A Study of TAK-994 in Adults With Type 1 and Type 2 Narcolepsy

Study Overview
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Brief Summary
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The main aims of the study are: To check for side effects from TAK-994 and check what dose of TAK-994 participants can tolerate. To check what dose range provides adequate relief of narcolepsy symptoms. To check how much TAK-994 stays in the blood of participants, over time. The study will have 4 parts. Participants can only join 1 of the parts. A. Participants with type 1 narcolepsy will take either TAK-994 or placebo tablets for 28 days. A placebo looks just like TAK-994 but will not have any medicine in it. B. Participants with type 1 narcolepsy will take 1 of 3 doses of TAK-994 or placebo tablets for 56 days. C. Participants with type 1 narcolepsy in China only will take TAK-994 or placebo tablets for 56 days. D. Participants with type 2 narcolepsy will take either TAK-994 or placebo tablets for 28 days.

Detailed Description
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The drug being tested in this study is called TAK-994. TAK-994 is being tested in participants with NT1 and NT2. The study will enroll up to approximately 202 participants. The study has 4 Parts: Parts A, B, C (China only) and D. Part A - Part A has 2 cohorts [Cohorts (A1a and A1b) A2] In both of these Cohorts, participants will be randomly assigned (by chance, like flipping a coin) in a 2:1 ratio to receive TAK-994 or placebo up to 28 days: Part B: In Part B, participants will be randomized in 1:1:1:1 ratio in four parallel arms to receive TAK-994 Dose 1, 2 or 3 or placebo for 56 days. Depending upon their eligibility participants completing Part B of the study treatment will be enrolled to participate in an Extension study. Part C: In Part C, participants only from China will be enrolled and randomized in a 2:1 ratio to receive TAK-994 and placebo for 56 days. Part D: Participants will be included in two cohorts [Cohorts (D1a and D1b) and D2] and will be randomized in 2:1 ratio to receive TAK-994 or placebo for 28 days. The dose will be selected based on the safety and tolerability in Part A. This multi-center trial will be conducted in the United States, Japan, China, Italy, France, and European Union. The overall duration of the study is 63 days. Participants will be followed up for 7 days after the last dose of study drug.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled, Multiple Rising Oral Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of TAK-994 in Patients With Narcolepsy With or Without Cataplexy (Narcolepsy Type 1 or Narcolepsy Type 2)

Conditions
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Narcolepsy Type 1 (NT1), Narcolepsy Type 2 (NT2)

Intervention / Treatment
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* Drug: TAK-994
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has a diagnosis of narcolepsy type 1 (NT1) (Parts A-C) or NT2 (Part D) by polysomnography (PSG)/ multiple sleep latency test (MSLT) performed within the past 10 years meeting the minimal acceptable criteria for the proper performance of the PSG/MSLT as outlined by the International Classification of Sleep Disorders, 3rd edition criteria. The participant's Epworth Sleepiness Scale (ESS) score must be greater than or equal to (>=) 10 at Day -1. Must be willing to discontinue all medications used for the treatment of NT1/NT2. The human leukocyte antigen (HLA) genotype: Part A: should test positive for human leukocyte antigen (HLADQB1)* 06:02 (PARTs A-C)- (positive results for either homozygous or heterozygous alleles will be considered positive and acceptable). However, if the HLA test is negative (i.e. negative for the heterozygous allele) and the PI feels strongly that the participant has narcolepsy with cataplexy (NT1) then a discussion should be initiated between the PI and the sponsor or designee about the advisability of doing a spinal tap to determine the participant's cerebrospinal fluid (CSF) orexin-1 (OX-1) level. If the CSF result shows the orexin 1 (OX-1) concentration is either less than or equal to<110 pg/mL, or less than one-third of mean values obtained in normal participants with the same standardized assay, then the diagnosis of NT1 is established allowing the participant to be enrolled and randomized, If the CSF OX-1 concentration is >110 pg/mL then the participant will not be allowed to continue in the study . For Parts A, B, and C, during the screening period, participant, must have >=4 partial or complete episodes of cataplexy/week (WCR), and >=4 partial or complete episodes of cataplexy/week during the screening period when off of anticataplexy medications, averaged over 2 weeks (14 consecutive days) minimum. WCR recording taken during following period will be considered for study eligibility: after the participant has stopped taking anticataplexy medications for at least 7 days (minimum 7-day washout) and study Day -2. Exclusion Criteria: Has a risk of suicide according to endorsement of Item 4 or 5 of the screening/baseline visit Columbia suicide severity rating scale (C-SSRS) or has made a suicide attempt in the previous 12 months. Is an excessive (>600 mg/day) caffeine user 1 week before to the study screening. Has a history of cancer (except carcinoma in situ that has been resolved without further treatment or basal cell skin cancer); past or current epilepsy, seizure; a lifetime history of major psychiatric disorder other than depression or anxiety; a clinically significant history of head injury or head trauma; a history of cerebral ischemia, transient ischemic attack, intracranial aneurysm, or arteriovenous malformation; known coronary artery disease, a history of myocardial infarction, angina, cardiac rhythm abnormality, or heart failure; or current or recent (within 6 months) gastrointestinal disease expected to influence the absorption of drugs. Any history of Roux-en-Y gastric bypass is considered exclusionary and any other surgical intervention that may influence the absorption of drugs should be discussed and approved by the sponsor or designee before enrolling the participants. Has a medical disorder, other than narcolepsy, associated with EDS. This includes clinically significant moderate to severe obstructive sleep apnea and/or with or without treatment with mandibular advanced device hypoglossal nerve stimulation and/or positive airway pressure (PAP) therapy) and/or restless legs syndrome (RLS)/periodic limb movement disorder that has a significant impact on daytime sleepiness. This is evidenced by a clinical history of sleep apnea syndrome (loud snoring with observed respiratory pauses in the absence of nPSG) and/or RLS causing historical sleep onset/maintenance insomnia with resultant insufficient sleep. Or any as evaluated during the clinical interview at screening. pPast PSG data demonstrating any of the following sleep disturbances: apnea Hypopnea Index ≥15 or apnea index ≥10, an oxygen saturation of <80 for >10 seconds, periodic leg movement arousal index of ≥15/h) or as evaluated on interview at the time of screening. Asshould be considered exclusionary unless, based on a clinical evaluation by the investigator, a meaningful change in clinical status has occurred that would impact the results. Because nPSG data is obtained on Day -2, subjects may fail screening if criteria are not meet on the Day -2 nPSG. Has a usual bedtime later than 2400 (12:00 AM, midnight) or an occupation requiring nighttime shift work or variable shift work within the past 6 months or travel within more than 3 time zones, within 14 days before Study Day -2. Has a nicotine dependence that is likely to have an effect on sleep (e.g., a participant who routinely awakens at night to smoke) and/or an unwillingness to discontinue all smoking and nicotine use during the confinement portions of the study. Participants undergoing optional CSF collection. Has a local infection at the puncture site. Has developed signs of lumbar radiculopathy, including lower extremity pain and paresthesia. Has any known focal neurological deficit that might suggest an increase in intracranial pressure.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Part A, Cohorts A1a and Cohorts A1b and A2 (Optional), NT1 Participants: Placebo<br>TAK-994 placebo-matching tablets for 28 days, in participants with NT1. | Drug: Placebo<br>* TAK-994 placebo-matching tablets.<br>|
| Experimental: Part A, Cohort A1a, NT1 Participants: TAK-994 TBD<br>TAK-994, tablets, dose level 1 for 28 days, in participants with NT1. | Drug: TAK-994<br>* TAK-994 tablets.<br>|
| Experimental: Part A, Cohort A1b, NT1 Participants: TAK-994<br>TAK-994 tablets, dose to be determined (TBD) based on safety, tolerability and/or efficacy in Cohort A1a participants with NT1. | Drug: TAK-994<br>* TAK-994 tablets.<br>|
| Experimental: Part A, Cohort A2 (Optional), NT1 Participants: TAK-994 TBD<br>TAK-994 tablets, TBD based on safety, tolerability and/or efficacy data of Cohort A1, for 28 days. | Drug: TAK-994<br>* TAK-994 tablets.<br>|
| Experimental: Part B, NT1 Participants: TAK-994 Dose 1<br>TAK-994 dose 1, tablets, for 56 days in participants with NT1. | Drug: TAK-994<br>* TAK-994 tablets.<br>|
| Experimental: Part B, NT1 Participants: TAK-994 Dose 2<br>TAK-994 dose 2, tablets, for 56 days in participants with NT1. | Drug: TAK-994<br>* TAK-994 tablets.<br>|
| Experimental: Part B, NT1 Participants: TAK-994 Dose 3<br>TAK-994 dose 3, tablets, 56 days in participants with NT1. | Drug: TAK-994<br>* TAK-994 tablets.<br>|
| Placebo Comparator: Part B, NT1 Participants: Placebo<br>TAK-994 placebo-matching tablets for 56 days in participants with NT1. | Drug: Placebo<br>* TAK-994 placebo-matching tablets.<br>|
| Placebo Comparator: Part C, NT1 Participants in China: Placebo<br>TAK-994 placebo-matching tablets for 56 days, in participants with NT1 in China. | Drug: Placebo<br>* TAK-994 placebo-matching tablets.<br>|
| Experimental: Part C, NT1 Participants in China: TAK-994<br>TAK-994 tablets, dose TBD based on safety and tolerability in Part B, for 56 days in participants with NT1 in China. | Drug: TAK-994<br>* TAK-994 tablets.<br>|
| Placebo Comparator: Part D, Cohort D1a, D1b and D2, NT2 Participants: Placebo<br>TAK-994 placebo-matching tablets for 28 days, in participants with NT2. | Drug: Placebo<br>* TAK-994 placebo-matching tablets.<br>|
| Experimental: Part D, Cohort D1a, NT2 Participants: TAK-994<br>TAK-994 tablets, dose TBD based on safety, tolerability and/or efficacy in Part A , for 28 days in participants with NT2. | Drug: TAK-994<br>* TAK-994 tablets.<br>|
| Experimental: Part D, Cohort D1b, NT2 Participants: TAK-994<br>TAK-994 tablets, dose TBD based on safety and/or tolerability efficacy in Cohort D1a participants with NT2. | Drug: TAK-994<br>* TAK-994 tablets.<br>|
| Experimental: Part D, Cohort D2, NT2 Participants (Optional) : TAK-994 TBD<br>TAK-994 tablets, TBD based on safety, tolerability and/or efficacy data of Cohort D1, for 28 days. | Drug: TAK-994<br>* TAK-994 tablets.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parts A and D: Number of Participants who Experience at least 1 Treatment Emergent Adverse Events (TEAEs) During the Study | An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE is defined as an AE with an onset that occurs after receiving study drug. | First dose of study treatment to end of study follow-up (up to Day 35) | 
| Parts A and D: Number of Participants who Meet the Markedly Abnormal Criteria for Safety Laboratory Tests at least Once Postdose During the Study | Standard safety laboratory values (serum chemistry, hematology, and urine analysis) will be collected and compared to pre-specified criteria for markedly abnormal values throughout the study. | Baseline up to Day 35 | 
| Parts A and D: Number of Participants who Meet the Markedly Abnormal Criteria for Vital Sign Measurements at least Once Postdose During the Study | Vital signs (body temperature, heart rate, respiratory rate, sitting blood pressure and pulse) will be collected and compared to pre-specified criteria for markedly abnormal values throughout the study. | Baseline up to Day 35 | 
| Parts A and D: Number of Participants who Meet the Markedly Abnormal Criteria for Safety Electrocardiogram (ECG) Parameters at least Once Postdose During the Study | A 12 lead ECG will be performed, the ECG values will be compared to pre-specified criteria for markedly abnormal values. | Baseline up to Day 35 | 
| Parts B and C: Change From Baseline in Average Sleep Latency as Assessed by the 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. During each MWT session (1 session = 40 minutes), participants will be instructed to sit quietly and remain awake for as long as possible. Sleep latency in each session will be recorded on electroencephalography (EEG). If no sleep has been observed according to these rules, then the latency will be defined as 40 minutes. | Baseline and Week 8 (Day 56) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Parts A and D: Day 1, Cmax: Maximum Observed Plasma Concentration After Single Dose of TAK-994 |  | Day 1: Pre-dose and at multiple time points (Up to 14 hours) post-dose | 
| Parts A and D: Day 1, Tmax: Time of First Occurrence of Cmax After Single Dose of TAK-994 |  | Day 1: Pre-dose and at multiple time points (Up to 14 hours) post-dose | 
| Parts A and D: Day 1, AUC(0-last): Area Under the Concentration-time Curve from Time 0 to Time of the Last Quantifiable Concentration After Single Dose of TAK-994 |  | Day 1: Pre-dose and at multiple time points (Up to 14 hours) post-dose | 
| Parts A and D: Day 28, Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-994 |  | Day 28: Pre-dose and at multiple time points (Up to 14 hours) post-dose | 
| Parts A and D: Day 28, Tmax: Time of First Occurrence of Cmax After Multiple Doses of TAK-994 |  | Day 28: Pre-dose and at multiple time points (Up to 14 hours) post-dose | 
| Parts A and D: Day 28, AUC(0-t): Area Under the Concentration-time Curve from Time 0 to Time tau Over a Dosing Interval of TAK-994 |  | Day 28: Pre-dose and at multiple time points (Up to 14 hours) post-dose | 
| Parts B and C: Change From Baseline in Subjective Daytime Sleepiness as Assessed by ESS Score | The ESS is a subjective, self-administered, validated scale (scored 0 to 3) to respond to each of the 8 questions of daily life that asks them how likely they are to fall asleep in those situations. The scores are summed to give an overall score of 0 to 24. Higher scores indicate stronger subjective daytime sleepiness, and scores below 10 are considered to be within the normal range. | Baseline and Week 8 (Day 56) | 
| Parts B and C: Change From Baseline in Weekly Cataplexy Rate (WCR) as Reported in the Patient-Reported Sleep Diary | Participants will complete a daily patient-reported sleep diary to record self-reported narcolepsy symptoms. Participants will record episodes of cataplexy in the diary. The total number of events averaged for a week will be reported. | Baseline and Week 8 (Day 56) | 
| Parts B and C: Number of Participants who Experience at least 1 Treatment Emergent Adverse Events (TEAEs) During the Study | An Adverse Event (AE) is defined as any untoward medical occurrence in a clinical investigation participant administered a drug; it does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (example, a clinically significant abnormal laboratory finding), symptom, or disease temporally associated with the use of a drug, whether or not it is considered related to the drug. A TEAE is defined as an AE with an onset that occurs after receiving study drug. | First dose of study treatment to end of study follow-up (Up to Day 63) | 
| Parts B and C: Number of Participants who Meet the Markedly Abnormal Criteria for Safety Laboratory Tests at least Once Postdose During the Study | Standard safety laboratory values (serum chemistry, hematology, and urine analysis) will be collected and compared to pre-specified criteria for markedly abnormal values throughout the study. | Baseline up to Day 63 | 
| Parts B and C: Number of Participants who Meet the Markedly Abnormal Criteria for Vital Sign Measurements at least Once Postdose During the Study | Vital signs (body temperature, heart rate, respiratory rate, sitting blood pressure and pulse) will be collected and compared to pre-specified criteria for markedly abnormal values throughout the study. | Baseline up to Day 63 | 
| Parts B and C: Number of Participants who Meet the Markedly Abnormal Criteria for Safety Electrocardiogram (ECG) Parameters at least Once Postdose During the Study | A 12 lead ECG will be performed, the ECG values will be compared to pre-specified criteria for markedly abnormal values. | Baseline up to Day 63 | 
| Change from Baseline in Sleep Latency as Assessed by the 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. During each MWT session (1 session = 40 minutes), participants will be instructed to sit quietly and remain awake for as long as possible. Sleep latency in each session will be recorded on electroencephalography (EEG). If no sleep has been observed according to these rules, then the latency will be defined as 40 minutes. | Baseline up to Week 4 | 
| Change From Baseline in Subjective Daytime Sleepiness as Assessed by Epworth Sleepiness Scale (ESS) Score | The ESS is a subjective, self-administered, validated scale (scored 0 to 3) to respond to each of the 8 questions of daily life that asks them how likely they are to fall asleep in those situations. The scores are summed to give an overall score of 0 to 24. Higher scores indicate stronger subjective daytime sleepiness, and scores below 10 are considered to be within the normal range. | Baseline up to Week 4 | 
| Parts A, B and C: Change From Baseline in Weekly Cataplexy Rate (WCR) as Reported in the Patient-Reported Sleep Diary | Participants will complete a daily patient-reported sleep diary to record self-reported narcolepsy symptoms. Participants will record episodes of cataplexy in the diary. The total number of events per week will be calculated. | Baseline up to Week 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Drug therapy