Clinical trial NCT04096560: A Study of TAK-994 in Adults With Type 1 and Type 2 Narcolepsy
Official title: 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)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Narcolepsy Type 1 (NT1)
Narcolepsy Type 2 (NT2)
Keywords: Drug therapy
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2019-09-20
Enrollment: 97
Sex: ALL
Minimum age (years): 18
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Criteria:

1. 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.
2. The participant's Epworth Sleepiness Scale (ESS) score must be greater than or equal to (\>=) 10 at Day -1.
3. Must be willing to discontinue all medications used for the treatment of NT1/NT2.
4. 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 .
5. 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:

1. 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.
2. Is an excessive (\>600 mg/day) caffeine user 1 week before to the study screening.
3. 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.
4. 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.
5. 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.
6. 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.
7. Has a local infection at the puncture site.
8. Has developed signs of lumbar radiculopathy, including lower extremity pain and paresthesia.
9. Has any known focal neurological deficit that might suggest an increase in intracranial pressure.

Primary outcomes:
measure: Part A: Number of Participants Who Experience at Least One Treatment Emergent Adverse Event (TEAE) During the Study
timeFrame: First dose of study treatment to end of study follow-up (up to Day 35) in Part A
measure: Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study
timeFrame: First dose of study treatment to end of study follow-up (up to Day 35) in Part A
measure: Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study
timeFrame: First dose of study treatment to end of study follow-up (up to Day 35) in Part A
measure: Part A: Number of Participants Who Meet the Markedly Abnormal Value Criteria for Safety Electrocardiogram (ECG) Parameters at Least Once Postdose During the Study
timeFrame: First dose of study treatment to end of study follow-up (up to Day 35) in Part A
measure: Parts B and C: Change From Baseline in Average Sleep Latency as Assessed by the Maintenance of Wakefulness Test (MWT)
timeFrame: Baseline and Week 8 (Day 56) in Parts B and C
Secondary outcomes:
measure: Part A: Cmax: Maximum Observed Plasma Concentration After Single Dose of TAK-994 at Day 1
timeFrame: Pre-dose and at multiple time points (up to 14 hours) post-dose at Day 1 in Part A
measure: Part A: Tmax: Time of First Occurrence of Cmax After Single Dose of TAK-994 at Day 1
timeFrame: Pre-dose and at multiple time points (Up to 14 hours) post-dose at Day 1 in Part A
measure: Part A: 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 at Day 1
timeFrame: Pre-dose and at multiple time points (up to 24 hours) post-dose at Day 1 in Part A
measure: Part A: Cmax: Maximum Observed Plasma Concentration After Multiple Doses of TAK-994 at Day 28
timeFrame: Pre-dose and at multiple time points (up to 14 hours) post-dose at Day 28 in Part A
measure: Part A: Tmax: Time of First Occurrence of Cmax After Multiple Doses of TAK-994 at Day 28
timeFrame: Pre-dose and at multiple time points (up to 14 hours) post-dose at Day 28 in Part A
measure: Part A: AUC(0-t): Area Under the Concentration-time Curve From Time 0 to Time Tau Over a Dosing Interval of TAK-994 at Day 28
timeFrame: Pre-dose and at multiple time points (Up to 12 hours) post-dose at Day 28 in Part A
measure: Parts B and C: Change From Baseline in the Epworth Sleepiness Scale (ESS) Total Score to Week 8
timeFrame: Baseline and Week 8 (Day 56) in Parts B and C
measure: Parts B and C: Change From Baseline in Weekly Cataplexy Rate (WCR) at Week 8
timeFrame: Baseline and Week 8 (Day 56) in Parts B and C
measure: Parts B and C: Number of Participants Who Experience at Least 1 TEAE During the Study
timeFrame: First dose of study drug to end of study follow-up (up to Day 63) in Parts B and C
measure: Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Safety Laboratory Tests at Least Once Postdose During the Study
timeFrame: Up to Day 63 in Parts B and C
measure: Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for Vital Sign Measurements at Least Once Postdose During the Study
timeFrame: Up to Day 63 in Parts B and C
measure: Parts B and C: Number of Participants Who Met the Markedly Abnormal Value Criteria for ECG Parameters at Least Once Postdose During the Study
timeFrame: Up to Day 63 in Parts B and C
Other outcomes:
Locations:
city: Alabaster
country: United States
facility: Wright Clinical Research
state: Alabama
city: Phoenix
country: United States
facility: Mayo Clinic Arizona
state: Arizona
city: Bellflower
country: United States
facility: CITrials - Bellflower
state: California
city: Los Angeles
country: United States
facility: Santa Monica Clinical Trials
state: California
city: Redwood City
country: United States
facility: Stanford School of Medicine
state: California
city: San Diego
country: United States
facility: Pacific Research Network, Inc
state: California
city: Santa Ana
country: United States
facility: SDS Clinical Trials, Inc.
state: California
city: Boulder
country: United States
facility: Alpine Clinical Research Center
state: Colorado
city: Colorado Springs
country: United States
facility: Delta Waves Sleep Disorders and Research Center
state: Colorado
city: Clearwater
country: United States
facility: St. Francis Medical Institute
state: Florida
city: Miami
country: United States
facility: Sleep Medicine Specialists of South Florida
state: Florida
city: Miami
country: United States
facility: Clinical Trials of Florida
state: Florida
city: Tampa
country: United States
facility: JSV Clinical Research Study, Inc
state: Florida
city: Winter Park
country: United States
facility: Florida Pulmonary Research Institute, LLC
state: Florida
city: Atlanta
country: United States
facility: NeuroTrials Research, Inc.
state: Georgia
city: Decatur
country: United States
facility: iResearch Atlanta, LLC
state: Georgia
city: Macon
country: United States
facility: Sleep Practitioners, LLC
state: Georgia
city: Stockbridge
country: United States
facility: Global Research Associates
state: Georgia
city: Honolulu
country: United States
facility: Hawaii Pacific Neuroscience
state: Hawaii
city: Fort Wayne
country: United States
facility: Lutheran Sleep Disorder Center
state: Indiana
city: Kansas City
country: United States
facility: University of Kansas Medical Center Research Institute, Inc.
state: Kansas
city: Chevy Chase
country: United States
facility: Helene A. Emsellem, MD PC trading as "The Center for Sleep & Wake Disorders"
state: Maryland
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Newton
country: United States
facility: Neurocare, Inc., dba Neurocare Center for Research
state: Massachusetts
city: Denver
country: United States
facility: Research Carolina Elite LLC
state: North Carolina
city: Gastonia
country: United States
facility: Clinical Research of Gastonia
state: North Carolina
city: Raleigh
country: United States
facility: Raleigh Neurology Associates
state: North Carolina
city: Cincinnati
country: United States
facility: CTI Clinical Research Center
state: Ohio
city: Cincinnati
country: United States
facility: Intrepid Research
state: Ohio
city: Cleveland
country: United States
facility: The Cleveland Clinic Foundation
state: Ohio
city: Dublin
country: United States
facility: Ohio Sleep Medicine and Neuroscience Institute
state: Ohio
city: Wyomissing
country: United States
facility: Respiratory Specialists
state: Pennsylvania
city: Charleston
country: United States
facility: Medical University of South Carolina (MUSC)
state: South Carolina
city: Columbia
country: United States
facility: Bogan Sleep Consultants, LLC
state: South Carolina
city: San Antonio
country: United States
facility: Sleep Therapy & Research Center
state: Texas
city: Sugar Land
country: United States
facility: Comprehensive Sleep Medicine Associates
state: Texas
city: Ottawa
country: Canada
facility: West Ottawa Sleep Centre
state: Ontario
city: Toronto
country: Canada
facility: Toronto Sleep Institute
state: Ontario
city: Toronto
country: Canada
facility: Jodha Tishon Inc.
state: Ontario
city: Beijing
country: China
facility: Xuanwu Hospital Capital Medical University
state: Beijing
city: Tianhe
country: China
facility: The First Affiliated Hospital of Jinan University
state: Guangdong
city: Changchun
country: China
facility: The First Hospital of Jilin University
state: Jilin
city: Shanghai
country: China
facility: Huashan Hospital, Fudan University
state: Shanghai
city: Hradec Kralove
country: Czechia
facility: Fakultni nemocnice Hradec Kralove
city: Ostrava
country: Czechia
facility: Fakultni nemocnice Ostrava
city: Praha 2
country: Czechia
facility: Vseobecna fakultni nemocnice v Praze
city: Helsinki
country: Finland
facility: Terveystalo Helsinki Uniklinikka
city: Turku
country: Finland
facility: Turku University Hospital
city: Montpellier
country: France
facility: Hopital Gui de Chauliac
state: Herault
city: Lille
country: France
facility: Hopital Roger Salengro - CHU Lille
state: Nord
city: Budapest
country: Hungary
facility: SomnoCenter Budapest
city: Troina
country: Italy
facility: IRCCS Oasi Maria SS
state: Enna
city: Bologna
country: Italy
facility: Universita di Bologna-Clinica Neurologica-Dipartimento di Scienze Neurologiche
city: Milano
country: Italy
facility: Ospedale San Raffaele (San Raffaele Turro)
city: Roma
country: Italy
facility: Azienda Ospedaliera Universitaria Policlinico Tor Vergata
city: Fukuoka-shi
country: Japan
facility: SOUSEIKAI PS Clinic
state: Fukuoka-Ken
city: Kitakyushu-shi
country: Japan
facility: You Ariyoshi Sleep Clinic
state: Fukuoka-Ken
city: Kurume-shi
country: Japan
facility: Kurume University Hospital
state: Fukuoka-Ken
city: Yokohama-shi
country: Japan
facility: Kaiseikai Kita Shin Yokohama Internal Medicine Clinic
state: Kanagawa-Ken
city: Kumamoto-shi
country: Japan
facility: Howakai Kuwamizu Hospital
state: Kumamoto-Ken
city: Isahaya-shi
country: Japan
facility: Jinyukai Kotorii Isahaya Hospital
state: Nagasaki-Ken
city: Nagasaki-shi
country: Japan
facility: Shunkaikai Inoue Hospital
state: Nagasaki-Ken
city: Osaka-shi
country: Japan
facility: Gokeikai Osaka Kaisei Hospital
state: Osaka-Fu
city: Sakai-shi
country: Japan
facility: Kyowakai Hannan Hospital
state: Osaka-Fu
city: Bunkyo-ku
country: Japan
facility: Koishikawa Tokyo Hospital
state: Tokyo-To
city: Itabashi-ku
country: Japan
facility: Nihon University Itabashi Hospital
state: Tokyo-To
city: Shibuya-ku
country: Japan
facility: Yoyogi Sleep Disorder Center
state: Tokyo-To
city: Shinagawa-ku
country: Japan
facility: Sleep Support Clinic
state: Tokyo-To
city: Shinagawa-ku
country: Japan
facility: Sleep & Stress Clinic
state: Tokyo-To
city: Sumida-ku
country: Japan
facility: Sumida Hospital
state: Tokyo-To
city: Suwon-si
country: Korea, Republic of
facility: The Catholic University of Korea, St. Vincent's Hospital
state: Gyeonggi-do
city: Daegu
country: Korea, Republic of
facility: Keimyung University Dongsan Hospital
city: Heemstede
country: Netherlands
facility: Stichting Epilepsie Instelling Nederland, Heemstede
city: Heeze
country: Netherlands
facility: Kempenhaeghe, Heeze
city: Vitoria
country: Spain
facility: Hospital Universitario Araba Sede Santiago
state: Alava
city: Castellon de la Plana
country: Spain
facility: Hospital General de Castellon
state: Castellon
city: Barcelona
country: Spain
facility: Hospital Clinic de Barcelona
city: Madrid
country: Spain
facility: Hospital Vithas Nuestra Senora de America
Study officials:
affiliation: Takeda
name: Medical Director
role: STUDY_DIRECTOR
References: