| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Narcolepsy With or Without Cataplexy |
| Narkoleszpia kataplexiával vagy kataplexia nélkül |
|
| E.1.1.1 | Medical condition in easily understood language |
| Extreme sleepiness With or Without episodes of sudden muscle weakness |
| Extrém álmosság hirtelen fellépő izomgyengeséggel vagy anélkül |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
PART A and PART D
To assess the safety and tolerability of TAK-994 following multiple oral
doses in subjects with narcolepsy with or without cataplexy (NT1 or NT2).
PART B and PART C (Primary Efficacy Objectives)
To assess the efficacy of TAK-994 on reducing excessive daytime sleepiness as measured by prolongation of sleep onset in MWT procedure. |
|
| E.2.2 | Secondary objectives of the trial |
PART A and PART D
To characterize the PK of TAK-994 following multiple oral doses in
subjects with narcolepsy with or without cataplexy (NT1 or NT2).
PART B and PART C (Secondary Objectives)
To assess the efficacy of TAK-994 on WCR and ESS reduction.
To assess the safety and tolerability of TAK-994 following chronic administration. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Main Criteria for Inclusion:
To be eligible for randomization on Day 1, subjects must:
Be male or female subjects aged 18 to 65 years (inclusive), at the time of informed consent.
Be judged in good health by the investigator based on clinical evaluations including laboratory safety tests. See Section 7.1 for details.
Have a body mass index ≥17.0 and ≤40.0 kg/m2 at the screening visit).
Have a diagnosis of NT1 (PARTS A, B and C) or NT2 (PART D) (as per International Classification of Sleep Disorders - 3rd Edition) made by 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 ICSD-3 Note: If there is a potential subject with a diagnosis of NT1 or NT2 whose diagnostic nPSG/MSLT was performed more than 10 years ago or is not available, special exemptions, ie, ability of the site to repeat the diagnostic PSG/MSLT will be considered on a case-by-case basis after discussions between the investigator and the sponsor or designee.
Have ≥10 ESS score at Day -1.
Part A: the human leukocyte antigen (HLA) genotype should test positive for HLA-DQB1*06:02 - (positive results for either homozygous or heterozygous alleles will be considered "positive" and acceptable). However, if the HLA test is negative (ie. negative for the heterozygous allele) and the PI feels strongly that the subject 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 subject's cerebrospinal fluid (CSF) orexin-1 (OX-1) level.
If the CSF result shows the OX-1 concentration is either less than or equal to 110 pg/mL, or less than one-third of mean values obtained in normal subjects with the same standardized assay, then the diagnosis of NT1 is established allowing the subject to be enrolled and randomized. If
the CSF OX-1 concentration is higher than 110 pg/mL, then the subject will not be allowed to continue in the study. Subjects previously excluded in Part A for being HLA negative will not be included in Part B.
Parts B and C: HLA genotyping will be done for these subjects as well; however, HLA test results are not a study entry criteria. Subjects who present with CSF testing results indicating OX-1 concentration either less than or equal to 110 pg/mL, or less than one-third of mean values obtained in normal subjects with the same standardized assay, may be considered for enrollment into Parts B and C after a discussion with the sponsor or designee. For all subjects in Parts B and C, site staff will complete the cataplexy questionnaire during screening. This questionnaire along with a copy of the most recent PSG/MSLT report will be submitted to the sponsor for adjudication by a committee of experts in the field of narcolepsy/cataplexy to be chosen by the sponsor. This committee will to determine eligibility for the study and the committee's determination will be final for study entry criteria. Additional documentation may be requested by the sponsor.
For Parts A, B, and C during the screening period, the subject must have ≥4 partial or complete episodes of cataplexy/week (WCR), averaged over 2 weeks (14 consecutive days) minimum. WCR recording taken during the following period will be considered for study eligibility: after the patient has stopped taking anticataplexy medications for at least 7 days (minimum 7-day washout) and completed before study Day -2.
Refer to Section 9.3.2.7 for details.
Be willing to discontinue all medications used for the treatment of NT1 or NT2.
BP <140 mmHg (systolic) and <90 mmHg (diastolic). The subject may have a history of hypertension and be on antihypertensive medication
treatment as long as the BP meets these criteria. BP measurements
should be obtained after the subject has been resting for a minimum of 10 minutes and will be repeated 3 times. The median BP obtained will be
used. |
|
| E.4 | Principal exclusion criteria |
A subject must be excluded from participating in the study if the subject:
Has a positive pregnancy test or is a lactating/nursing female subject.
Has a known hypersensitivity to any component of the formulation of TAK-994 or related compounds.
Has a risk of suicide according to endorsement of Item 4 or 5 of the screening/baseline visit Columbia Suicide Severity Rating Scale and/or has made a suicide attempt in the previous 12 months.
Has a screening ECG with a QT interval with Fridericia’s correction method >450 ms (men) or >470 ms
(women).
Has a resting pulse rate outside of the range of 40 to 100 beats per minute, confirmed on repeat testing within a maximum of 30 minutes.
Has renal creatinine clearance ≤50 mL/min.
Has LFTs (alanine aminotransferase, aspartate aminotransferase) higher than 1.5× ULN at screening.
Is an excessive (>600 mg/day) caffeine user 1 week before the study screening.
Has a history of cancer (does not apply to carcinoma in situ that has been resolved without further treatment or basal cell skin cancer); these subjects may be included after approval by the sponsor or designee.
Has past or current epilepsy or seizure, except for febrile seizure in childhood.
Has a lifetime history of major psychiatric disorder (such as bipolar disorder or schizophrenia), a current active major depressive disorder (MDD), or has had active MDD in the past 6 months.
Has a clinically significant history of head injury or head trauma per the judgment of the investigator.
Has 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
Has current or recent (within 6 months) gastrointestinal disease expected to influence the absorption of drugs.See Section 7.2 for details.
Subjects on fluoxetine (any dose) or on ≥300 mg per day of venlafaxine will be excluded due to the drug's long elimination half-life or clinically significant tapering/washout difficulties. See Section 7.3 for a complete list of medications that are not allowed during the treatment period and the guidelines for washout for stimulant, anticataplexy, antidepressant medications and sodium, and/or multisalt oxybate, when applicable.
Be unwilling to abstain from driving and operating dangerous or hazardous machinery during study
participation, starting from when narcolepsy medications are discontinued and extending until after the follow-up visit (Day 35 ±2 days or Day 63 ±2 days as applicable).
Has a medical disorder (including moderate to severe sleep apnea syndrome with or without treatment with mandibular advanced device hypoglossal nerve stimulation and/or positive airway pressure therapy), other than narcolepsy, associated with excessive daytime sleepiness, or has any other medical condition (eg, anxiety, depression, epilepsy, heart disease, or significant hepatic, pulmonary, or renal disease) that requires the subject to take excluded medications or at the time of screening the subject is being treated with nasal /oro-nasal positive airway pressure for any reason. See Section 7.2 for details.
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 times zones, within 14 days before Study Day -2.
The subject has a nicotine dependence that is likely to have an effect on sleep (eg, a subject 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
PART A and PART D-Primary Endpoints
The primary endpoints assessing safety and tolerability are:
Number of subjects with at least 1 treatment-emergent AE (TEAE) during the study.
Number of subjects with at least 1 markedly abnormal value (MAV) for post dose laboratory values during the study.
Number of subjects with at least 1 MAV for vital signs during the study.
Number of subjects with at least 1 MAV for ECGs during the study.
PART B and PART C-Primary Endpoints:
The primary endpoints assessing efficacy is:
Change from baseline in average sleep latency from MWT to Week 8.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| As defined in the protocol. |
|
| E.5.2 | Secondary end point(s) |
PART A and PART D
The secondary endpoints assessing the PK of TAK-994 are:
Day 1: maximum observed concentration [Cmax], time to reach Cmax [tmax], area under the concentration-time curve [AUC] from time 0 to time of the last quantifiable concentration [AUClast]
Day 28: Cmax, tmax, area under the concentration-time curve during a dosing interval, where τ is the length of the dosing interval [AUCτ]
Secondary Endpoints-PART B and PART C:
The secondary endpoints assessing efficacy are:
Change from baseline in the ESS total score to Week 8.
WCR at Week 8.
The secondary endpoints assessing safety are:
Number of subjects with at least 1 TEAE during the study.
Number of subjects with at least 1 MAV for post dose laboratory values during the study.
Number of subjects with at least 1 MAV for vital signs during the study.
Number of subjects with at least 1 MAV for ECGs during the study. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| As defined in the protocol. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Parallel groups in Part B of the study |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| China |
| Japan |
| Korea, Republic of |
| United States |
| Finland |
| France |
| Hungary |
| Italy |
| Netherlands |
| Spain |
| Czechia |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
The end of the study is defined as when the last subject completes the last planned or follow-up visit/interaction
associated with a planned visit, withdraws from the study, or is lost to follow-up. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | 24 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 24 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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