Phase 1 TAK-925 Study in Healthy Adult and Elderly Volunteers and Participants With Narcolepsy

Study Overview
=================
Brief Summary
-----------------
The purpose of this study is to investigate safety, tolerability, and pharmacokinetics of TAK-925 when a single dose of TAK-925 is administered to healthy adult participants, healthy elderly participants and patients with type 1 narcolepsy.

Detailed Description
-----------------
Orexins are neuropeptides that play a role in the regulation of sleep and wakefulness. In type 1 narcolepsy, there is a loss of orexin producing neurons in the brain. The investigational drug, TAK-925, is an orexin 2 receptor agonist that is being tested in healthy adult participants, healthy elderly participants and patients with narcolepsy in order to evaluate the safety, tolerability, and pharmacokinetics (PK) of a single intravenous administration. The study will enroll approximately 20 healthy participants and 16 healthy elderly participants in Part 1 of the study and approximately 20 patients with narcolepsy in Part 2. In Part 1, the study consists of 4 cohorts of 8 or 4 participants each. Participants will be randomly assigned (by chance, like flipping a coin) to one of the following treatment groups to receive TAK-925 or placebo: - Part 1, Cohort 1; TAK-925 (Dose Level 1, 3, 5), Cohort 2; TAK-925 (Dose Level 2, 4, 6), Cohort 3 and 4; TAK-925 (Dose Level 5) For Cohort 1-4, healthy adult and elderly participants will be administered TAK-925 or placebo once in each cohort or dose level. The dose at the start (Cohort 1 dose level 1) is 7 mg of TAK-925 and following doses in Cohorts 1-4 will be determined based on available data from previous Cohorts/dose levels. In Part 2 of the study, the study consists of 3 cohorts of 4 to 12 patients with narcolepsy. Patients will be randomly assigned to one of the treatment groups of Cohort 5-7 and will be administered TAK-925 or placebo once in each cohort. The dose of TAK-925 in Cohort 5-7 is TBD and will be decided based on available data from Part 1 and previous Cohorts. - Part 2, Cohort 5-7 This multi-center trial will be conducted in Japan. Participants will make multiple visits to the clinic. Visits in Part 1 will include a screening period (Day -28 to -2), Check-in on Day -1, Treatment period (Day 1 and 2), and follow-up visit on Day 7. In Part 2 of the study, the visits include a screening period (Day -42 to -2), Check-in on Day -1, Cross-over period (Day 1 to 4), and follow-up visit on Day 7.

Official Title
-----------------
A Phase 1 Study of TAK-925 to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of a Single Dose of TAK-925 in Healthy Adult and Elderly Volunteers and Patients With Narcolepsy

Conditions
-----------------
Healthy Participants and Patients With Narcolepsy

Intervention / Treatment
-----------------
* Drug: TAK-925
* Drug: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy adult participants and Healthy elderly participants: - Participant weighs at least 50 kilogram (kg) (Healthy adults participants) / 40 kg (Healthy elderly participants) and has a body mass index (BMI) from 18.5 to 30 kilogram per square meter (kg/m^2), inclusive at Screening. Narcolepsy patients: Patient weighs at least 40 kg inclusive at Screening. A diagnosis of narcolepsy Type 1, as defined by the International Classification of Sleep Disorders, Third Edition (ICSD-3). HLA narcolepsy test positivity. At Day -1, Epworth sleepiness scale (ESS) score greater than or equal to (>=) 10 Blood pressure less than (<) 140 systolic and < 90 diastolic. The patient may have a history of hypertension and be on antihypertensive medication treatment as long as the BP meets these criteria. Exclusion Criteria: All Participants: Participant has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse within 2 years prior to the Screening visit. Past or current epilepsy, convulsion, tremor or the disorders of related symptoms. Has a lifetime history of major psychiatric disorder, such as major depressive disorder, bipolar disorder, or schizophrenia. HV (only Cohort 4): - Participant has had CSF collection performed within 14 days prior to check-in (Day -1). Narcolepsy patients Medical disorder associated with excessive sleepiness other than narcolepsy (including sleep apnea syndrome). Excessive caffeine (greater than [>] 400 milligram per day [mg/day]) use one week prior to study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Sequential Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: TAK-925 (Cohort 1; Dose Level 1)<br>TAK-925, Intravenous single administration. Healthy adults will be enrolled in double blind manner. | Drug: TAK-925<br>* TAK-925 Intravenous Infusion<br>|
| Experimental: Part 1: TAK-925 (Cohort 2; Dose Level 2)<br>TAK-925, Intravenous single administration. Dose level will be determined by targeted plasma level of TAK-925 (Dose level 2). Dose selected based on safety, tolerability and PK data from previous Cohorts. Healthy adults will be enrolled in double blind manner. | Drug: TAK-925<br>* TAK-925 Intravenous Infusion<br>|
| Experimental: Part 1: TAK-925 (Cohort 1; Dose Level 3)<br>TAK-925, Intravenous single administration. Dose level will be determined by targeted plasma level of TAK-925 (Dose level 3). Dose selected based on safety, tolerability and PK data from previous Cohorts. Healthy adults will be enrolled in double blind manner. | Drug: TAK-925<br>* TAK-925 Intravenous Infusion<br>|
| Experimental: Part 1: TAK-925 (Cohort 2; Dose Level 4)<br>TAK-925, Intravenous single administration. Dose level will be determined by targeted plasma level of TAK-925 (Dose level 4). Dose selected based on safety, tolerability and PK data from previous Cohorts. Healthy adults will be enrolled in double blind manner. | Drug: TAK-925<br>* TAK-925 Intravenous Infusion<br>|
| Experimental: Part 1: TAK-925 (Cohort 1; Dose Level 5)<br>TAK-925, Intravenous single administration. Dose level will be determined by targeted plasma level of TAK-925 (Dose level 5). Dose selected based on safety, tolerability and PK data from previous Cohorts. Healthy adults will be enrolled in double blind manner. | Drug: TAK-925<br>* TAK-925 Intravenous Infusion<br>|
| Experimental: Part 1: TAK-925 (Cohort 2; Dose Level 6)<br>TAK-925, Intravenous single administration. Dose level will be determined by targeted plasma level of TAK-925 (Dose level 6). Dose selected based on safety, tolerability and PK data from previous Cohorts. Healthy adults will be enrolled in double blind manner. | Drug: TAK-925<br>* TAK-925 Intravenous Infusion<br>|
| Placebo Comparator: Part 1: Placebo (Cohort 1-2)<br>TAK-925 Placebo, Intravenous single administration. Healthy adults will be enrolled in double blind manner. | Drug: Placebo<br>* TAK-925 Placebo Intravenous Infusion<br>|
| Experimental: Part 1: TAK-925 (Cohort 3; Dose Level 5)<br>TAK-925, Intravenous single administration. Dose level will be determined by targeted plasma level of TAK-925 (Dose level 5). Healthy elderly participants will be enrolled in double blind manner. | Drug: TAK-925<br>* TAK-925 Intravenous Infusion<br>|
| Placebo Comparator: Part 1: Placebo (Cohort 3)<br>TAK-925 Placebo, Intravenous single administration. Healthy elderly participants will be enrolled in double blind manner. | Drug: Placebo<br>* TAK-925 Placebo Intravenous Infusion<br>|
| Experimental: Part 1: TAK-925 (Cohort 4; Dose Level 5)<br>TAK-925, Intravenous single administration. Dose level will be determined by targeted plasma level of TAK-925 (Dose level 5). Healthy adults will be enrolled in non-blinded manner. | Drug: TAK-925<br>* TAK-925 Intravenous Infusion<br>|
| Experimental: Part 2: TAK-925 TBD (Cohort 5)<br>TAK-925, Intravenous single administration. Dose in Cohort 5 will be based on safety and tolerability in the Part 1. Patients with Narcolepsy will be enrolled in double blind manner (sponsor open). | Drug: TAK-925<br>* TAK-925 Intravenous Infusion<br>|
| Experimental: Part 2: TAK-925 TBD (Cohort 6)<br>TAK-925, Intravenous single administration. Dose in Cohort 6 TBD based on safety, tolerability, PK data, and results of the Maintenance Wakefulness Test (MWT) from previous Cohorts. Patients with Narcolepsy will be enrolled in double blind manner (sponsor open). | Drug: TAK-925<br>* TAK-925 Intravenous Infusion<br>|
| Experimental: Part 2: TAK-925 TBD (Cohort 7)<br>TAK-925, Intravenous single administration. Dose in Cohort 7 TBD based on safety, tolerability, PK data, and results of the Maintenance of Wakefulness Test (MWT) from previous Cohorts. Patients with Narcolepsy will be enrolled in double blind manner (sponsor open). | Drug: TAK-925<br>* TAK-925 Intravenous Infusion<br>|
| Placebo Comparator: Part 2: Placebo (Cohort 5-7)<br>TAK-925 Placebo, Intravenous single administration. Patients with Narcolepsy will be enrolled in double blind manner (sponsor open). | Drug: Placebo<br>* TAK-925 Placebo Intravenous Infusion<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Reporting One or More Treatment-emergent Adverse Events (TEAEs) |  | Baseline up to Day 7 | 
| Number of Participants Who Experience at Least One TEAE Related to Vital Signs |  | Baseline up to Day 7 | 
| Number of Participants Who Experience at Least One TEAE Related to Body Weight |  | Baseline up to Day 7 | 
| Number of Participants Who Experience at Least One TEAE Related to 12-lead Electrocardiogram (ECG) |  | Baseline up to Day 7 | 
| Number of Participants Who Experience at Least One TEAE Related to Clinical Laboratory Tests |  | Baseline up to Day 7 | 
| Part 1, AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-925 and Its Metabolites M1 and M2 |  | Day 1 pre-infusion and at 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 9 hours after the start of infusion and at 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 10 and 15 hours post-infusion | 
| Part 2, AUClast: Area Under the Plasma Concentration-time Curve From Time 0 to the Time of the Last Quantifiable Concentration for TAK-925 and Its Metabolites M1 and M2 |  | Days 1-4 pre-infusion and at 1, 2, 4, 6 and 9 hours after the start of infusion and at 0.17, 0.5, 1, 2 and 15 hours post-infusion | 
| Part 1, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-925 and Its Metabolites M1 and M2 |  | Day 1 pre-infusion and at 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 9 hours after the start of infusion and at 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 10 and 15 hours post-infusion | 
| Part 2, AUC∞: Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for TAK-925 and Its Metabolites M1 and M2 |  | Days 1-4 pre-infusion and at 1, 2, 4, 6 and 9 hours after the start of infusion and at 0.17, 0.5, 1, 2 and 15 hours post-infusion | 
| Part 1, Cmax: Maximum Observed Plasma Concentration for TAK-925 and Its Metabolites M1 and M2 |  | Day 1 pre-infusion and at 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 9 hours after the start of infusion and at 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 10 and 15 hours post-infusion | 
| Part 2, Cmax: Maximum Observed Plasma Concentration for TAK-925 and Its Metabolites M1 and M2 |  | Days 1-4 pre-infusion and at 1, 2, 4, 6 and 9 hours after the start of infusion and at 0.17, 0.5, 1, 2 and 15 hours post-infusion | 
| Part 1, Ceoi: Concentration at the End of Infusion for TAK-925 and Its Metabolites M1 and M2 |  | Day 1 pre-infusion and at 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 9 hours after the start of infusion and at 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 10 and 15 hours post-infusion | 
| Part 2, Ceoi: Concentration at the End of Infusion for TAK-925 and Its Metabolites M1 and M2 |  | Days 1-4 pre-infusion and at 1, 2, 4, 6 and 9 hours after the start of infusion and at 0.17, 0.5, 1, 2 and 15 hours post-infusion | 
| Part 1, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-925 and Its Metabolites M1 and M2 |  | Day 1 pre-infusion and at 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 9 hours after the start of infusion and at 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 10 and 15 hours post-infusion | 
| Part 2, Tmax: Time to Reach the Maximum Plasma Concentration (Cmax) for TAK-925 and Its Metabolites M1 and M2 |  | Days 1-4 pre-infusion and at 1, 2, 4, 6 and 9 hours after the start of infusion and at 0.17, 0.5, 1, 2 and 15 hours post-infusion | 
| Part 1, t1/2z: Terminal Disposition Phase Half-life of TAK-925 and Its Metabolites M1 and M2 |  | Day 1 pre-infusion and at 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 9 hours after the start of infusion and at 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 10 and 15 hours post-infusion | 
| Part 2, t1/2z: Terminal Disposition Phase Half-life of TAK-925 and Its Metabolites M1 and M2 |  | Days 1-4 pre-infusion and at 1, 2, 4, 6 and 9 hours after the start of infusion and at 0.17, 0.5, 1, 2 and 15 hours post-infusion | 
| Part 1, Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-925 |  | Day 1 pre-infusion and at 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 9 hours after the start of infusion and at 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 10 and 15 hours post-infusion | 
| Part 2, Vss: Volume of Distribution at Steady State After Intravenous Administration for TAK-925 |  | Days 1-4 pre-infusion and at 1, 2, 4, 6 and 9 hours after the start of infusion and at 0.17, 0.5, 1, 2 and 15 hours post-infusion | 
| Part 1, Vz: Volume of Distribution During the Terminal Phase After Intravenous Administration for TAK-925 |  | Day 1 pre-infusion and at 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 9 hours after the start of infusion and at 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 10 and 15 hours post-infusion | 
| Part 2, Vz: Volume of Distribution During the Terminal Phase After Intravenous Administration for TAK-925 |  | Days 1-4 pre-infusion and at 1, 2, 4, 6 and 9 hours after the start of infusion and at 0.17, 0.5, 1, 2 and 15 hours post-infusion | 
| Part 1, CL: Total Clearance After Intravenous Administration for TAK-925 |  | Day 1 pre-infusion and at 0.5, 1, 1.5, 2, 3, 4, 6, 8 and 9 hours after the start of infusion and at 0.17, 0.33, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 10 and 15 hours post-infusion | 
| Part 2, CL: Total Clearance After Intravenous Administration for TAK-925 |  | Days 1-4 pre-infusion and at 1, 2, 4, 6 and 9 hours after the start of infusion and at 0.17, 0.5, 1, 2 and 15 hours post-infusion | 
| Part 1, Ae(0-24): Amount of TAK-925 and Its Metabolites M1 and M2 Excreted in Urine From Time 0 to Time 24 | Urine assessments were done only in Part 1, as planned. | Day 1 pre-infusion and 0-9 hours after the start of infusion and at 0-3, 3-6, 6-15 and 15-24 hours post-infusion | 
| Part 1, Fe(0-24): Fraction of Administered Dose of Drug Excreted in Urine From Time 0 to Time 24 for TAK-925 and Its Metabolites M1 and M2 | Urine assessments were done only in Part 1, as planned. | Day 1 pre-infusion and 0-9 hours after the start of infusion and at 0-3, 3-6, 6-15 and 15-24 hours post-infusion | 
| Part 1, CLR: Renal Clearance of TAK-925 and Its Metabolites M1 and M2 | Urine assessments were done only in Part 1, as planned. | Day 1 pre-infusion and 0-9 hours after the start of infusion and at 0-3, 3-6 and 6-15 hours post-infusion | 
| Part 1, R(CSF/Plasma,ss): Cerebrospinal Fluid/Plasma Drug Concentration at Steady State for TAK-925 and Its Metabolites M1 and M2 in Cohort 4 |  | Day 1 at 6 hours after start of infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 2: Average Sleep Latency in Maintenance of Wakefulness Test (MWT) | The MWT is a validated objective measure that evaluates a person's ability to remain awake under soporific conditions for a defined period of time. This tendency to fall asleep is measured via electroencephalography-derived sleep latency. Sleep onset is defined as the first epoch of greater than 15 seconds of cumulative sleep in a 30-second epoch. Trials were ended after 40 minutes if no sleep occurs, or after unequivocal sleep, defined as 3 consecutive epochs of stage 1 sleep, or 1 epoch of any other stage of sleep. If no sleep has been observed according to these rules, then the latency is defined as 40 minutes. MWT sleep latency ranges from 0 to 40 minutes, with higher scores indicating greater ability to stay awake. | Days 1 and 3 up to 8 hours following the start of infusion |