Lemborexant for Insomnia in a Patient With Dementia: An N-of-1 Trial
Phase: PHASE4
Conditions: Insomnia, Dementia, Frontotemporal Dementia
Sponsor: Nova Scotia Health Authority

Romeo File No. 1030001 
 
Version 2.1 / 17 January 2024 
 
 
Research Protocol 
 
 
Lemborexant for insomnia in a patient with dementia: An N-of-1 trial 
 
 
 
Version 2.1 
January 17, 2024 
 
 
 
 
 
 
Principal Investigator: 
Shanna C Trenaman, BScH, BScPharm, MAHSR, ACPR, PhD 
College of Pharmacy, Dalhousie University 
5968 College Street 
Halifax, NS B3H 4R2 
 
Qualified Investigator: 
Kenneth Rockwood, MD, FRCP, FRCPC 
Division of Geriatric Medicine 
5955 Veterans Memorial Lane 
Halifax, NS B3H 2E1 
 
 
 
 

Research Protocol: Lemborexant for insomnia in a patient with dementia: An N-of-1 trial 
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Background & Rationale 
Insomnia is a highly common, chronic disorder for older adults (1) that can also affect those 
living with dementia (2). Insomnia can be distressful for people living with dementia, but also 
introduces challenges for caregivers and can give rise to a heavy burden on the healthcare and 
caregiver team (3,4). 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 (5). The negative aspects of sleeping aid use are exaggerated for older, frail 
adults and are more severe for adults living with dementia.  
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 (6). 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 OX1R and OX2R, which is thought to suppress wake drive. Unlike other traditional 
sleeping aids, 1emborexant has not shown to be significantly associated with driving 
impairment, rebound insomnia, or dependence/withdrawal symptoms (7). 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 1emborexant 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 1emborexant will be helpful in an N of 1 trial to understand the 
details of effect and tolerability in individuals living with dementia and insomnia. 
Hypothesis 
We 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. 

Research Protocol: Lemborexant for insomnia in a patient with dementia: An N-of-1 trial 
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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 
Design: 
This is an investigator led, 8-week, N of 1 trial for adults with early onset dementia and 
insomnia, where treatment with lemborexant is altered with a placebo in an “ABBABAAB” 
format. N of 1 study methodology allows us to present data from one case in isolation and re-
deploy the study when a new patient meets the eligibility criteria (find supplemental 
inclusion/exclusion criteria).   
Participant Selection: 
Participants will be recruited from Dr. Rockwood’s Geriatric Ambulatory Care Clinic located in 
the Camp Hill Veterans Memorial Building in the Central Zone of the Nova Scotia Health 
Authority. While this trial is designed for a particular patient case (i.e. recruitment of 1 
participant), we anticipate that there may be opportunities in the future for this N-of-1 trial to 
be redeployed to other adults living with early onset dementia and insomnia with a maximum 
enrollment of 3 patients over the following 5 years.  
Inclusion/Exclusion Criteria: 
Inclusion criteria are a referral to investigator 1’s memory clinic, early onset dementia (any 
type) as defined by age at less than 65 years at diagnosis, symptoms of insomnia or reduced 
sleep that is distressing to the patient or their caregiver. 
A pagent must have all inclusion criteria and none of the exclusion criteria to be eligible to 
pargcipate in the study. 
 
Inclusion Criteria 
A diagnosis of early onset demenga (demenga before age 65) 
Experiencing insomnia that is distressful to the pagent or the pagent’s care givers 
Have a caregiver to support complegng the sleeping response log 
 

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Exclusion Criteria 
Hypersensigvity or intolerance to the drug or any ingredient in the formulagon 
Intolerance of lactose  
Diagnosis of the hereditary diseases of galactose intolerance  
Severe hepagc impairment  
Severe COPD 
Pregnancy 
Breasheeding 
Use of medicagons that moderate or strong inhibitors of CYP 3A  
A history of distressing sleep paralysis 
 
Study Procedures: 
1. Patients identified to have early onset dementia and insomnia by the Qualified 
Investigator (Geriatrician) during routine patient care will be approached to determine 
their interest in the N of 1 trial.  
2. Principal investigator  (Pharmacist and Researcher) will 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 we will ensure that a caregiver or substitute 
decision maker will participate in these discussions as well. 
3. If the patient provides informed consent 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 defends against both linear 
secular trends and nonlinear trends. Medication will be provided in 7-day packs 
(plastic or cardboard dosettes) marked to correspond to the assigned treatment 
week and assigned as follows. 
Week 1 = placebo 
Week 2 = lemborexant 5 mg 

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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 weeklong 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 not well characterized and vary among individuals, the 
safest course is to choose the weeklong treatment length 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 from the Principal 
Investigator 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) 
Whether at the medication was taken 
ii) 
total sleep time,  
iii) 
sleep onset latency (SOL),  
iv) 
wake time after sleep onset (WASO),  
v) 
number of night awakenings to be measured nightly based on patient and caregiver 
estimate,  

Research Protocol: Lemborexant for insomnia in a patient with dementia: An N-of-1 trial 
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Risk outcome that will be measured will include:  
i) 
presence & severity of adverse drug reactions (ADRs); this may include somnolence, 
headache, sleep paralysis, etc.),  
ii) 
patient's willingness to drop-out due to ADRs.  
And will be assessed at the telephone call check-ins that occur every week over the 8-week 
study. 
Furthermore, provision of follow-up care will be ensured by the Qualified Investigator. 
Statistical Analysis 
We will calculate basic descriptive statistics (means, standard deviations, medians, and ranges) 
for each outcome variable (total sleep time, sleep onset latency (SOL), wake time after sleep 
onset (WASO), and number of night awakenings) across each week of treatment/placebo. The 
assumption will be that each week is an independent event and will allow us to compare 
response over time (by week). We will generate time series plots to visualize trends over time 
with marking to identify periods of active treatment and placebo. Examination of these time 
dependent graphs for each outcome will be visually inspected for patterns, trends, and 
potential relationships between variables. We will utilize the R statistical computing language 
for the statistical analysis. 
Equity, Diversity, and Inclusion Considerations 
The study investigators will invite a very specific patient type for the N of 1 trial without 
consideration of sex, gender, ethnicity, or sexual orientation. 
Feasibility, Challenges, and Mitigation Strategies 
This is an intensive evaluation for the patent and caregiver due to tracking sleep (own outcome 
recording) but we will attempt to manage this with two check-ins by the co-investigator that 
will help inform adverse events and any tolerability concerns. 
4.1 
Confidentiality 
Information collected for purposes of this study will be handled confidentially.  

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Participants’ name, contact information, age, height, and weight measurements may be used in 
the study records but no identifying information will leave the Nova Scotia Health Authority. All 
study information will be stored in a separate research database on a password protected 
drive, in which all patients will be identified with a unique number. A separate file will link 
patients to their study identification numbers and will also be password protected. The only 
hardcopy documentation will be the signed consent forms (stored separately from other hard 
copy data) which will be kept in a locked drawer, in a locked room. No identifying information 
will be publicly available; patients will be identified only by their study identification numbers. 
Access to any file relevant to this study will be limited to the study personnel at NSHA, the 
NSHA Research Ethics Board (NSHA-REB) and auditors, upon request.  
Results from this study may be presented at scientific meetings or published in a peer-reviewed 
journal. The population studied will be described in general terms. No identifying data will be 
disclosed when presenting study results. 
4.2 
Harms 
The potential harms associated with the proposed study are minimal. Participants risk an 
adverse drug reaction which may manifest as headache, drowsiness, or other symptom.  It is 
possible that the medication will not help with sleep or may worsen the insomnia. Serious 
adverse reactions that could occur include a drug-related delirium or an episode of sleep 
paralysis. 
4.3 
Benefits 
While there are no direct benefits to participants over standard care as a result of participating 
in this study, this research works towards identifying a method to support sleep in someone 
living with dementia and insomnia.  
4.4 
Disclosure of any Financial Compensation 
Participants will receive no monetary compensation. There will be no direct expenses incurred 
by participants, and therefore there will be no reimbursement for such costs. 
References 

Research Protocol: Lemborexant for insomnia in a patient with dementia: An N-of-1 trial 
Version 2.1 (2024-Jan-17) 
 
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1. Brewster GS, Riegel B, Gehrman PR. Insomnia in the Older Adult. Sleep Med Clin. 2022 
Jun;17(2):233–9.  
2. Lee S, Nelson ME, Hamada F, Wallace ML, Andel R, Buxton OM, et al. Sleep Disorders and 
Cognitive Aging among Cognitively Impaired vs. Unimpaired Older Adults. The Gerontologist. 
2023 Nov 7;gnad152.  
3. Benca R, Herring WJ, Khandker R, Qureshi ZP. Burden of Insomnia and Sleep Disturbances 
and the Impact of Sleep Treatments in Patients with Probable or Possible Alzheimer’s 
Disease: A Structured Literature Review. J Alzheimers Dis JAD. 2022;86(1):83–109.  
4. Brewster GS, Wang D, McPhillips MV, Epps F, Yang I. Correlates of Sleep Disturbance 
Experienced by Informal Caregivers of Persons Living with Dementia: A Systematic Review. 
Clin Gerontol. 2022 Oct 31;1–28.  
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psychiatric disorders? A critical reappraisal. Eur Psychiatry J Assoc Eur Psychiatr. 2013 
Jan;28(1):7–20.  
6. Picton JD, Marino AB, Nealy KL. Benzodiazepine use and cognitive decline in the elderly. Am J 
Health-Syst Pharm AJHP Off J Am Soc Health-Syst Pharm. 2018 Jan 1;75(1):e6–12.  
7. Pan B, Ge L, Lai H, Hou L, Tian C, Wang Q, et al. The Comparative Effectiveness and Safety of 
Insomnia Drugs: A Systematic Review and Network Meta-Analysis of 153 Randomized Trials. 
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