Understanding the Role of the Locus Coeruleus in Insomnia (LOCUSleep)

An Alpha2-adrenoceptor Agonist to Reduce Locus Coeruleus Activity During Sleep in Adults With Insomnia Disorder: a Pilot Randomised Placebo-controlled Cross-over Study

This research project aims to better understand the neurobiological mechanistic underpinnings of insomnia disorder. The main question is whether cortical hyperarousal in individuals with insomnia disorder, measured by electroencephalograhic (EEG) infraslow oscillation coupling of sigma power during non-rapid eye movement (NREM) sleep and theta power during rapid eye movement (REM) sleep, is related to locus coeruleus activity.

Study Overview

• Status: Not yet recruiting
• Conditions: Insomnia
• Intervention / Treatment: Drug: Dexmedetomidine; Drug: Placebo

Detailed Description

This trial is a double-blinded, placebo-controlled, randomised controlled cross over trial of dexmedetomidine or placebo in adults with insomnia disorder. Participants will be recruited using social media, bulletin boards and patient referrals from the Woolcock Institute of Medical Research clinics. Participants will be asked to complete an online pre-screening webpage (RedCap) to check for eligibility, and provided with the Participant Information Sheet (PIS) and asked for contact details for an in-person screening visit. The participants will have the study explained in detail during the screening visit followed by written informed consent. The participant will then undergo a medical screening for diagnosis of insomnia disorder and the medical officer will sign the consent form. Thereafter, the participant will complete baseline questionnaires and be randomised to either dexmedetomidine or placebo for the 2 sleep laboratory visits. Participants will then be instructed to maintain their regular sleep-wake patterns for seven days before the first sleep laboratory visit (Visit 1). During Visit 1, participants will undergo a number of assessments (pre-sleep locus coeruleus activity measured using pupillometry, electroencephalography (EEG), functional near-infrared spectroscopy (fNIRS) before and during sleep and questionnaires about subjective hyperarousal. Participants will receive either dexmedetomidine or placebo. Following Visit 1, participants will have a 14-day washout, before Visit 2, which will repeat the procedures of Visit 1, but participants will receive the alternate condition (placebo or dexmedetomidine). The study will be coordinated from the Woolcock Institute of Medical Research, Sydney, Macquarie University, NSW, 2113, Australia.

• Study Type: Interventional
• Enrollment (Estimated): 15
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Christopher Gordon, PhD; Phone Number: +61 2 9805 3096; Email: c.gordon@mq.edu.au
• Study Contact Backup: Name: Camilla Hoyos, PhD; Email: camilla.hoyos@mq.edu.au

Study Locations

• Australia
  • New South Wales
    • Macquarie Park, New South Wales, Australia, 2113
      • Woolcock Institute of Medical Research
      • Contact: Greg Kaplan, PhD; Phone Number: +61 2 9805 3232; Email: grigori.kaplan@woolcock.org.au
      • Principal Investigator: Christopher Gordon, PhD
      • Principal Investigator: Brendon Yee, MBChB, PhD

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Diagnosis of insomnia disorder (DSM-5-TR)
• Insomnia severity index (ISI) score ≥15
• Able to provide informed consent
• Fluent English literacy

Exclusion Criteria:

• Medically diagnosis of sleep disordered breathing (i.e. sleep apnea) or sleep or circadian disorder other than insomnia
• Uncontrolled psychiatric disorders
• High dependence on medical care
• History of, or current suicide ideation (Patient Health Questionnaire (PHQ-9) questionnaire)
• Pregnancy or actively trying to conceive, or lactating
• Shiftwork - defined as work outside of business hours (before 8am or after 6pm) conducted at least once per week
• Travel across time zones of over 2 h time difference in the past week
• Contraindicate the patient's participation in the clinical trial due to safety concerns or compliance with clinical study procedures
• Concomitant use of medicines that are inhibitors, or moderate to strong inducers, of CYP3A4; regular use of hypnotics and other medications that can cause additive sedation or psychostimulants or non-amphetamine psychostimulants within 14 days of starting the clinical trial
• Ongoing use of THC- or CBD-containing products; dependence or any other drug or alcohol dependence
• 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: Dexmedetomidine; A 96 µg dexmedetomidine tablet taken during the sleep laboratory visit only	Drug: Dexmedetomidine; A buccal tablet containing 96 µg dexmedetomidine will be taken before habitual bedtime.
Active Comparator: Placebo; Matching placebo tablet taken during the sleep laboratory visit only	Drug: Placebo; Placebo tablets will contain identical excipient without the active ingredient (dexmedetomidine) 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
Electrographic (EEG) signatures	Electrographic (EEG) infraslow oscillations (~50 sec) of sigma power and sleep spindle coupling during non-rapid eye movement (NREM) sleep and theta power during rapid eye movement (REM) sleep.	Baseline and 14 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Sleep Fragmentation	Polysomnography (PSG) measure conducted during the intervention and control (wake after sleep onset)	Baseline and 14 days
EEG power	Electroencephalographic (EEG) power during non-rapid eye movement (NREM) (stages 2 and 3) and rapid eye movement (REM) sleep. Unit of measurement is μV^2.	Baseline and 14 days
Neurovascular activity (fNIRS)	Measurement of global blood flow using functional near-infrared spectroscopy (fNIRS).	Baseline and 14 days
Cardiopulmonary Coupling (CPC)	Cardiopulmonary coupling provides a global measure of autonomic function	Baseline and 14 days
Pupillometry	Pupil sizes will be assessed as a surrogate of locus coeruleus activity	Baseline and 14 days
Subjective hyperarousal	Pre-Sleep Arousal Scale (PSAS) before sleep. Scored by summing 16 items (rated 1 (not at all) to 5 (extremely)) with a total score between 16 to 80	Baseline and 14 days
Subjective sleep quality	Self-reported rating of sleep quality (0-9) with higher scores indicating worse sleep. This will assessed in the morning after the overnight sleep study.	Baseline and 14 days

Collaborators and Investigators

• Sponsor: Woolcock Institute of Medical Research
• Investigators: Principal Investigator: Christopher Gordon, PhD, Woolcock Institute of Medical Research; Principal Investigator: Brendon Yee, MBChB, PhD, Woolcock Institute of Medical Research

Study record dates

Study Major Dates

• Study Start (Estimated): February 1, 2026
• Primary Completion (Estimated): March 1, 2027
• Study Completion (Estimated): March 1, 2027

Study Registration Dates

• First Submitted: December 8, 2025
• First Submitted That Met QC Criteria: January 29, 2026
• First Posted (Actual): February 6, 2026

Study Record Updates

• Last Update Posted (Actual): February 6, 2026
• Last Update Submitted That Met QC Criteria: January 29, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Sleep; Electroencephalography; Locus coeruleus; Hyperarousal
• Additional Relevant MeSH Terms: Nervous System Diseases; Mental Disorders; Sleep Wake Disorders; Sleep Disorders, Intrinsic; Dyssomnias; Sleep Initiation and Maintenance Disorders; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Imidazoles; Dexmedetomidine
• Other Study ID Numbers: 19522

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 Woolcock Institute of Medical Research 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; ICF; ANALYTIC_CODE

Drug and device information, study documents

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