Lemborexant for Insomnia in a Patient With Dementia: An N-of-1 Trial

Insomnia is a highly common, chronic disorder that is distressful for the patient but also for caregivers and can give rise to a heavy burden on the healthcare team. Sleeping aids like benzodiazepines and other sedatives (e.g., zolpidem, zopiclone) have been widely used to help treat insomnia. However, sleeping aids are also known to cause adverse drug reactions such as drowsiness and dizziness, that increases the risk of falls, driving impairment, visual impairment, cognitive impairment, and upon discontinuation may cause paradoxical rebound insomnia, delirium, and nightmares all of which exacerbate the initial insomnia. All of the negative aspects of sleeping aid use are exaggerated for older, frail adults.

Some patients experience an early (young-age) onset dementia with a substantial component of insomnia. Due to the many risks associated with traditional sleeping aids they are often inappropriate in adults living with cognitive impairment and/or frailty. Lemborexant comes from a new class of medications for insomnia. Lemborexant is a dual orexin receptor antagonist that blocks the binding of wake-promoting neuropeptides orexin A and orexin B to their receptors orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R), which is thought to suppress wake drive. Unlike other traditional sleeping aids, lemborexant has not shown to be significantly associated with driving impairment, rebound insomnia, or dependence/withdrawal symptoms. Also, in clinical trials it only rarely causes the types of adverse events associated with benzodiazepines and other traditional sedatives and is less often associated with discontinuations due to adverse events.

While lemborexant is available on the Canadian market it is unclear how this medication will be tolerated by patients living with an early onset dementia. Understanding the effectiveness and tolerability of lemborexant will be helpful in an N of 1 trial to understand the details of effect and effectiveness in individual patients.

Study Overview

• Status: Recruiting
• Conditions: Insomnia; Dementia; Frontotemporal Dementia
• Intervention / Treatment: Drug: Lemborexant 5 MG

Detailed Description

Background & Rationale Insomnia is a highly common, chronic disorder that is distressful for the patient but also for caregivers and can give rise to a heavy burden on the healthcare team. Sleeping aids like benzodiazepines and other sedatives (e.g., zolpidem, zopiclone) have been widely used to help treat insomnia. However, sleeping aids are also known to cause adverse drug reactions such as drowsiness and dizziness, that increases the risk of falls, driving impairment, visual impairment, cognitive impairment, and upon discontinuation may cause paradoxical rebound insomnia, delirium, and nightmares all of which exacerbate the initial insomnia. All of the negative aspects of sleeping aid use are exaggerated for older, frail adults.

Some patients experience an early (young-age) onset dementia with a substantial component of insomnia. Due to the many risks associated with traditional sleeping aids they are often inappropriate in adults living with cognitive impairment and/or frailty. Lemborexant comes from a new class of medications for insomnia. Lemborexant is a dual orexin receptor antagonist that blocks the binding of wake-promoting neuropeptides orexin A and orexin B to their receptors orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R), which is thought to suppress wake drive. Unlike other traditional sleeping aids, lemborexant has not shown to be significantly associated with driving impairment, rebound insomnia, or dependence/withdrawal symptoms. Also, in clinical trials it only rarely causes the types of adverse events associated with benzodiazepines and other traditional sedatives and is less often associated with discontinuations due to adverse events.

While lemborexant is available on the Canadian market it is unclear how this medication will be tolerated by patients living with an early onset dementia. Understanding the effectiveness, tolerability, and safety of lemborexant will be helpful in an N of 1 trial to understand the details of effect and effectiveness in individual patients living with dementia and insomnia.

Hypothesis The investigators hypothesize that lemborexant will be effective and safe in the treatment of insomnia in adults living with both early-onset dementia and concomitant sleep difficulty.

Objective The objective of this study is to evaluate lemborexant for efficacy and safety as a sedative medication for insomnia in adults living with both early-onset dementia and insomnia.

Methods This is an investigator led N of 1 trial for adults with early onset dementia and insomnia. While this trial is designed for a particular patient case the investigators anticipate that there may be opportunities in the future for this N of 1 trial to be redeployed additional times to other adults living with early onset dementia.

Study Procedures:

1. Patients identified to have early onset dementia and insomnia by a co-principal investigator during routine patient care will be considered for the N of 1 trial.
2. The other co-investigator will then meet the potential patient, review of the project details and study objectives. There will be a discussion of risks and benefits and the consent form will be reviewed. There will be an invitation for the patient to provide informed consent. Given that the study will include people living with dementia and cognitive impairment investigators will ensure that a caregiver or substitute decision maker will participate in these discussions as well.
3. Once the patient provides informed consent with support from a substitute decision maker if necessary, the patient will be considered enrolled in the study and will be provided with (1) Study medication and (2) Study reporting tool.

(1) Study medication will be provided for an 8 week period. Medications will be dispensed in an ABiBABAAB sequence where each letter represents 7 days of treatment, A represents placebo, Bi represents lemborexant 5mg and B represents lemborexant 10 mg. This doubly counterbalanced design to defends against both linear secular trends and nonlinear trends. Medication will be provided in 7 day packs (plastic or cardboard dosette) marked to correspond to the assigned treatment week and assigned as follows.

Week 1 = placebo Week 2 = lemborexant 5mg Week 3 = lemborexant 10 mg Week 4 = placebo Week 5 = lemborexant 10 mg Week 6 = placebo Week 7 = placebo Week 8 = lemborexant 10 mg Medications will be placed inside an opaque capsule to minimize the difference in appearance for the active and inactive treatments. Dispensing details of the 3 treatments will be provided with each of the 8 week long medication supplies. Please note that there will be no washout time between treatment periods (For practical purposes, washout periods may not be necessary when treatment effects (e.g., therapeutic half-lives) are short relative to the length of the treatment periods. Since treatment half-lives are often not well characterized and vary among individuals, the safest course may be to choose treatment lengths long enough to accommodate patients with longer than average treatment half-lives and to take frequent (e.g., daily) outcome measurements.

(2) The patient will also be provided with a Study reporting tool (Appendix 1) where they can record details of drug response and any other noticed events/effects.

4. The participant/caregiver will receive weekly follow up phone calls by the researcher to report the efficacy and harms that the participant experienced in the last 7 days for the 8-week duration and ensure that the treatment is being tolerated. These details will be recorded for consideration and assessment when determining patient response.

5. Efficacy outcome that will be measured in the Study Reporting tool will include: i) total sleep time, ii) sleep onset latency (SOL), iii) wake time after sleep onset (WASO), iv) sleep efficiency, v) number of awakenings to be measured nightly based on patient and caregiver estimate, vi) quality of sleep (see Appendix 2), vii) quality of life of both the patient and the caregiver.

Risk outcome that will be measured will include:

i) presence & severity of adverse drug reactions (ADRs) (somnolence, headache, sleep paralysis, etc.), ii) patient's willingness to drop-out due to ADRs. Furthermore, provision of follow-up care will be ensured by the co-investigator.

Statistical Analysis N of 1 trials are completed with a signal analysis which analyzes the differences in effect between the periods of treatment and the periods of comparator. In this study the treatment will be lemborexant and the comparator will be placebo. Investigators will assess each of the efficacy measures and risk outcomes and then compare across periods of active treatment and comparator.

• Study Type: Interventional
• Enrollment (Estimated): 1
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Shanna C Trenaman, BScPharm, PhD; Phone Number: 19024310559; Email: shanna.trenaman@dal.ca

Study Locations

• Canada
  • Nova Scotia
    • Halifax, Nova Scotia, Canada, B3H 2E1
      • Recruiting
      • Nova Scotia Health
      • Contact: Shanna C Trenaman; Phone Number: 1902310559; Email: shanna.trenaman@dal.ca

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Identified by clinician investigator to have early-onset dementia and a significant component of insomnia.

Exclusion Criteria:

• Known sleep disorders that are contraindications for orexin antagonist therapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: lemborexant; The study will be an N of 1 trial over 8 weeks were treatment with lemborexant being alternated with a placebo in an "ABBABAAB" format.	Drug: Lemborexant 5 MG; The participant will receive 8 weeks of treatment Week 1 = placebo Week 2 = lemborexant 5mg Week 3 = lemborexant 10 mg Week 4 = placebo Week 5 = lemborexant 10 mg Week 6 = placebo Week 7 = placebo Week 8 = lemborexant 10 mg; Other Names: Lemborexant 10 MG

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total sleep time	Total number of hours of sleep	Daily for 8 weeks
Sleep onset latency (SOL)	How long it takes to fall asleep the first time the patient goes to sleep in minutes	Daily for 8 weeks
Wake time after sleep onset	How long the patient is awake overnight	Daily for 8 weeks
Number of night awakenings	How many times the patient wakes overnight	Daily for 8 weeks
Quality of sleep	Based on sleep quality questionnaire	Weekly for 8 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Presence & severity of ADRs	Monitor events that may be related to medication use	Daily for 8 weeks
Drop-out due to ADR	Monitor events that may be related to medication use	Daily for 8 weeks

Collaborators and Investigators

• Sponsor: Nova Scotia Health Authority

Study record dates

Study Major Dates

• Study Start (Actual): December 11, 2023
• Primary Completion (Estimated): December 11, 2028
• Study Completion (Estimated): December 11, 2028

Study Registration Dates

• First Submitted: October 6, 2023
• First Submitted That Met QC Criteria: October 16, 2023
• First Posted (Actual): October 23, 2023

Study Record Updates

• Last Update Posted (Actual): February 14, 2024
• Last Update Submitted That Met QC Criteria: February 12, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Wake Disorders; Neurologic Manifestations; Neurobehavioral Manifestations; Neurocognitive Disorders; Neurodegenerative Diseases; TDP-43 Proteinopathies; Proteostasis Deficiencies; Tauopathies; Language Disorders; Communication Disorders; Speech Disorders; Frontotemporal Lobar Degeneration; Aphasia; Sleep Initiation and Maintenance Disorders; Dementia; Alzheimer Disease; Frontotemporal Dementia; Aphasia, Primary Progressive; Pick Disease of the Brain; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Hypnotics and Sedatives; Sleep Aids, Pharmaceutical; Orexin Receptor Antagonists; Lemborexant
• Other Study ID Numbers: LembN01

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Not applicable. No planned sharing of results but upon reasonable request findings may be shared if other researchers wish to pursue inclusion as part of the study team and submit ethics approval for that permission.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes