Daridorexant for preventing Alzheimer disease

Double Blind Clinical Trial of Daridorexant (Dual Orexin Receptor Antagonist) for Alzheimer Disease Prevention

This trial will try nightly daridorexant to see if it helps clear Alzheimer's-linked proteins and protect brain health in adults who do not have dementia.

Quick facts

• Phase: PHASE2
• Study type: Interventional
• Enrollment: 240 (estimated)
• Ages: 50 Years to 90 Years
• Sex: All
• Sponsor: Douglas Mental Health University Institute (other)
• Locations: 1 site (Montreal, Quebec)
• Trial ID: NCT07213349 on ClinicalTrials.gov

What this trial studies

This single-site, double-blind, randomized (1:1), placebo-controlled Phase 2 trial will enroll 240 participants and compare daridorexant 50 mg nightly to placebo for 12 months. The primary biological outcome is the change from baseline to 12 months in the plasma p-tau181/np-tau181 ratio; secondary outcomes include other plasma biomarkers, cognitive tests, sleep measures, and safety. The trial is testing a dual orexin receptor antagonist (DORA) because preclinical and early human work suggests DORAs may promote clearance of amyloid and tau, reduce neuroinflammation, and influence cognition through sleep-related and independent mechanisms. Daridorexant is chosen for its favorable tolerability profile among available DORAs.

Who should consider this trial

Good fit: Adults without dementia (cognitive screening cutoffs: MoCA >21 or MMSE >24 or CDR <1), with at least six years of education, capacity to consent in English or French, and stable psychoactive medications are the intended participants.

Not a fit: People with established major neurocognitive disorder (dementia), unstable psychiatric or medical conditions, recent substance dependence, current DORA use, or who require contraindicated interacting medications are unlikely to benefit from participation.

Why it matters

Potential benefit: If successful, daridorexant could slow or prevent early Alzheimer-related protein accumulation and help preserve cognition in people without dementia.

How similar studies have performed: Early animal studies and small human biomarker studies suggest DORAs can change amyloid and tau markers, but preventive benefit in humans has not yet been proven.

Eligibility criteria

Inclusion Criteria:

* Without dementia as determined by: MoCA \>21 or MMSE \> 24 or Clinical Dementia Rating \<1
* Minimum of 6 years of formal education
* Stable psychoactive medication for 1 month prior to screening with no intention to change dose during treatment period
* Capacity to provide written consent in English or French

Exclusion Criteria:

* Clinical diagnosis of major neurocognitive disorder
* Unstable psychiatric condition:
* Clinically significant active suicidal ideations
* Unstable medical condition in the opinion of the investigator.
* Known or suspected history of drug or alcohol dependence or abuse within one year of the screening visit
* Currently taking a DORA
* Allergy or significant adverse reaction to DORA
* Use of benzodiazepines or z-drugs \> 2 times per week in the last month.
* Use of major and moderate CYP3A4 inducers and inhibitors
* Use of strong central nervous system depressants, opioids, strong analgesics, antipsychotics, sedative antidepressants.
* Active use of cholinesterase inhibitors or memantine
* Women who are breast feeding or pregnant
* Severe obstructive sleep apnea (OSA)\*
* Clinically significant non-treated rapid eye movement (REM) sleep behavior disorder, restless leg syndrome or parasomnia;
* Diagnosis of narcolepsy

Where this trial is running

Montreal, Quebec

• Centre StoP-Alzheimer (Douglas Mental Health University Institute - Research Centre) — Montreal, Quebec, Canada (RECRUITING)

Study contacts

• Principal investigator: Sylvia Villeneuve, PhD — McGill University
• Study coordinator: Jennifer Tremblay-Mercier, MSc

Conditions: Alzheimer Disease, Prevention, Sleep, Amyloid, Tau, Cognitive decline, Dual Orexin Receptor Antagonist, Daridorexant