Inhaled versus oral melatonin for adults with insomnia

A Novel Inhaled Formulation of Melatonin to Treat Adults With Insomnia Disorder: a Randomised Open-Label Crossover Trial

This trial will test whether a low-dose inhaled melatonin taken each night helps adults aged 55 and older with insomnia sleep differently than a standard oral melatonin tablet.

Quick facts

• Phase: Early Phase 1
• Study type: Interventional
• Enrollment: 10 (estimated)
• Ages: 55 Years and up
• Sex: All
• Sponsor: Woolcock Institute of Medical Research (Academic / other)
• Locations: 1 site (Macquarie Park, New South Wales)
• Trial ID: NCT06802913 on ClinicalTrials.gov

What this trial studies

This randomized, open-label crossover early-phase study compares nightly inhaled melatonin (100 µg) with oral melatonin tablets (4 mg) in adults aged 55+ who meet DSM-5 criteria for insomnia. Ten participants will be randomized to one treatment for two weeks, then cross over to the other treatment for two weeks, with an overnight polysomnography at the start of each treatment period and blood collection at the end of each period. The main outcomes are changes in sleep microarchitecture and sleep onset latency measured by polysomnography, with exploratory biomarker analyses from blood samples. Recruitment and all overnight visits occur at a single center in Macquarie Park, New South Wales, and several common sleep and psychiatric disorders are excluded.

Who should consider this trial

Good fit: Ideal candidates are adults aged 55 or older with DSM-5 insomnia, an ISI score ≥15, and a history of sleep onset latency ≥30 minutes on at least three nights per week who can attend overnight lab visits and provide informed consent.

Not a fit: Patients with untreated moderate-to-severe sleep apnea, circadian disorders, narcolepsy, severe restless legs syndrome, REM sleep behavior disorder, uncontrolled psychiatric disorders, or those highly dependent on medical care are unlikely to benefit from participation.

Why it matters

Potential benefit: If successful, inhaled melatonin could produce faster or more reliable sleep onset than oral melatonin, offering a more rapid-acting option for older adults with insomnia.

How similar studies have performed: Oral melatonin has shown modest benefit for sleep onset in some adults, but inhaled melatonin formulations are novel with very limited clinical data to date.

Eligibility criteria

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.
* History of subjective sleep onset latency (sSOL) ≥30 minutes on at least 3 nights per week in the previous 4 weeks.
* Able to provide informed electronic consent.
* Fluent English literacy.
* Adults aged 55+ years old.

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. Female participants of childbearing potential with a fertile sexual partner must have a negative serum pregnancy test result at the screening visit. Women will be advised to use contraception for the duration of the study.
* 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.
* 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).
* Regular use of drugs that are CYP1A2 inhibitors (e.g. amiodarone, cimetidine, ciprofloxacin, fluvoxamine) or CYP1A2 inducers (e.g. carbamazepine, phenobarbital, rifampin, tobacco).

Where this trial is running

Macquarie Park, New South Wales

• Woolcock Institute of Medical Research — Macquarie Park, New South Wales, Australia (Recruiting)

Study contacts

• Principal investigator: Hui Xin Ong, PhD — Woolcock Institute of Medical Research
• Study coordinator: Hui Xin Ong, PhD

Conditions Insomnia; Melatonin; Polysomnography; Biomarkers; Inhaled Therapy; Sleep Onset Latency