The main aim of this study is to learn how effective TAK-861 is in improving excessive sleepiness during the day (called excessive daytime sleepiness or EDS) after 3 months of treatment. Other aims are to learn how effective TAK-861 is in lowering the number of sudden, unexpected attacks of muscle weakness while staying conscious (cataplexy) in a week; to learn the effect TAK-861 has on participants' ability to maintain attention, participant's overall quality of life, the spectrum of narcolepsy symptoms and daily life functions; and to learn about the safety of TAK-861.

The drug being tested in this study is called TAK-861. TAK-861 is being tested to evaluate its efficacy and safety in participants with narcolepsy with cataplexy (narcolepsy type 1 [NT1]).

The study will enroll approximately 93 participants. Participants will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups:

1. TAK-861
2. Placebo

The study drug will be administered for 12 weeks. This multi-center trial will be conducted globally.

Inclusion Criteria:

1. The participant has a body mass index (BMI) within the range 18 to 40 kilograms per meter square (kg/m^2).
2. The participant has an International Classification of Sleep Disorders, Third Edition (ICSD-3) or International Classification of Sleep Disorders, Third Edition, Text Revision (ICSD-3-TR) diagnosis of NT1.
3. The participant has greater than or equal to (≥)4 partial or complete episodes of cataplexy/week (WCR).
4. The participant is positive for the human leukocyte antigen (HLA) genotype HLA-DQB1*06:02 or results from radioimmunoassay indicate the participant's cerebrospinal fluid (CSF) orexin (OX)/hypocretin-1 concentration is less than or equal to (≤)110 picograms per milliliter (pg/mL) [or less than one-third of the mean values obtained in normal participants within the same standardized assay].

Exclusion Criteria:

1. The participant has a current medical disorder, other than narcolepsy with cataplexy, associated with EDS.
2. The participant: (a) has a history of myocardial infarction; (b) has a history of clinically significant hepatic disease, thyroid disease, coronary artery disease, cardiac rhythm abnormality or heart failure; or (c) has any medical condition (such as unstable cardiovascular, pulmonary, renal or gastrointestinal disease).
3. The participant has current or recent (within 6 months) gastrointestinal disease that is expected to influence the absorption of drugs.
4. The participant has a history of cancer in the past 5 years.
5. The participant has a clinically significant history of head injury or head trauma.
6. The participant has a history of epilepsy, seizure, or convulsion.
7. The participant has any current unstable psychiatric disorder or current active major depressive episode (MDE) or an active MDE in the past 6 months.

Takeda provides access to the de-identified individual participant data (IPD) for eligible studies to aid qualified researchers in addressing legitimate scientific objectives (Takeda's data sharing commitment is available on https://clinicaltrials.takeda.com/takedas-commitment?commitment=5). These IPDs will be provided in a secure research environment following approval of a data sharing request, and under the terms of a data sharing agreement.

IPD from eligible studies will be shared with qualified researchers according to the criteria and process described on https://vivli.org/ourmember/takeda/. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.