Evaluation of TAK-861 Efficacy and Safety in Patients with Narcolepsy Type 1 with Cataplexy: A Randomized, Double-Blind, Placebo-Controlled Trial

The primary objective of this study is to evaluate the effect of **TAK-861** on excessive daytime sleepiness (EDS) in patients with narcolepsy with cataplexy, also known as Narcolepsy Type 1. This is measured using the Epworth Sleepiness Scale (ESS) total score. Addressing EDS is clinically significant as it is a core symptom of narcolepsy, impacting patients' daily functioning and quality of life.

Secondary objectives include:

• Assessing the effect of TAK-861 on EDS using the Maintenance of Wakefulness Test (MWT).
• Evaluating the impact on cataplexy through the weekly cataplexy rate (WCR).
• Measuring sustained attention using the psychomotor vigilance test (PVT).
• Assessing overall narcolepsy symptoms with the Patient Global Impression of Change (PGI-C) scale.
• Evaluating the overall severity of narcolepsy symptoms using the Narcolepsy Severity Scale for Clinical Trials (NSS-CT).
• Determining the functional impacts of narcolepsy with the Functional Impacts of Narcolepsy Instrument (FINI).
• Assessing the quality of life of participants using the Short Form-36 Survey (SF-36).
• Evaluating the safety of TAK-861 by monitoring treatment-emergent adverse event (TEAE) incidence.

The clinical trial involves a total of **20 participants** diagnosed with **Narcolepsy with Cataplexy (Narcolepsy Type 1)**. The study population comprises both male and female subjects, aged between 18 to 70 years. Participants were selected based on specific inclusion criteria, including a body mass index ranging from 18 to 40 kg/m² and a confirmed diagnosis of Narcolepsy Type 1 according to ICSD-3 or ICSD-3-TR standards. Additionally, participants exhibit at least four partial or complete episodes of cataplexy per week and meet certain genetic or biochemical markers, such as the presence of the HLA-DQB1*06:02 genotype or a cerebrospinal fluid hypocretin-1 concentration below 110 pg/mL. The trial does not include a vulnerable population, and all participants are deemed sufficiently healthy to partake in the study, as determined by comprehensive clinical evaluations. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized, double-blind, placebo-controlled** study to evaluate the efficacy and safety of TAK-861 for the treatment of **narcolepsy with cataplexy** (Narcolepsy Type 1). The trial will involve adult participants aged 18 to 70 years who meet specific inclusion criteria, such as having a diagnosis of Narcolepsy Type 1 according to ICSD-3 or ICSD-3-TR, and experiencing at least four partial or complete episodes of cataplexy per week. The study will assess the primary endpoint of change from baseline to Week 12 in the Epworth Sleepiness Scale (ESS) total score, with secondary endpoints including changes in mean sleep latency, cataplexy episodes, and various quality of life measures.

Participants will be randomly assigned to receive either TAK-861 or a placebo, both administered in tablet form via **oral use**. The trial will span approximately 12 weeks, with the estimated recruitment start date set for October 18, 2024, and an estimated end date of July 21, 2026. The sequence of study visits will begin with a screening visit to confirm eligibility, followed by regular follow-up visits to monitor safety and efficacy, and concluding with an end-of-study visit to assess final outcomes. The expected length of participant involvement is 12 weeks, with conditions for early termination including adverse events or withdrawal of consent.

The clinical trial involves the administration of **TAK-861**, an investigational medication developed by Takeda Development Center Americas, Inc. **TAK-861** is formulated as a **tablet** and is classified as a small molecule. The active substance in **TAK-861** is **N-{(2S,3R)-4,4-difluoro-1-(2-hydroxy-2-methylpropanoyl)-2-[(2,3',5'-trifluoro[1,1'-biphenyl]-3-yl)methyl]pyrrolidin-3-yl}ethanesulfonamide**, which is of chemical origin. The medication is administered orally. The trial is designed to evaluate the efficacy and safety of **TAK-861** for the treatment of narcolepsy with cataplexy, specifically focusing on excessive daytime sleepiness (EDS) as measured by the Epworth Sleepiness Scale (ESS) total score. The maximum treatment period for **TAK-861** is 12 weeks, with the dosage and administration schedule determined by the study protocol.

In addition to the experimental medication, the study includes a **placebo** group. The **placebo** is designed to match the **TAK-861** tablet in appearance and contains the same excipients, but lacks the active substance. The use of a placebo allows for a double-blind, placebo-controlled study design, ensuring that neither the participants nor the investigators know which treatment is being administered, thereby reducing bias. The placebo is also administered orally, following the same schedule as the active treatment group. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol.

The efficacy of TAK-861 in the treatment of **Narcolepsy with Cataplexy** (Narcolepsy Type 1) will be assessed through a randomized, double-blind, placebo-controlled clinical trial. The primary endpoint for evaluating efficacy is the change from baseline to Week 12 in the Epworth Sleepiness Scale (ESS) total score, which measures excessive daytime sleepiness (EDS). Secondary endpoints include changes from baseline to Week 12 in mean sleep latency from the 4 Maintenance of Wakefulness Test (MWT) wake trials, weekly cataplexy rate (WCR) at Week 12, and changes in various patient-reported outcomes such as the Patient Global Impression of Change (PGI-C) score, Narcolepsy Severity Scale-Clinician Total (NSS-CT) score, and Functional Outcomes of Sleep Questionnaire (FINI) domain scores. Additionally, changes in the SF-36 mental and physical component summary scores will be evaluated.

Efficacy parameters will be measured and collected at baseline and at Week 12. The ESS, MWT, and other patient-reported outcomes will be utilized as tools for these assessments. The trial is designed to ensure that data collection and analysis are conducted in a manner that maintains the integrity and reliability of the results. The study is expected to conclude by July 2026, with recruitment starting in October 2024.