0433 An Auditory Neuromodulation-Based Prescription Digital Therapeutic for Insomnia Disorder: Phase 3 Trial Protocol (SERENE)

Abstract Introduction Insomnia affects 10-15% of adults worldwide. While pharmacotherapy offers rapid symptom relief, concerns about dependence limit its use. Prescription digital therapeutics (PDTs) have emerged as scalable alternatives, yet existing PDTs largely replicate CBT-I principles and face similar adherence challenges inherent to behavioral interventions requiring sustained patient engagement. BELL-001 represents the first PDTs designed to translate the mechanism of hypnotics rather than behavioral modification. Using auditory stimulation, BELL-001 induces acute autonomic downregulation within the first 30 minutes of use, targeting hyperarousal through real-time biosignal capturing and dynamic acoustic feedback. This pharmacomimetic approach enables immediate effects without multi-week behavioral conditioning. The SERENE trial (Sleep Efficacy Randomized Evaluation of a digital thErapeutic for iNsomnia) was designed to rigorously evaluate the short-term efficacy and safety of BELL-001 in adults with insomnia. Methods SERENE is a multicenter, prospective, randomized, double-blind, sham-controlled, superiority trial. A minimum of 114 participants aged 19-75 years diagnosed with insomnia according to ICD-11 criteria and with an Insomnia Severity Index (ISI) score ≥15 will be enrolled from six medical centers in the Republic of Korea. Eligible participants will be randomized 1:1 to the BELL-001 or sham group. The primary endpoint is the change in ISI score from baseline to 4 weeks. Secondary endpoints include proportion of clinical responders (≥6-point ISI reduction), subjective sleep onset latency and wake after sleep onset from sleep diaries, and validated questionnaires assessing sleepiness, fatigue, depression, anxiety, quality of life, and work productivity. Treatment-emergent adverse events will be evaluated for safety analysis. Results The trial has received Korean Ministry of Food and Drug Safety (MFDS; K-FDA) approval in the Republic of Korea. Conclusion SERENE trial is the first Phase 3 evaluation of a pharmacomimetic prescription digital therapeutic designed to translate hypnotics mechanism. This study will provide evidence on whether BELL-001 can establish a neuromodulation-based PDTs delivering rapid efficacy with a favorable safety profile, offering clinicians a safe and effective treatment option for patients with insomnia disorder. Support (if any) BELL Therapeutics Inc.