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

Narcolepsy Type 1 (NT1) Clinical Trial

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)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04096560
• Other study ID #: TAK-994-1501
• Secondary ID: JapicCTI-2051782
• Status: Terminated
• Phase: Phase 2
• Start date: February 27, 2020
• Est. completion date: November 5, 2021

Study information

• Verified date: March 2023
• Source: Takeda
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 257
• Est. completion date: November 5, 2021
• Est. primary completion date: November 5, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 65 Years

Eligibility

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.

Related Conditions & MeSH terms

• Narcolepsy
• Narcolepsy Type 1 (NT1)
• Narcolepsy Type 2 (NT2)

Intervention

Drug:
• TAK-994
TAK-994 tablets.
• Placebo
TAK-994 placebo-matching tablets.

Locations

Country	Name	City	State
Canada	West Ottawa Sleep Centre	Ottawa	Ontario
Canada	Jodha Tishon Inc.	Toronto	Ontario
Canada	Toronto Sleep Institute	Toronto	Ontario
China	Xuanwu Hospital Capital Medical University	Beijing	Beijing
China	The First Hospital of Jilin University	Changchun	Jilin
China	Huashan Hospital, Fudan University	Shanghai	Shanghai
China	The First Affiliated Hospital of Jinan University	Tianhe	Guangdong
Czechia	Fakultni nemocnice Hradec Kralove	Hradec Kralove
Czechia	Fakultni nemocnice Ostrava	Ostrava
Czechia	Vseobecna fakultni nemocnice v Praze	Praha 2
Finland	Terveystalo Helsinki Uniklinikka	Helsinki
Finland	Turku University Hospital	Turku
France	Hopital Roger Salengro - CHU Lille	Lille	Nord
France	Hopital Gui de Chauliac	Montpellier	Herault
Hungary	SomnoCenter Budapest	Budapest
Italy	Universita di Bologna-Clinica Neurologica-Dipartimento di Scienze Neurologiche	Bologna
Italy	Ospedale San Raffaele (San Raffaele Turro)	Milano
Italy	Azienda Ospedaliera Universitaria Policlinico Tor Vergata	Roma
Italy	IRCCS Oasi Maria SS	Troina	Enna
Japan	Koishikawa Tokyo Hospital	Bunkyo-ku	Tokyo-To
Japan	SOUSEIKAI PS Clinic	Fukuoka-shi	Fukuoka-Ken
Japan	Jinyukai Kotorii Isahaya Hospital	Isahaya-shi	Nagasaki-Ken
Japan	Nihon University Itabashi Hospital	Itabashi-ku	Tokyo-To
Japan	You Ariyoshi Sleep Clinic	Kitakyushu-shi	Fukuoka-Ken
Japan	Howakai Kuwamizu Hospital	Kumamoto-shi	Kumamoto-Ken
Japan	Kurume University Hospital	Kurume-shi	Fukuoka-Ken
Japan	Shunkaikai Inoue Hospital	Nagasaki-shi	Nagasaki-Ken
Japan	Gokeikai Osaka Kaisei Hospital	Osaka-shi	Osaka-Fu
Japan	Kyowakai Hannan Hospital	Sakai-shi	Osaka-Fu
Japan	Yoyogi Sleep Disorder Center	Shibuya-ku	Tokyo-To
Japan	Sleep & Stress Clinic	Shinagawa-ku	Tokyo-To
Japan	Sleep Support Clinic	Shinagawa-ku	Tokyo-To
Japan	Sumida Hospital	Sumida-ku	Tokyo-To
Japan	Kaiseikai Kita Shin Yokohama Internal Medicine Clinic	Yokohama-shi	Kanagawa-Ken
Korea, Republic of	Keimyung University Dongsan Hospital	Daegu
Korea, Republic of	The Catholic University of Korea, St. Vincent's Hospital	Suwon-si	Gyeonggi-do
Netherlands	Stichting Epilepsie Instelling Nederland, Heemstede	Heemstede
Netherlands	Kempenhaeghe, Heeze	Heeze
Spain	Hospital Clinic de Barcelona	Barcelona
Spain	Hospital General de Castellon	Castellon de la Plana	Castellon
Spain	Hospital Vithas Nuestra Senora de America	Madrid
Spain	Hospital Universitario Araba Sede Santiago	Vitoria	Alava
United States	Wright Clinical Research	Alabaster	Alabama
United States	NeuroTrials Research, Inc.	Atlanta	Georgia
United States	CITrials - Bellflower	Bellflower	California
United States	Boston Children's Hospital	Boston	Massachusetts
United States	Alpine Clinical Research Center	Boulder	Colorado
United States	Medical University of South Carolina (MUSC)	Charleston	South Carolina
United States	Helene A. Emsellem, MD PC trading as "The Center for Sleep & Wake Disorders"	Chevy Chase	Maryland
United States	CTI Clinical Research Center	Cincinnati	Ohio
United States	Intrepid Research	Cincinnati	Ohio
United States	St. Francis Medical Institute	Clearwater	Florida
United States	The Cleveland Clinic Foundation	Cleveland	Ohio
United States	Delta Waves Sleep Disorders and Research Center	Colorado Springs	Colorado
United States	Bogan Sleep Consultants, LLC	Columbia	South Carolina
United States	iResearch Atlanta, LLC	Decatur	Georgia
United States	Research Carolina Elite LLC	Denver	North Carolina
United States	Ohio Sleep Medicine and Neuroscience Institute	Dublin	Ohio
United States	Lutheran Sleep Disorder Center	Fort Wayne	Indiana
United States	Clinical Research of Gastonia	Gastonia	North Carolina
United States	Hawaii Pacific Neuroscience	Honolulu	Hawaii
United States	University of Kansas Medical Center Research Institute, Inc.	Kansas City	Kansas
United States	Santa Monica Clinical Trials	Los Angeles	California
United States	Sleep Practitioners, LLC	Macon	Georgia
United States	Clinical Trials of Florida	Miami	Florida
United States	Sleep Medicine Specialists of South Florida	Miami	Florida
United States	Neurocare, Inc., dba Neurocare Center for Research	Newton	Massachusetts
United States	Mayo Clinic Arizona	Phoenix	Arizona
United States	Raleigh Neurology Associates	Raleigh	North Carolina
United States	Stanford School of Medicine	Redwood City	California
United States	Sleep Therapy & Research Center	San Antonio	Texas
United States	Pacific Research Network, Inc	San Diego	California
United States	SDS Clinical Trials, Inc.	Santa Ana	California
United States	Global Research Associates	Stockbridge	Georgia
United States	Comprehensive Sleep Medicine Associates	Sugar Land	Texas
United States	JSV Clinical Research Study, Inc	Tampa	Florida
United States	Florida Pulmonary Research Institute, LLC	Winter Park	Florida
United States	Respiratory Specialists	Wyomissing	Pennsylvania

Sponsors (1)

Lead Sponsor	Collaborator
Takeda

Countries where clinical trial is conducted

United States,  Canada,  China,  Czechia,  Finland,  France,  Hungary,  Italy,  Japan,  Korea, Republic of,  Netherlands,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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
Primary	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
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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)
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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

External Links

•   : To obtain more information on the study, click here/on this link