A Dual Orexin Receptor Antagonist to Reduce Biomarkers of Neurodegeneration in Adults With Insomnia.

A Dual Orexin Receptor Antagonist to Reduce Biomarkers of Neurodegeneration in Adults With Insomnia Disorder: a Randomised Placebo-controlled Cross-over Study.

The goal of this clinical trial is to explore the potential neuroprotective benefits of a dual orexin receptor antagonist (DORA) in adults with insomnia. The main questions it aims to answer are:

• Does the DORA reduce blood-based phosphorylated TAU181, in adults with insomnia, when compared to placebo
• Does the DORA reduce other blood-based biomarkers of neurodegeneration, including phosphorylated TAU217, amyloid beta 40:42 ratio, Neurofilament Light Chain (NFL) and Glial Fibrillary Acidic Protein (GFAP), when compared to placebo.

Participants will:

• Take 10mg Lemborexant nightly for two weeks
• Take a matching placebo nightly for two weeks
• Visit the research institute for a screening visit and for an overnight visit at the conclusion of each study drug treatment (3 visits in total).

This is a randomised placebo-controlled cross-over study of a dual orexin receptor antagonist (DORA) versus placebo in adults with insomnia.

To be enrolled in the study, participants are required to complete an online pre-screening survey. Eligible participants will be directed to a separate webpage where they will be invited to review and download the Participant Information Sheet (PIS) and asked to provide their contact details and consent for a follow up call/email from the research team to book in a screening visit. At the screening visit the study team will explain the study to each participant and ensure they have had ample time prior to the visit to read and understand the PIS and have had the opportunity to ask any questions. The consent form will be signed by both the participant and a medical officer and participants will be randomised into their first treatment period; DORA (Lemborexant) or placebo.

Participants will take the treatment orally, nightly for 2 weeks. There will be a 2-4 week washout period between treatments. At the conclusion of both two-week treatment phases, participants will attend the laboratory for an overnight visit. The visit will take approximately 18 hours (including sleep time). During this visit, participants will partake in a number of assessments including HD-EEG, fNIRS, questionnaires and pupillometry. Participants will also have blood samples collected in the morning of the overnight study (hourly for four hours).

The study will recruit primarily through social media advertisements. The study will be coordinated from the Woolcock Institute of Medical Research, Sydney, Macquarie University, NSW, 2113, Australia.

Inclusion Criteria:

• Diagnosis of insomnia disorder as defined by the DSM-5 (difficulty initiating or maintaining sleep or waking up too early for at least 3 nights per week, for at least 3 months, with adequate opportunity and circumstances for sleep and at least one daytime impairment related to the sleep difficulty) and a score ≥15 on the ISI.
• Able to provide informed electronic consent.
• Fluent English literacy.
• Adults aged between 40-65 years.

Exclusion Criteria:

• People highly dependent on medical care as determined by a medical officer.
• Untreated moderate-severe sleep apnoea as diagnosed using in-home wrist oximetry (oxygen desaturation index>15, ongoing effectively treated sleep apnoea with insomnia will be allowed).
• Circadian disorders, narcolepsy, severe restless legs syndrome, and REM sleep behaviour disorder or uncontrolled psychiatric disorders.
• History of attempted suicide or current suicide ideation (indicated by a score >0 on Q9 of the Patient Health Questionnaire-9) at pre-screening.
• Objective cognitive decline measured by scoring ≤26 on the Montreal Cognitive Assessment (MoCA)
• Regular shift work, jet lag or trans-meridian travel (over 2h time difference) in the past week before randomisation.
• Pregnancy or lactation. Women will be advised to use contraception for the duration of the study and a urine pregnancy test will be performed when necessary.
• Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical trial due to safety concerns or compliance with clinical study procedures.
• Currently participating in or has participated in a research study of an investigational agent or device within 4 weeks of enrolment.
• Concomitant use of medicines that are inhibitors (e.g., diltiazem, fluvoxamine, fluconazole, itraconazole, verapamil), or moderate to strong inducers of CYP3A4 (e.g., carbamazepine, modafinil, phenytoin, rifampicin, St John's Wort)
• Ongoing use of anti-psychotic medication, bosentan, efavirenz, etravirine, modafinil, rifampin, carbamazepine or illicit stimulants.
• Regular use of hypnotics (including melatonin, valerian, kava, benzodiazepines and Z-drugs), and other medications that can cause additive sedation (e.g. sedating antihistamines, tricyclic antidepressants, antipsychotics) within 14 days or 4-5 half-lives (whichever is longer) of starting the clinical trial.
• Regular use of psychostimulants (e.g., dexamfetamine, lisdexamfetamine, methylphenidate) or non-amphetamine psychostimulants (e.g., armodafinil, modafinil, atomoxetine) within 14 days or 4-5 half-lives (whichever is longer) of starting the clinical trial.
• Use of antidepressant medications for treatment of low mood for less than one year or dose changes (escalation or tapering) or change in antidepressant medications within the past year.
• Regular use opioids within 14 days or 4-5 half-lives (whichever is longer) of starting the clinical trial.
• Ongoing use of THC- or CBD-containing products within 14 days prior to the start of the trial.
• Dependence or any other drug or alcohol dependence within the past two years (alcohol to be limited to no more than 2 standard drinks per day during trial period).
• Allergy to lactose.