| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Irregular Sleep-Wake Rhythm Disorder in Subjects with Mild to Moderate Alzheimer’s Disease Dementia |
|
| E.1.1.1 | Medical condition in easily understood language |
| Irregular Sleep-Wake Rhythm Disorder |
|
| E.1.1.2 | Therapeutic area | Psychiatry and Psychology [F] - Behaviours [F01] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Sleep-Related Objectives
Determine the dose response of lemborexant 2.5 mg, 5 mg , 10 mg and 15 mg compared to placebo on the change from baseline in actigraphy-derived Sleep Efficiency during the last week of treatment in subjects with ISWRD and Alzheimer’s disease dementia
Determine the efficacy of LEM2.5, LEM5, LEM10 and LEM15 compared to PBO on the change from baseline of aSE during each week of treatment
Determine the efficacy of LEM2.5, LEM5, LEM10 and LEM15 compared to PBO on the change from baseline on the Sleep Fragmentation Index during each week of treatment
Determine the change from baseline of the mean duration of wake bouts over each week of treatment |
|
| E.2.2 | Secondary objectives of the trial |
Wake-Related Objectives
Determine the dose response of lemborexant 2.5 mg, 5 mg, 10 mg and 15 mg compared to placebo on the change from baseline in actigraphy-derived Wake Efficiency during the last week of treatment in subjects with ISWRD and Alzheimer’s disease dementia.
Circadian Rhythm-Related Objectives
◦ Onset and course of treatment effect as measured by change from baseline of
intradaily variability (IV), interdaily stability (IS), amplitude of the rest-activity
rhythm (AMP), relative amplitude of the rest-activity rhythm (RA), and other
actigraphy variables during each week of treatment |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female, age 60 to 90 years at the time of informed consent
2. Able to provide informed consent. If a subject lacks capacity to consent in the investigator's opinion, the subject'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)
3. Documentation of diagnosis with AD-D on the basis of the National Institute on Aging/Alzheimer’s Association Diagnostic Guidelines
4. MMSE 10 to 26 at Screening
5. Meets criteria for Circadian Rhythm Sleep Disorder, Irregular Sleep-Wake Type (Diagnostic and Statistical Manual of Mental Disorders – 5th edition [DSM-5]) and the 10th revision of the International Classification of Diseases (ICD-10), as follows: Complaint by the subject or
caregiver of difficulty sleeping during the night and/or excessive daytime sleepiness associated with multiple irregular sleep bouts during a 24-hour period
6. Frequency of complaint of sleep and wake fragmentation ≥3 days per week
7. Duration of complaint of sleep and wake fragmentation ≥3 months
8. During the Screening Period, mean aSE <87.5% within the defined nocturnal sleep period and mean aWE <87.5% during the defined wake period
9. 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
10. 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 subjects and their caregivers reside is acceptable)
11. 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
12. Has a reliable and competent caregiver (or caregiver and informants) who can accompany the subject to study visits, administer study medication on a nightly basis and provide information on the status of the subject
13. For subjects taking a cholinesterase inhibitor and/or memantine, dosing regimen must have been stable for at least 3 months
Inclusion Criteria for Caregivers
14. Able to provide informed consent
15. Spends at least 10 hours per week with the subject
16. Able to meet caregiver requirements
17. Willing to provide information on himself/herself regarding sleep quality and caregiver burden |
|
| E.4 | Principal exclusion criteria |
1. 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
2. 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
3. An Apnea-Hypopnea Index or equivalent ≥15 events/hour on diagnostic sleep study conducted prior to Baseline or within 6 months of Screening
4. A clinically significant movement disorder that would affect the differentiation of sleep and wake by the actigraphy analytic algorithm
5. Current symptoms or history during the past year of Rapid Eye Movement (REM) Behavior Disorder or sleep-related violent behavior
6. Probable Major Depression, as evidenced by score >10 on the CSDD at Screening
7. Unable to tolerate wearing the actigraph. At a minimum, subjects 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
8. Excessive caffeine use that in the opinion of the investigator contributes to the subject’s ISWRD
9. History of drug or alcohol dependency or abuse within approximately the previous 2 years
10. 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
11. Known to be human immunodeficiency virus positive
12. Active viral hepatitis (B or C) as demonstrated by positive serology at Screening
13. A prolonged QTcF interval (QTcF >450 ms) as demonstrated by a repeated ECG at Screening (repeated only if initial ECG indicates a QTcF interval >450 ms) (subjects 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)
14. Current evidence of clinically significant disease that in the opinion of the investigator(s) could affect the subject’s safety or interfere with the study assessments
15. 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 subject’s safety or interfere with the study assessments
16. History of malignancy within the previous 5 years except for adequately treated basal cell or squamous cell skin cancer or cervical carcinoma in situ
17. 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 eC-SSRS
18. Any suicidal behavior within the past 10 years based on the eC-SSRS
19. History of violence toward the caregiver or others
20. Scheduled for surgery using general anesthesia during the study
21. 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
22. 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
23. Failed treatment with Belsomra® (efficacy and/or safety) following treatment with an appropriate dose and of adequate duration in the opinion of the investigator
24. 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
25. Hypersensitivity to lemborexant or to its excipients
26. Currently enrolled in another clinical trial, except for observational studies with no treatment component
27. 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)
28. Previously participated in any clinical trial of lemborexant |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The sleep-related endpoints are:
The change from baseline of mean aSE during the last week of treatment with LEM
compared to PBO
The change from baseline of aSE during each week of treatment with LEM compared to
PBO
Change from baseline in mean SFI during each week of treatment
Change from baseline of the mean duration of wake bouts (aMeanDurWB) over each week of treatment
Wake-Related Endpoints
The change from baseline of mean aWE during each week of treatment with LEM compared
to PBO
Change from baseline of the mean duration of sleep bouts (aMeanDurSB) over each week of treatment
Change from baseline of mean WFI during each week of treatment
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The sleep-related endpoints are:
The change from baseline of mean aSE during the last week of treatment with LEM
compared to PBO
The change from baseline of aSE during each week of treatment with LEM compared to
PBO
Change from baseline in mean SFI during each week of treatment
Change from baseline of the mean duration of wake bouts (aMeanDurWB) over each week of treatment
Wake-Related Endpoints
The change from baseline of mean aWE during each week of treatment with LEM compared
to PBO
Change from baseline of the mean duration of sleep bouts (aMeanDurSB) over each week of treatment
Change from baseline of mean WFI during each week of treatment
Circardian Rhythm-Related Endpoints
Change from baseline of IV, IS, L5, M10, AMP, and RA over each week of treatment |
|
| E.5.2 | Secondary end point(s) |
Circardian Rhythm-Related Endpoints
Change from baseline of IV, IS, L5, M10, AMP, and RA over each week of treatment |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Circardian Rhythm-Related Endpoints
Change from baseline of IV, IS, L5, M10, AMP, and RA over each week of treatment |
|
| 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 | Yes |
| 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 | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| 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 | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| This study will consist of a Core Study and an Open-Label Extension Phase |
|
| 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 | 5 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 |
|
| 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
|
|
| 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 | 11 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 11 |
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