| Field |
Value |
| NCT ID |
NCT06274528 |
| Title |
Effect of a Dual Orexin Receptor Antagonist on CSF Alzheimer's Disease Biomarkers |
| Phase |
Phase 2 |
| Status |
Recruiting |
| Enrollment |
201 participants |
| Study Start |
March 11, 2024 |
| Primary Completion |
March 11, 2029 |
| Sponsor |
Washington University School of Medicine |
| Collaborators |
National Institutes of Health (NIH), Eisai Inc., National Institute on Aging (NIA) |
| Principal Investigator |
Brendan Lucey, MD (Washington University) |
| Location |
Washington University in St. Louis, School of Medicine, St Louis, Missouri |
This trial tests the hypothesis that enhanced sleep via orexin receptor antagonism can reduce Alzheimer's disease biomarkers. The scientific premise is based on:
- Sleep-Amyloid Connection: The glymphatic system clears amyloid-beta during sleep, particularly during slow-wave sleep
- Orexin Role: Orexin (hypocretin) is a wake-promoting neuropeptide; blockade increases sleep duration and quality
- Biomarker Reduction: Improved sleep over 6 months may decrease phosphorylated tau and amyloid biomarkers in both CSF and blood
- Type: Interventional
- Allocation: Randomized
- Intervention Model: Parallel
- Masking: Triple (Participant, Care Provider, Investigator)
- Primary Purpose: Treatment
¶ Arms and Interventions
| Arm |
Type |
Description |
| Lemborexant 10 mg |
Experimental |
Capsule, oral, once nightly, 30 minutes before bed, 6 months |
| Lemborexant 20 mg |
Experimental |
Capsule, oral, once nightly, 30 minutes before bed, 6 months |
| Placebo |
Placebo Comparator |
Capsule, oral, once nightly, 30 minutes before bed, 6 months |
- Measure: Change in plasma pT181/T181 ratio (phosphorylated tau-181/total tau-181)
- Timeframe: 6 months
- Comparison: Lemborexant 10 mg and 20 mg vs. Placebo
- Safety: Number of treatment-related adverse events (6 months)
- Pharmacokinetics: Blood concentration of lemborexant and dose-response relationship with CSF pT181/T181
- Amyloid Biomarkers: Changes in blood plasma and CSF amyloid-beta isoforms (Aβ38, Aβ40, Aβ42, Aβ42/Aβ40)
- Tau Biomarkers: Changes in blood plasma and CSF tau forms (T181, pT181, pT181/T181, S202, pS202, T217, pT217, pT217/T217)
- CSF TREM2 (microglial marker)
- CSF NPTX2 (synaptic marker)
- CSF NfL (neurodegeneration marker)
- Blood plasma NfL
- Male or female, any race/ethnicity
- Age ≥ 65 years
- Global Clinical Dementia Rating (CDR) 0 (cognitively normal)
- Willing and able to undergo study procedures
- History of restless legs syndrome, narcolepsy, or parasomnia
- Untreated sleep apnea (AHI >15)
- Plasma p-Tau217/np-Tau217% < 2.5 (indicates insufficient amyloid pathology)
- Stroke history
- Renal impairment (eGFR < 45 mL/min/1.73m²)
- Hepatic impairment (AST/ALT ≥ 2X ULN)
- HIV/AIDS
- Substance abuse in preceding 6 months
- Regular alcohol consumption > 2 beverages within 3 hours of bedtime
- Clinically significant medical/psychiatric conditions
- Suicidal ideations
- Pregnant or breastfeeding
This trial is significant because:
- Mechanistic Novelty: Tests whether sleep enhancement through orexin antagonism can modify AD pathology
- Biomarker Focus: Uses both CSF and plasma biomarkers to assess target engagement
- Prevention Potential: Enrolls cognitively normal adults with amyloid positivity - primary prevention population
- Repurposing: Uses FDA-approved sleep medication (Dayvigo/lemborexant) in new indication
- Phase 3 Readiness: If successful, would inform Phase 3 secondary prevention trials