A Dual Orexin Receptor Antagonist to Reduce Biomarkers of Neurodegeneration in Adults With Insomnia. (Neuro-DORA)

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).

Study Overview

• Status: Recruiting
• Conditions: Insomnia
• Intervention / Treatment: Drug: Lemborexant 10 MG; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Camilla Hoyos, MPH, PhD; Phone Number: 0438801044; Email: camilla.hoyos@mq.edu.au
• Study Contact Backup: Name: Rhearne Ryan, HScHons, PhD; Phone Number: +61 2 9805 3274; Email: rhearne.ryan@woolcock.org.au

Study Locations

• Australia
  • New South Wales
    • Macquarie Park, New South Wales, Australia, 2113
      • Recruiting
      • Woolcock Institute of Medical Research
      • Contact: Grigori Kaplan, PhD; Phone Number: +61 9114 0412; Email: grigori.kaplan@sydney.edu.au
      • Principal Investigator: Camilla Hoyos, PhD
      • Principal Investigator: Brendon Yee, PhD FRACP

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dual Orexin Receptor Antagonist (DORA); 10mg Lemborexant tablet taken orally, nightly for two weeks	Drug: Lemborexant 10 MG; An orally ingested tablet containing 10mg Lemborexant taken before bedtime. The investigational product is manufactured under Good Manufacturing Practice and is compliant with the TGA Therapeutic Order #101 that stipulates quality control requirements for capsule and pill-based products used in Australia.; Other Names: Dayvigo
Placebo Comparator: Placebo; Matching placebo tablet taken orally, nightly for two weeks	Drug: Placebo; Placebo tablets will contain similar excipients without the active ingredient (Lemborexant) and manufactured under the same condition as the active. Placebo tablets, packs and instructions will be identical in every respect to enable the double-blind study design.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood levels of TAU181	Morning blood-based phosphorylated TAU (standardised pTAU181:TAU181 ratio)	5 samples hourly for 4 hours after awakening in the morning of the overnight treatment period visits (approximately 7am-11am). We will test whether there is a difference between treatments over the time period.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Blood levels of TAU217	Morning blood-based phosphorylated TAU217, analysed within each participant.	5 samples hourly for 4 hours after awakening in the morning of the overnight treatment period visits (approximately 7am-11am). We will test whether there is a difference between treatments over the time period.
Blood levels of Beta amyloid	Morning blood-based Beta Amyloid 40:42 ratio, analysed within each participant.	5 samples hourly for 4 hours after awakening in the morning of the overnight treatment period visits (approximately 7am-11am). We will test whether there is a difference between treatments over the time period.
Blood levels of NFL	Morning blood-based Neurofilament Light Chain (NFL), analysed within each participant.	5 samples hourly for 4 hours after awakening in the morning of the overnight treatment period visits (approximately 7am-11am). We will test whether there is a difference between treatments over the time period.
Blood levels of GFAP	Morning blood-based Fibrillary Acidic Protein (GFAP), analysed within each participant.	5 samples hourly for 4 hours after awakening in the morning of the overnight treatment period visits (approximately 7am-11am). We will test whether there is a difference between treatments over the time period.

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Absolute Electroencephalographic (EEG) Power During Non-Rapid Eye Movement (NREM) (stages 2 and 3) and REM sleep.	High-density EEG, spectral power for frequency ranges low-delta: 0.5-1 Hz; delta: 1-4.5 Hz; theta: 4.5-8Hz; alpha: 8-12Hz; sigma: 12-15 Hz; beta: 15-25 Hz; gamma: 25-40 Hz. Absolute Electroencephalographic (EEG) Power During Non-Rapid Eye Movement (NREM) and REM sleep (12 statistical comparisons). Unit of measurement is μV^2.	14th night after treatment starts.

Collaborators and Investigators

• Sponsor: Woolcock Institute of Medical Research
• Investigators: Principal Investigator: Camilla Hoyos, MPH, PhD, Woolcock Institute of Medical Research; Principal Investigator: Brendon Yee, MBChB, FRACP, FCCP, PhD, Woolcock Institute of Medical Research

Study record dates

Study Major Dates

• Study Start (Actual): May 13, 2025
• Primary Completion (Estimated): April 1, 2026
• Study Completion (Estimated): April 1, 2026

Study Registration Dates

• First Submitted: January 28, 2025
• First Submitted That Met QC Criteria: February 6, 2025
• First Posted (Actual): February 12, 2025

Study Record Updates

• Last Update Posted (Estimated): October 3, 2025
• Last Update Submitted That Met QC Criteria: September 29, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Sleep; Dementia; Tau; Beta Amyloid; DORA
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Pathological Conditions, Anatomical; Neurocognitive Disorders; Sleep Wake Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Frontotemporal Lobar Degeneration; Frontotemporal Dementia; Pathological Conditions, Signs and Symptoms; Sleep Initiation and Maintenance Disorders; Dementia; Pick Disease of the Brain; Plaque, Amyloid; Sleep Aids, Pharmaceutical; Orexin Receptor Antagonists; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Neurotransmitter Agents; Hypnotics and Sedatives; lemborexant
• Other Study ID Numbers: 16837

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Non-identifiable IPD will be shared upon reasonable request to the Principal Investigators.
• IPD Sharing Time Frame: Non-identifiable IPD will become available one year after the Actual Study Completion Date and will be available for ten years.
• IPD Sharing Access Criteria: A copy of the non-identifiable dataset may be requested by academic collaborators not affiliated with the WIMR through a data request form which outlines the investigators, aims and hypotheses, data to be included, a statistical analysis plan, ethics approval, and security measures. Contact the Coordinating Principal Investigator for access to data.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; ANALYTIC_CODE

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