigarettes and were assigned to a 5% nicotine pod-based electronic cigarette were more likely to achieve cigarette abstinence at 6 weeks than those assigned to a nicotine-free device, according to findings from a randomized clinical trial published in JAMA Network Open.
However, the trial’s primary endpoint — urinary 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, a biomarker of exposure to the tobacco-specific lung carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone — was not statistically significantly lower in the 5% nicotine group than in the nicotine-free group after full adjustment for baseline outcome measures, age, sex, race, and body mass index.
Researchers conducted the double-blind, placebo-controlled, parallel-group trial at Penn State University College of Medicine in Hershey, Pennsylvania, from April 22, 2022, to December 12, 2023. The study enrolled 104 adults aged 21 to 70 years who smoked at least 5 cigarettes per day and reported interest in switching completely from combustible cigarettes to an electronic cigarette.
Participants were randomly assigned 1:1 to receive a tobacco-flavored standardized research electronic cigarette with either 5% nicotine, equivalent to 58 mg/mL, or 0% nicotine for 6 weeks. The randomized phase included clinic visits at 3 and 6 weeks, followed by a telephone follow-up at 10 weeks.
The primary outcome was creatinine-corrected urinary total NNAL at 6 weeks. Secondary outcomes included exhaled carbon monoxide, urinary cotinine, cigarettes smoked per day, cigarette abstinence, withdrawal and craving measures, and biomarkers of volatile organic compound exposure.
The trial was smaller than originally planned. Researchers planned to enroll 84 participants per group to provide at least 90% power for the NNAL endpoint, but manufacturing delays and the COVID-19 pandemic limited randomization to 104 participants total. The researchers did not conduct a post hoc power analysis.
At 6 weeks, mean NNAL levels declined from 338 pg/mg at baseline to 155 pg/mg in the 5% nicotine group and from 575 pg/mg to 412 pg/mg in the 0% nicotine group among participants with available NNAL data. The fully adjusted between-group difference favored the 5% nicotine group but was not statistically significant.
The researchers noted that NNAL has a half-life of approximately 10 to 20 days and wrote that residual NNAL from prior cigarette smoking or ongoing attempts to fully switch may have attenuated between-group differences during the 6-week follow-up period.
The 5% nicotine group had lower levels of cyanoethyl mercapturic acid and 3-hydroxypropyl mercapturic acid, biomarkers of acrylonitrile and acrolein exposure, respectively, compared with the 0% nicotine group. Researchers did not identify statistically significant adjusted between-group differences in exhaled carbon monoxide, cigarettes smoked per day, 8-isoprostane levels, or 1,3-butadiene exposure.
The researchers wrote that differences in toxicant exposure between groups were primarily driven by participants who achieved cigarette abstinence. At 6 weeks, participants who were abstinent had lower levels of NNAL, cyanoethyl mercapturic acid, 3-hydroxypropyl mercapturic acid, and exhaled carbon monoxide than those who were not abstinent.
At 6 weeks, 19 of 52 participants in the 5% nicotine group, or 36.5%, achieved carbon monoxide–verified 7-day cigarette abstinence compared with 6 of 52 participants, or 11.5%, in the 0% nicotine group. Continuous abstinence during weeks 3 through 6, verified by carbon monoxide levels at both visits, occurred in 13 of 52 participants, or 25.0%, assigned to the 5% nicotine device compared with 4 of 52 participants, or 7.7%, assigned to the nicotine-free device.
At the 10-week telephone follow-up, conducted 4 weeks after the randomized phase ended, point-prevalence abstinence did not differ statistically between groups. Week 10 abstinence was self-reported rather than carbon monoxide–verified. Participants assigned to the 5% nicotine device were more likely to be abstinent at both the week 6 and week 10 follow-up visits, at 32.7% vs 7.7%.
Participants assigned to the 5% nicotine device also reported lower withdrawal scores at week 1 and lower craving scores at weeks 1 and 6 compared with participants assigned to the nicotine-free device. Urinary cotinine levels were higher in the 5% nicotine group at follow-up. The researchers wrote that cotinine levels in the 5% group were similar at baseline and follow-up, “suggesting that participants titrated their nicotine use across products to maintain stable nicotine levels.”
The study population had a mean age of 51 years, and participants smoked a mean of 18 cigarettes daily at baseline. Sixty-five percent of participants were female, 90% were White, 7% were Black, and 1% reported Hispanic ethnicity. Overall, 69 participants completed the 6-week follow-up visit, and 64 participants were included in the NNAL analysis.
Researchers reported no statistically significant between-group differences in blood pressure, lung function, heart rate variability, or electrocardiographic measures at follow-up.
Sixty-eight adverse events were reported during the study, including 30 in the 5% nicotine group and 38 in the 0% nicotine group. One serious adverse event occurred in the 5% nicotine group and was ruled unrelated to study participation. Psychiatric adverse events occurred in 7 participants assigned to the nicotine-free device and none assigned to the 5% nicotine device. The researchers wrote that these events may have been at least partly related to nicotine withdrawal.
The researchers cited several limitations, including the small sample size, short follow-up duration, single-site recruitment, limited racial and ethnic diversity, participant attrition, and use of tobacco-flavored pods only. Because eligibility required interest in switching completely from cigarettes to electronic cigarettes, the findings speak most directly to that population.
Because the comparator was a nicotine-free standardized research electronic cigarette rather than an approved cessation therapy, the trial does not show how the 5% nicotine device compares with nicotine replacement therapy, varenicline, bupropion, or counseling. In this trial, assignment to a 5% nicotine standardized research electronic cigarette was associated with higher short-term cigarette abstinence and lower exposure to some tobacco-related toxicants compared with assignment to a nicotine-free device among adults who smoked and wanted to switch completely. The findings suggest that nicotine delivery may play a role in helping adults who smoke switch away from combustible cigarettes, although the trial was short, underenrolled, and did not compare electronic cigarettes with approved cessation therapies.
Disclosures can be found in the study.
Source: JAMA Network Open
