Daridorexant for Alzheimer Disease Prevention

Not Applicable

Not yet recruiting

• Conditions: Alzheimer Disease (AD)
• Interventions: Drug: Daridorexant 50 mg; Drug: Placebo

• Registration Number: NCT07213349
• Lead Sponsor: Douglas Mental Health University Institute

Brief Summary

This study will evaluate whether daridorexant, a DORA sleep medication, can support brain health by promoting the clearance of proteins linked to the development and progression of Alzheimer's disease. The trial is preventive and is open to participants who do not have Alzheimer's disease dementia, regardless of whether or not they experience sleep problems.

Detailed Description

Alzheimer's disease (AD) begins decades before symptoms with the accumulation of amyloid plaques and tau tangles, and interventions that slow or prevent this process could greatly reduce its impact. Dual orexin receptor antagonists (DORAs), drugs developed for insomnia, may help clear amyloid and tau, reduce neuroinflammation, and improve cognition through mechanisms that could be both related and unrelated to sleep quality. Early animal and human studies suggest that DORAs can alter biomarkers of Alzheimer's pathology making the orexin pathway modulation a promising strategy for Alzheimer's prevention. Daridorexant, one of the two DORAs available in Canada, stands out as a well-tolerated candidate for prevention due to its safety profile.

We want to evaluate the potential of Daridorexant for prevention of AD in this single-site, double-blind, randomized (1:1), placebo-controlled trial evaluating 50 mg of daridorexant versus placebo over 12 months in 240 participants. The primary biological outcome is the change from baseline to 12 months in the plasma ratio of phosphorylated tau181 to unphosphorylated tau181 (p-tau181/np-tau181). Secondary outcomes include changes in additional plasma biomarkers, cognitive performance, sleep parameters, and safety measures.

Study Timeline

• Study First Submitted: 2025-09-24
• Status Verified: 2025-10
• Study First Submitted QC: 2025-10-01
• Last Update Submitted: 2025-10-01
• Study Start: 2025-10-07
• Study First Posted: 2025-10-08
• Last Update Posted: 2025-10-08
• Primary Completion: 2028-12
• Study Completion: 2029-12-01

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 240

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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Daridorexant 50 mg	Daridorexant 50 mg	-
Placebo	Placebo	-

Primary Outcome Measures

Name	Time	Method
Change in plasma p-tau217/np-tau217 ratio	baseline up to estimated 12 months	Change from baseline in biological progression as measured by p-tau217/np-tau217 ratio. To determine whether Daridorexant 50mg is superior to placebo in reducing plasma tau phosphorylation (p-tau217/np-tau217)

Secondary Outcome Measures

Name	Time	Method
Change in plasma p-tau181/np-tau181 ratio	baseline up to estimated 12 months	Change from baseline in biological progression as measured by p-tau181/np-tau181 ratio. To determine whether Daridorexant 50mg is superior to placebo in reducing plasma tau phosphorylation (p-tau181/np-tau181)
Change in plasma Aβ42/Aβ40 ratio	baseline up to estimated 12 months	Change from baseline in biological progression as measure by Aβ42/Aβ40 ratio in plasma. To determine whether Daridorexant 50mg is superior to placebo in reducing Aβ accumulation.
Change from baseline on Preclinical Alzheimer Cognitive Composite (PACC) score	baseline up to estimated 12 months	Change from baseline in cognitive progression as measured with a modified version of the PACC score
Change from baseline on XpressO MoCA	baseline up to estimated 12 months	Change from baseline in cognitive progression as measured with the XpressO MoCA medical screening tool

Trial Locations

Locations (1)

Centre StoP-Alzheimer (Douglas Mental Health University Institute - Research Centre); 🇨🇦 Montreal, Quebec, Canada