Low-frequency rTMS in combination with nicotine replacement therapy for smoking cessation: a phase II non-comparative Fleming-type randomized, double-blind, sham-controlled trial

INTRODUCTION: Innovative interventions such as repetitive transcranial magnetic stimulation (rTMS) may hold promise for individuals seeking smoking cessation support. In this Phase II pilot trial, we explored the potential of low-frequency rTMS (1 Hz) combined with nicotine replacement therapy to contribute to sustained tobacco abstinence. METHODS: A non-comparative single-step Fleming-type Phase II randomized, double-blind, sham-controlled design was used to test the eligibility of active rTMS for a Phase III trial. The primary outcome was biochemically confirmed Continuous Abstinence Rate (CAR) at six weeks post-randomization in the active rTMS group. Secondary outcomes included 12-week and 12-month CAR, craving, mood and safety evaluations in both groups. RESULTS: 78 participants were randomized to the active (n=39) or sham rTMS group (n=39). All participants received nicotine replacement therapy. In the active rTMS group, at 6-week follow-up, 16 patients (41%) were abstinent versus 18 patients (46%) in the sham rTMS group. At the 12-week and 12-month follow-up assessments, abstinence rates declined in both groups, with 26% and 15% of participants maintaining abstinence in the active rTMS group, compared with 15% and 10% in the sham group, respectively. Craving scores decreased in both groups, and mood scores were equally distributed. Eleven mild-to-moderate adverse events were reported in the active group versus twenty-three in the sham group. CONCLUSION: Given our definition of treatment efficacy, active low-frequency rTMS can be considered effective and eligible for a phase III trial. However, this result requires careful consideration since the sham rTMS group exhibited similar outcomes. The remaining uncertainty suggests a need for further research, particularly to assess nicotine's influence on cortical excitability.