narcolepsy

Evaluating the efficacy of ALKS 2680 in treating EDS in NT1 participants.

ALKS 2680 2 mg tablet
ALKS 2680 4 mg tablet
ALKS 2680 6 mg tablet
ALKS 2680 Placebo Tablet Orange

ALKS 2680
ALKS 2680
ALKS 2680
NA

Tablets
Tablets
Tablets
Tablets

2 mg
4 mg
6 mg
NA

Variation in mean sleep onset time from baseline to week 12 in wakefulness maintenance tests, differentiated by dose concentration.

Each participant in this trial must meet all of the following inclusion criteria:

1. Be between 18 and 70 years of age at the time of signing the participant consent form.

2. Be willing and able to provide participant consent prior to participation, in accordance with local regulations and the requirements of the Independent Ethics Committee (IEC).

3. Have a body mass index (BMI) ≥18 and ≤40 kg/m² at the first follow-up visit.

4. Meet the diagnostic criteria for NT1 according to the ICSD-3-TR (International Classification of Sleep Disorders [Third Edition], revised in written form), and be confirmed by diagnostic evaluation (PSG [Multiple Physiological Examination of Sleep]/MSLT [Multiple Sleep Latency Test]* or CSF [Cephalospinal Fluid] Hypothalamic-1 concentration).

In addition, meet the following trial protocol requirements:

a. Demonstrate residual EDS (Excessive Daytime Sleepiness) with a total ESS (Epworth Sleepiness Scale) score >12 at the fourth follow-up visit. b. Confirmed HLA (Human Leukocyte Antigen)-DQB1*06:02 positivity via past medical history or at the first follow-up visit, or a recorded hypothalamic-pituitary-1 (CSF) concentration ≤110 pg/mL**.

c. An average of >4 cataplexy events per week during the last two weeks of the screening period.

d. MSL (mean sleep latency) ≤15 minutes in 4 MWT (maintenance of wakefulness) tests performed during the screening period.

* If no prior diagnostic PSG/MSLT is available, the testing unit may repeat confirmatory assessments during the screening period with prior authorization from the client.

** If clear NT1 diagnostic features are present (e.g., cataplexy, REM sleep onset, and short sleep latency), and with prior authorization from the client, hypothalamic-pituitary-1 concentration can be collected and analyzed via lumbar puncture during the screening period.

5. The cataplexy pre-screening questionnaire has been reviewed and approved by the external NT1 adjudication committee.

6. Based on the trial administrator's judgment, the candidate can safely discontinue any medication during the trial and adhere to all washout periods detailed in the trial protocol (including medications prescribed to manage narcolepsy symptoms).

7. Based on the trial administrator's judgment, the candidate is willing and able to understand and follow the requirements of the trial protocol, including the following:

a. Lifestyle considerations and restrictions detailed in the trial protocol.

b. Contraception guidelines detailed in the trial protocol.

8. The candidate is willing and able to follow the requirements of the wrist movement meter, cataplexy log (completion rate ≥70%), and sleep log during the screening period.

9. If currently receiving OSA (obstructive sleep apnea) treatment, the candidate must adhere to primary OSA treatment for 30 days prior to the first follow-up visit (as confirmed by the trial administrator) and throughout the trial period (including overnight follow-ups). Compliance is defined as follows:

− Positive pressure ventilation (NPPV) for ≥4 hours per night for ≥70% of the nights (≥5 out of 7 nights per week), and for ≥4 hours per night during overnight follow-up visits.

− Intraoral devices are used for ≥70% of the nights (≥5 out of 7 nights per week) and during overnight follow-up visits.

Participants in this trial must not meet any of the following exclusion criteria: Sleep Disorders
1. Poorly controlled and clinically significant sleep-disordered breathing (according to the AASM [American Academy of Sleep Medicine] Scoring Manual [Rule 1B]) at the most recent diagnostic PSG or at the 4th follow-up visit:

a. Apnea-hypopnea index ≥15 per hour.

b. If undergoing OSA treatment, an average apnea-hypopnea index ≥10 per hour within the 30 days prior to the 1st follow-up visit.

c. Central apnea index >5 per hour.

2. Other comorbid sleep disorders or conditions that may affect the sleep-wake cycle:

a. Narcolepsy symptoms secondary to other medical conditions (e.g., central nervous system injury or lesion, craniopharyngioma).

b. Have worked shift work (night shift) or engaged in other life activities (e.g., continuous nighttime care for a child waking up at night) that disrupt regular nighttime sleep within the past 30 days prior to the 4th follow-up visit.

c. Have an implanted hypoglossal nerve stimulation device (e.g., the Inspire® upper respiratory tract stimulation system).

d. Have a nicotine dependence that affects sleep (e.g., participants who habitually wake up at night to smoke).

e. Have excessive caffeine use in the week prior to the 4th follow-up visit, or are expected to have excessive caffeine use during the trial (defined as caffeine >600 mg/day).

Medical Conditions:

3. Have had a major cardiovascular event, including the following, within 2 years prior to the screening period or the 1st follow-up visit:

a. Myocardial infarction, ischemic heart disease, heart failure, or clinically significant arrhythmia (including atrial fibrillation).

b. Atrial fibrillation, or an abnormal ECG showing a clinically significant arrhythmia, including a QT interval >450 msec (male) and >470 msec (female) after Fridericia formula correction. Left bundle branch block is not an exclusion criterion if the study administrator determines it to be an asymptomatic and clinically insignificant isolated ECG finding.

c. Sinus tachycardia with a resting heart rate (HR) >100 beats per minute, confirmed by a repeat measurement approximately 30 minutes after the initial measurement. If the HR is greater than 100 and the study administrator believes it is related to a reversible cause (e.g., tachycardia associated with stimulant use, expected to resolve after drug washout), the HR measurement may be repeated before or on the day of the fourth follow-up visit.

d. Uncontrolled hypertension, defined as systolic blood pressure >140 mmHg or diastolic blood pressure >90 mmHg during the first follow-up visit. One repeat test is permitted, but must be performed on the same day as the initial measurement. If the retest result is >140/90 mm Hg, the participant should be considered a screening failure; however, rescreening is permitted, but only after their BP has stabilized and is ≤140/90 mm Hg. In this case, rescreening must be performed at least 7 days after the initial BP value was measured.

e. Uncontrolled diabetes mellitus, defined as a hemoglobin (HbA1c) concentration >7%.

4. Major mental illness or substance use disorder as determined by the Diagnostic and Statistical Manual of Mental Disorders (5th Edition), including the following:

a. Schizophrenia spectrum disorder (i.e., schizophrenia, schizophrenia-like disorder, affective schizophrenia, acute or chronic psychotic disorder).

b. Bipolar disorder.

c. A major depressive episode currently or recently (within the past 12 months).

d. Currently diagnosed or previously (within the past 2 years) with moderate or severe substance use disorder.

e. The participant is currently at risk of suicidal behavior, or answered "yes" to question 4 or 5 of the C-SSRS (Columbia Suicide Severity Scale), and/or had a suicide attempt within the 12 months prior to the first follow-up visit up to the day of the fourth follow-up visit (inclusive).

5. Having other clinically significant (treated or untreated) illnesses, conditions, abnormalities, or surgical procedures in the past or at the first follow-up visit that, as determined by the trial administrator, may jeopardize the participant's safety, interfere with any trial assessments, or affect the participant's ability to complete the trial. This includes, but is not limited to, other major neurological disorders, including dementia, neurodegenerative disorders, stroke, or seizures (excluding simple febrile seizures in children).

6. Currently or recently (within the past 6 months) suffering from a gastrointestinal disorder that is expected to affect drug absorption (i.e., a history of malabsorption or any surgical intervention). Any history of Roux-en-Y gastric bypass surgery and any other gastric surgical intervention that may affect drug absorption is considered an exclusion criterion.

7. History of cancer within the past 5 years (treated or untreated) (Not applicable to participants with remission of carcinoma in situ requiring no further treatment, or basal cell carcinoma; these participants may be included with the approval of the trial commissioner or their designated personnel).

8. Known risk of angle-stenotic glaucoma (e.g., occlusive anterior chamber angle stenosis) or a history of angle-stenotic glaucoma.

Laboratory Evaluation:

9. Positive breathalyzer test or urine drug screening for possible abuse at the 4th follow-up visit.

10. The following laboratory abnormalities were present at the 1st follow-up visit (one repeat test may be permitted at the discretion of the trial administrator), including:

a. ALT (alanine transaminase) or AST (aspartate transaminase) elevated to >1.5 times the ULN (upper limit of normal). If the initial value is >3 times the ULN, retesting is not permitted; if the initial value is between 1.5 and 3 times the ULN, one retest is permitted during screening. ALT or AST values ​​>1.5 times the ULN must be recorded as medical history or pre-treatment adverse events (AEs) (if applicable).

b. History of HIV (human immunodeficiency virus) infection (participant previously tested positive for HIV-1 or HIV-2 antibodies), history of hepatitis B infection, or currently having active hepatitis C infection at the first follow-up visit.

Note: Participants who have been vaccinated against hepatitis B (positive for hepatitis B surface antibody) and whose other previous hepatitis B infection markers were negative (e.g., negative for hepatitis B core antibody) are eligible. Also note that participants who tested positive for hepatitis C antibodies are eligible if their hepatitis C viral load is negative by quantitative polymerase chain reaction (PCR).

c. Renal creatinine clearance (Cockcroft-Gault formula) ≤50 mL/min.

Medications:
11. Currently using (or planning to use) any prohibited prescription medications, including strong/moderate-intensity P-gp and/or CYP3A (cytochrome P450 3A) inhibitors (strong and moderate-intensity) listed in the trial protocol, or OTC (over-the-counter) medications, or will be unable to comply with the washout period required by the trial protocol.

12. Currently using, or having used, any antidepressant for any reason other than cataplexy control within the past 6 months. Antidepressants will be washed out during the screening period.

General:
13. Currently pregnant, breastfeeding, or planning to become pregnant during the trial.

14. Currently enrolled in another interventional clinical trial, or having received any investigational medication or used any interventional investigational device within 30 days prior to the first follow-up visit. Participants previously enrolled in the ALKS 2680-201 trial are ineligible for inclusion.

15. Employed by Alkermes, a CRO (Contract Research Organization), or a trial facility (as a permanent employee, temporary contract employee, or designated person responsible for trial execution), or an immediate family member (i.e., spouse, parent, sibling, or child, whether by blood or legal adoption) of an Alkermes, CRO, or trial facility employee.