Randomized, Double‑Blind, Placebo‑Controlled Trial of E2086 for Reducing Excessive Daytime Sleepiness in Adults with Narcolepsy

The primary objective is to determine the optimal dose(s) of E2086 compared with placebo for reducing excessive daytime sleepiness in adults with narcolepsy, as measured by Mean Sleep Latency derived from the first four maintenance of wakefulness tests. Secondary objectives are to identify the dose(s) achieving the greatest reduction in weekly cataplexy rate in narcolepsy type 1, to assess improvement in daytime sleepiness using the Epworth Sleepiness Scale, to evaluate the safety and tolerability profile of the dose range, to examine the effect of E2086 on blood pressure via ambulatory monitoring, and to characterize the pharmacokinetics of E2086 and its metabolite M1 after multiple dosing.

Thirteen participants (both male and female) aged 18 years and older were enrolled. All subjects had a confirmed diagnosis of narcolepsy within the preceding 10 years, meeting criteria for either type 1 (including cataplexy frequency) or type 2 based on polysomnography and Multiple Sleep Latency Test results. Inclusion required an Epworth Sleepiness Scale score of at least 10, body‑mass index between 18 and 35 kg/m², and regular sleep‑wake patterns (bedtime 22:00–01:00, waketime 05:00–10:00, total time in bed 7–9 hours). Participants were required to maintain a diary with ≥80 % compliance during screening. The cohort comprised generally healthy adults with the specified sleep disorder.

The study is a phase 4, randomized, double‑blind, placebo‑controlled trial evaluating multiple oral dose levels of the investigational product E2086 versus matching placebo in adults diagnosed with Narcolepsy. Eligible participants undergo an initial screening visit to confirm diagnostic criteria, assess the Epworth Sleepiness Scale (ESS ≥ 10), body‑mass index (18 ≤ BMI < 35 kg/m²), and diary compliance (≥ 80%). Following confirmation of eligibility, participants are randomized in a blinded fashion to receive either E2086 or placebo and begin a 4‑week treatment period. Study visits are scheduled as follows: • Baseline/randomization visit (Day 0) – collection of vital signs, laboratory tests, ECG, blood pressure monitoring, and the first maintenance of wakefulness test (MWT) series; • Weekly follow‑up visits (Weeks 1, 2, 3) – safety assessments, adverse‑event monitoring, diary review, and repeat MWTs as required; • End‑of‑study visit (Week 4) – final efficacy assessments including mean sleep latency (MSL) from the four MWTs, cataplexy rate, ESS score, pharmacokinetic sampling, and comprehensive safety evaluations. Participant involvement therefore extends from the screening visit through the end‑of‑study assessment, encompassing approximately five weeks of study-related activities. The trial recruitment period is projected to commence on 29 July 2026 and conclude by 1 March 2027.

The investigational product, E2086, is supplied as a film‑coated tablet for oral administration. Each tablet contains the active substance (2R)-2‑cyclopropyl‑2‑{(1R,3S,5S)-3‑[(3S,4R)-1-(5‑fluoropyrimidin‑2‑yl)-3‑methoxypiperidin‑4‑yl]-8‑azabicyclo[3.2.1]octan‑8‑yl}acetamide, with a nominal strength of 0 mg as defined in the study protocol. The trial enrolls adults diagnosed with narcolepsy, and the tablets are identical in shape and appearance across all treatment arms.

The control arm utilizes matching placebo tablets that are indistinguishable from the active tablets in size, shape, and coating. These tablets contain no active pharmaceutical ingredient.

All study medications are taken according to the dosing schedule specified in the protocol. Administration is recorded in participant diaries and verified by pill count at each study visit to monitor compliance.

Efficacy is primarily evaluated by the change from baseline to Week 4 in Mean Sleep Latency (MSL), which is measured from the first four maintenance of wakefulness test (MWT) sessions conducted in participants with narcolepsy type 1 (NT1) and type 2 (NT2).

Secondary efficacy parameters include the Weekly Cataplexy Rate (WCR) assessed at Week 4 in participants with NT1 and the change from baseline to Week 4 in the Epworth Sleepiness Scale (ESS) total score for both NT1 and NT2.

All efficacy assessments are performed at baseline and at the Week 4 visit. MWTs are administered in a controlled laboratory setting following validated protocols, and the ESS questionnaire is completed by participants as a patient‑reported outcome. Comparative analyses between each E2086 dose group and placebo will be conducted to determine the magnitude of change in these endpoints.