PART A and PART DTo 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 To assess the efficacy of TAK-994 on reducing excessive daytime…
ID
Source
Brief title
Condition
- Sleep disturbances (incl subtypes)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
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..
Secondary outcome
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 * is the length of the dosing interval [AUC*]
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.
Background summary
The orexinergic (OX) system is a major wake-promoting system of the brain. The
OX system acts to coordinate and synchronize the wake-promoting centers of the
brain.
Narcolepsy has been classified on the basis of the presence or absence of
cataplexy and on levels associated with demonstrably absent or low levels of OX
in the cerebrospinal fluid (CSF). Narcolepsy Type 1 (NT1) is characterized by
Excessive Daytime Sleepines (EDS) and the presence of cataplexy. CSF levels of
OX are absent or less than one-third of normal (typically <110 pg/mL). In
contrast, patients with Narcolepsy Type 2 (NT2) do not have cataplexy, and CSF
levels of OX are greater than one-third the normal value. Approximately 70% of
those with narcolepsy are classified as having NT1.
Based on the aforementioned data demonstrating that partial or complete OX
deficiency plays an important role in the development of EDS, OX replacement
therapy is expected to improve EDS through a pathophysiology-directed mechanism
of action. A novel drug that acts to help address the deficiency of OX may
address the spectrum of narcolepsy symptoms and may have greater efficacy than
currently approved drugs for EDS and cataplexy.
TAK-994 is a first-in-class, orally available, highly selective OXR agonist
being developed by Takeda for the treatment of narcolepsy with or without
cataplexy (NT1 or NT2).
In non-clinical pharmacology studies, TAK-994 showed strong wakefulness
promoting effects in wild type animals who have normal OX levels. The primary
potential risk from nonclinical safety data, is increased BP and is considered
limited to the mode of action.
TAK-994 has previously been studied in healthy subjects and showed no major
safety concerns.
Study objective
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
To assess the efficacy of TAK-994 on reducing excessive daytime sleepiness as
measured by prolongation of sleep onset in MWT procedure.
Study design
This is a phase 2, randomized, double-blind, placebo-controlled study to assess
the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of
multiple oral doses of TAK-994 administered to subjects with narcolepsy type 1
(NT1) or type 2 (NT2). The study will be conducted in 4 parts (A, B, C, and D).
Intervention
Part A:
Part A subjects will receive TAK-994 or matching placebo twice daily (BID)
(with randomization ratio of 2:1).
Part B:.
Part B will have 4 parallel arms with subjects randomized to 1 of 3 different
TAK-994 dose levels (dose 1, 2 or 3) or placebo in 1:1:1:1 ratio.
Part C (China-specific): art C subjects will receive TAK-994 BID or matching
placebo at a ratio of 2:1.
Part D:
Part D subjects will be randomized in a ratio of 2:1 to receive TAK-994 BID or
matching placebo.
Study burden and risks
Burden:
For part B the participation in the study will last for up to 110 days (56 days
treatment). During the study, there will be certain visits which involve an
overnight stay at the hospital. This will occur at least 3 and up to 5 times
(at least 6 nights and up to 8 nights).
For part D the participation will last for up to 82 days (28 days treatment).
During the study, there will be certain visits which involve an overnight stay
at the hospital. This will occur at least 3 and up to 5 times (at least 6
nights and up to 8 nights).
Part A and part C are not applicable for the Netherlands.
Subjects will need to fast at certain periods during the study, they need to
complete questionnaires, wear an accelerometer and complete an e-diary for the
study period, wear an Ambulatory Blood Pressure Monitoring device on certain
days and they will have a nocturnal polysomnography (nPSG) and a Maintenance of
Wakefulness Test (MWT) on various timepoints during the study. Furthermore, a
Multi Sleep Latency Test (MSLT) can be performed as a pre-screening assessment
in case not performed within the last 10 years.
Also venapunctures will be done at various days, and for part B there is an
optional CSF collection.
.
Risks:
No serious adverse events were reported in previous studies; the adverse events
observed in study participants to date varied from mild to moderate mostly
included Dizziness, Headache, Paresthesia (tingling or pricking), Nausea,
Urinary urgency (urgent need to pee), Increased sweating, Muscle weakness,
Frequent peeing, Urinary incontinence/incontinence (loss of bladder control),
Dysuria (painful urination), Excessively cautious (state of excessive
attention), Pain in the back and lower back, Insomnia (inability to sleep),
Euphoric mood (excitement and intense feelings), Increases in liver enzyme,
Heart rate increased and Blood pressure increased
Risk-benefit analyses
Patients with Narcolepsy are deficient or low in OX and hence are the first
individuals who would most benefit from treatment with an OXR agonist.
This study has been designed to mitigate potential safety risks based on
clinical and nonclinical findings. The principal mitigation strategy for these
risks includes appropriate selection of the study population; intermittent use
of the inpatient clinical research unit setting; and appropriate specified
monitoring procedures;
Overall, there is manageable risk associated with the proposed study.
Review of data supports a favorable benefit/risk ratio for this study of
TAK-994. To date, the observed nonclinical and clinical safety data for
TAK-994, including mild and manageable AEs, are acceptable considering its
potential clinical benefit.
Hayden Avenue 95
Lexington MA 02421
US
Hayden Avenue 95
Lexington MA 02421
US
Listed location countries
Age
Inclusion criteria
To be eligible for randomization on Day 1, subjects must:
Be male or female, 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.
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 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.
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.
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.
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.
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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2020-000777-24-NL |
| ClinicalTrials.gov | NCT04096560 |
| CCMO | NL76214.056.21 |