A Randomized, Double-Blinded, Placebo-Controlled, Dose-Finding, Adaptive Trial to Evaluate the Safety, Tolerability, and Efficacy of TAK-360 in Participants with Narcolepsy without Cataplexy (NT2)

The primary objective of this trial is to evaluate the safety and tolerability of TAK-360 in participants with narcolepsy without cataplexy (NT2). This assessment is clinically relevant as it establishes the foundational risk-benefit profile of the investigational compound in this patient population, which is essential before broader clinical implementation can be considered.

The secondary objectives are:

• To assess the effect of TAK-360 on excessive daytime sleepiness (EDS) as measured by the total score after 4 weeks of treatment.

• To assess the effect of TAK-360 on EDS as measured by sleep latency in the Maintenance of Wakefulness Test (MWT) after 4 weeks of treatment.

These secondary endpoints evaluate the therapeutic efficacy of TAK-360 in managing the cardinal symptom of narcolepsy, utilizing both subjective patient-reported outcomes and objective physiological measures of wakefulness.

This clinical trial enrolled a total of **64 participants** diagnosed with **narcolepsy without cataplexy (NT2)**. The study population consisted of adult participants aged **18 to 70 years** at the time of informed consent. Both **male and female** participants were included in the trial. Eligible participants were required to weigh at least **40 kg** and have a **body mass index (BMI)** ranging from **16 to 38 kg/m²**. A documented, current diagnosis of NT2 was a key requirement for enrollment. The trial did not include vulnerable populations. The primary objective of the study was to evaluate the **safety and tolerability** of TAK-360 in this patient population.

This is a randomized, double-blind, placebo-controlled, dose-finding, adaptive clinical trial designed to evaluate the safety, tolerability, and efficacy of TAK-360 in participants with narcolepsy without cataplexy (NT2). The study represents a Phase 2a investigation of this investigational medicinal product. The trial employs an adaptive design methodology to optimize dose selection during the course of the study.

The investigational product TAK-360 is formulated as a film-coated tablet for oral administration. The active substance is N-{(6R)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide, which is of chemical origin. The control arm receives placebo containing the same excipients as TAK-360 to maintain blinding integrity throughout the trial.

The primary objective of this trial is to evaluate the safety and tolerability of TAK-360. The primary endpoint is defined as the occurrence of at least one treatment-emergent adverse event (TEAE) during the trial. Secondary endpoints include the change from baseline at Week 4 in Epworth Sleepiness Scale (ESS) total score compared with placebo, and the change from baseline at Week 4 in mean sleep latency on the Maintenance of Wakefulness Test (MWT) compared with placebo.

Eligible participants must be adults aged 18 to 70 years inclusive at the time of signing the informed consent form. Additional inclusion criteria require participants to weigh at least 40 kg and have a body mass index (BMI) between 16 and 38 kg/m² inclusive. Participants must have a documented, current diagnosis of narcolepsy without cataplexy (NT2). The trial is not designed for paediatric populations, as all formulations are intended for adult use.

The maximum treatment period for participants receiving TAK-360 or placebo is 4 weeks. The estimated recruitment start date is December 11, 2025, with an estimated trial completion date of June 15, 2026. The overall duration of participant involvement encompasses the screening period, the 4-week treatment phase, and follow-up assessments. During the treatment period, participants undergo scheduled study visits to assess efficacy parameters, safety monitoring, and collection of adverse event data.

The trial design incorporates provisions for early termination of individual participants based on predefined criteria. Participants may be withdrawn from the study due to safety concerns, development of exclusion criteria during the trial, withdrawal of consent, loss to follow-up, or at the discretion of the investigator if continuation is deemed not in the participant's best interest. The adaptive nature of the trial design allows for modifications to dosing regimens based on accumulating safety and tolerability data during the conduct of the study.

The experimental medication **TAK-360** is formulated as a **film-coated tablet** for **oral administration**. The active pharmaceutical ingredient is N-{(6R)-7,7-difluoro-2-[5-fluoro-4-(2,4,6-trifluorophenyl)-1,2-benzoxazol-3-yl]-3-oxo-2,5,6,7-tetrahydro-3H-pyrrolo[1,2-c]imidazol-6-yl}methanesulfonamide, a chemical substance. The maximum treatment period for TAK-360 administration is 4 weeks. Multiple formulations of TAK-360 film-coated tablets are utilized in this clinical trial, manufactured by Takeda Development Center Americas, Inc.

A **placebo** comparator is included in this **randomized, double-blinded, placebo-controlled** trial. The placebo formulation contains the same excipients as TAK-360 to maintain blinding integrity throughout the study. The placebo is administered via the same route and schedule as the active treatment to ensure consistency in trial conduct and minimize bias in the assessment of safety, tolerability, and efficacy outcomes.

Efficacy will be assessed through the evaluation of secondary endpoints during the trial. The change from baseline at Week 4 in Epworth Sleepiness Scale (ESS) total score will be measured and compared with placebo. Additionally, the change from baseline at Week 4 in mean sleep latency on the Maintenance of Wakefulness Test (MWT) will be evaluated and compared with placebo. These assessments will be conducted in participants with narcolepsy without cataplexy to determine the efficacy of TAK-360 in managing symptoms associated with this condition.