Study of Lemborexant for Irregular Sleep-Wake Rhythm Disorder and Mild to Moderate Alzheimer's Disease Dementia
Condition: Irregular Sleep-Wake Rhythm Disorder
MeSH terms: Alzheimer Disease; Dementia
Intervention: Lemborexant 2.5 mg; Lemborexant 5 mg; Lemborexant 10 mg; Lemborexant 15 mg; Lemborexant-matched placebo
Intervention description: Lemborexant 2.5 mg tablets; Lemborexant 5 mg tablets; Lemborexant 10 mg tablets; Lemborexant 5 mg and 10 mg tablets; Lemborexant-matched placebo tablets
Intervention MeSH terms: Lemborexant
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 63.0
Sex: All
Minimum age: 60 Years
Maximum age: 90 Years
Healthy volunteers: No
Keywords: Mild to Moderate Alzheimer's Disease Dementia; sleep; circadian rhythms

Summary:

      This study will be conducted to determine the dose response of lemborexant (LEM) on the
      change from baseline in actigraphy-derived sleep-related parameters, wake-related parameters,
      and circadian-rhythm related parameters. Following the eligibility screening period, eligible
      participants will be assigned at random to 1 of 4 doses of LEM or to placebo for 4 weeks.
      After a 2-week follow-up period, eligible participants may enter an open-label extension
      period for up to 30 months or until the program discontinuation.
    

Eligibility criteria:

        Inclusion Criteria (Core Study):

          -  Male or female, age 60 to 90 years at the time of informed consent

          -  Able to provide informed consent. If a participant lacks capacity to consent in the
             investigator's opinion, the participant's assent should be obtained, if required in
             accordance with local laws, regulations and customs, and the written informed consent
             of a legal representative should be obtained (capacity to consent and definition of
             legal representative should be determined in accordance with applicable local laws and
             regulations).

          -  Documentation of diagnosis with Alzheimer's disease dementia (AD-D) on the basis of
             the National Institute on Aging/Alzheimer's Association Diagnostic Guidelines

          -  Mini Mental State Examination 10 to 26 at Screening

          -  Meets criteria for Circadian Rhythm Sleep Disorder, Irregular Sleep-Wake Type
             (Diagnostic and Statistical Manual of Mental Disorders - 5th edition) and the 10th
             revision of the International Classification of Diseases, as follows: Complaint by the
             participant or caregiver of difficulty sleeping during the night and/or excessive
             daytime sleepiness associated with multiple irregular sleep bouts during a 24-hour
             period

          -  Frequency of complaint of sleep and wake fragmentation ≥3 days per week

          -  Duration of complaint of sleep and wake fragmentation ≥3 months

          -  During the Screening Period, mean actigraphy-derived sleep efficiency (aSE) <87.5%
             within the defined nocturnal sleep period and mean actigraphy-derived wake efficiency
             (aWE) <87.5% during the defined wake period

          -  Confirmation by actigraphy of a combination of sleep bouts of >10 minutes during the
             wake period plus wake bouts of >10 minutes during the sleep period, totaling at least
             4 bouts per 24 hours period, ≥ 3 days per week

          -  Ambulatory and living in the community or in a residence not classified as a skilled
             nursing facility (an assisted living facility with separate living quarters where
             participants and their caregivers reside is acceptable)

          -  Willing not to start a behavioral or other treatment program for sleep or wake
             difficulties and not to start a new treatment for other symptoms of AD-D during
             participation in the study

          -  Has a reliable and competent caregiver (or caregiver and informants) who can accompany
             the participant to study visits, administer study medication on a nightly basis and
             provide information on the status of the participant

          -  For participants taking a cholinesterase inhibitor and/or memantine, dosing regimen
             must have been stable for at least 3 months

        Inclusion Criteria (Extension Phase):

          -  Completed the Core Study (End of Study [EOS] Visit). Participants who participated in
             the Core Study and completed the EOS Visit within 30 days may return to participate in
             the Extension Phase as long as there are no contraindications due to ongoing adverse
             events or prohibited medications.

        Inclusion Criteria for Caregivers:

          -  Able to provide informed consent

          -  Spends at least 10 hours per week with the participant

          -  Able to meet caregiver requirements

          -  Willing to provide information on himself/herself regarding sleep quality and
             caregiver Burden

        Exclusion Criteria:

          -  A diagnosis of vascular dementia, dementia following multiple strokes, or any
             synucleinopathy / Lewy body disorder. This includes Dementia with Lewy Bodies and
             Parkinson's disease with or without dementia.

          -  A current diagnosis of moderate to severe obstructive sleep apnea (OSA) or central
             sleep apnea, or current use of continuous positive airways pressure even if mild
             severity of OSA, restless legs syndrome, periodic limb movement disorder (with
             awakenings), or narcolepsy

          -  An Apnea-Hypopnea Index or equivalent ≥15 events/hour on diagnostic sleep study
             conducted prior to Baseline or within 6 months of Screening

          -  A clinically significant movement disorder that would affect the differentiation of
             sleep and wake by the actigraphy analytic algorithm

          -  Current symptoms or history during the past year of Rapid Eye Movement Behavior
             Disorder or sleep-related violent behavior

          -  Probable Major Depression, as evidenced by score >10 on the Cornell Scale for
             Depression in Dementia at Screening

          -  Unable to tolerate wearing the actigraph. At a minimum, participants must be able to
             wear the actigraph for 5 complete days out of 7 days' data. A day will be considered
             complete as long as data from 90% of the 24-hour period are able to be scored.

          -  Excessive caffeine use that in the opinion of the investigator contributes to the
             participant's Irregular Sleep-Wake Rhythm Disorder (ISWRD)

          -  History of drug or alcohol dependency or abuse within approximately the previous 2
             years

          -  Reports habitually consuming more than 14 drinks containing alcohol per week or
             habitually consumes alcohol within 3 hours before bedtime and unwilling to limit
             alcohol intake to 2 or fewer drinks per day or forego having alcohol within 3 hours
             before bedtime for the duration of his/her participation in the study

          -  Known to be human immunodeficiency virus positive

          -  Active viral hepatitis (B or C) as demonstrated by positive serology at Screening

          -  A prolonged QTcF interval (QTcF >450 milliseconds[ms]) as demonstrated by a repeated
             electrocardiogram (ECG) at Screening (repeated only if initial ECG indicates a QTcF
             interval >450 ms) (participants with evidence of bundle branch block are not excluded
             if the block is not clinically significant, as documented by the investigator in the
             source document)

          -  Current evidence of clinically significant disease that in the opinion of the
             investigator(s) could affect the participant's safety or interfere with the study
             assessments

          -  Any history of a medical or psychiatric condition other than Alzheimer's Disease
             dementia that in the opinion of the investigator(s) could affect the participant's
             safety or interfere with the study assessments

          -  History of malignancy within the previous 5 years except for adequately treated basal
             cell or squamous cell skin cancer or cervical carcinoma in situ

          -  Any suicidal ideation with intent with or without a plan, at the time of or within 6
             months of Screening, as indicated by answering "Yes" to questions 4 and 5 on the
             Suicidal Ideation section of the electronic version of the Columbia Suicide Severity
             Rating Scale (eC-SSRS)

          -  Any suicidal behavior within the past 10 years based on the eC-SSRS

          -  History of violence toward the caregiver or others

          -  Scheduled for surgery using general anesthesia during the study

          -  Used any prohibited prescription or over-the-counter concomitant medications within 1
             week or 5 half-lives, whichever is longer, before starting actigraphy during Screening

          -  Used any modality of treatment for ISWRD between Screening and Randomization based on
             approaches related to circadian rhythms, including phototherapy (light therapy),
             melatonin and melatonin agonists

          -  Failed treatment with Belsomra (efficacy and/or safety) following treatment with an
             appropriate dose and of adequate duration in the opinion of the investigator

          -  Transmeridian travel across more than 3 time zones between Screening and
             Randomization, or plans to travel across more than 3 time zones during the study

          -  Hypersensitivity to lemborexant or to its excipients

          -  Currently enrolled in another clinical trial, except for observational studies with no
             treatment component

          -  Used any investigational drug or device before informed consent (ie, within 30 days or
             5× the investigational drug half-life whichever is longer or 6 months for potential
             disease-modifying drugs)

          -  Previously participated in any clinical trial of lemborexant