DORA and LP in Alzheimer's Disease Biomarkers

Effect of a Dual Orexin Receptor Antagonist on CSF Alzheimer's Disease Biomarkers

The purpose of this study is to see if the sleep aid, lemborexant, can decrease the amount of amyloid-beta and tau in the blood. Amyloid-beta and tau are proteins involved in the disease process leading to Alzheimer's disease.

Study Overview

• Status: Recruiting
• Conditions: Alzheimer Disease
• Intervention / Treatment: Drug: Lemborexant 10 mg; Drug: Lemborexant 20mg; Drug: Placebo

Detailed Description

The overall goal of this project is to conduct an early stage (phase II) clinical trial of a dual orexin receptor antagonist (DORA), lemborexant, in cognitively normal older adults with amyloid deposition to demonstrate the feasibility and potential biological effectiveness of lemborexant's target engagement with multiple blood plasma and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers. Orexins (also called hypocretins) are wake-promoting neuropeptides and blockade of orexin with a DORA increases sleep. The scientific premise of this project is that increased or enhanced sleep over 6 months by treatment with lemborexant will decrease the ratio of phosphorylated tau-181/tau-181 (pT181/T181) in blood and the concentration of CSF and plasma AD biomarkers (amyloid-β (Aβ), tau and phosphorylated tau (p-tau)) as well as neurodegeneration, inflammatory and synaptic AD biomarkers such as neurofilament light chain (NfL) (a non-tau marker of neuronal degeneration), soluble triggering receptor expressed on myeloid cells 2 (sTREM2) (a marker for immune response/microglial function), and neuronal pentraxin-2 (NPTX2) a marker for synaptic function) compared to placebo in amyloid-positive cognitively normal older adults. In addition, the investigators will also determine lemborexant's safety, pharmacokinetics (PK), and pharmacodynamics (PD) in this population. This study will enhance trial design and methods by providing critical information about dosing, safety, and target engagement of lemborexant on CSF and blood AD biomarkers to power phase III secondary prevention trials using lemborexant.

• Study Type: Interventional
• Enrollment (Estimated): 201
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Crirstina Toedebusch; Phone Number: 314-747-0646; Email: toedebuschc@wustl.edu
• Study Contact Backup: Name: Chloe Meehan, MA; Phone Number: 314-273-0878; Email: cmeehan@wustl.edu

Study Locations

• United States
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University in St. Louis, School of Medicine
      • Sub-Investigator: J. Philip Miller, Ph.D.
      • Contact: Cristina Toedebusch, BS; Phone Number: 314-747-0646; Email: toedebuschc@wustl.edu
      • Contact: Chloe Meehan, BS, MA; Phone Number: 314-273-0878; Email: cmeehan@wustl.edu
      • Principal Investigator: Brendan P. Lucey, M.D.
      • Sub-Investigator: Jason Hassenstab, Ph.D.
      • Sub-Investigator: David Carr, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Older Adult
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Male or female.
• Any race or ethnicity.
• Participants must be age ≥ 65 years and able to sign informed consent.
• Global Clinical Dementia Rating (CDR) 0.
• Willing and able to undergo study procedures.

Exclusion Criteria:

• History or reported symptoms suggestive of restless legs syndrome, narcolepsy, or parasomnia.
• STOP-Bang score >6 for participants without PAP.
• Untreated sleep apnea AHI>15

• Poorly treated sleep apnea due to noncompliance or an AHI ≥ 10.

  - PAP compliance is defined as ≥ 4 hours per night >70% of the nights.

• Plasma p-Tau217/np-Tau217% <2.5
• Stroke.

• History of renal impairment

  • Defined as older adult patients with markers of kidney damage or eGFR < 45.0 ml/min/1.73m2.
  • Normal Limits ≥ 45.0 mL/min/1.73m2

• History of hepatic impairment

  • AST and/or ALT ≥ 2X upper limit of normal (ULN).
  • Normal Limits: AST 11-47 IU/L and ALT 6-53 IU/L
• HIV/AIDS.
• History of substance abuse or alcohol abuse in the preceding 6 months.
• Regular alcohol consumption 3 or more days a week over the last 6 months. Regular alcohol consumption is defined as having more than 2 alcoholic beverages within 3 hours of bedtime. Participants that agree to reduce alcohol consumption during the study may not be excluded.
• History of presence of any clinically significant medical condition, behavioral or psychiatric disorder, or surgical history based on medical record or participant report that could affect the safety of the participant or interfere with study assessments or in the judgement of the Principal-Investigator (PI) if participant is not a good candidate.

• Has any medical condition that, in the PI's or study team investigator's opinion, could increase risk to the participant, limit the participant's ability to tolerate the research procedures, or interfere with the collection/analysis of the data. Potential medical conditions that will be exclusionary at the PI's or study team investigator's discretion:

  • Cardiovascular disease requiring medication except for controlled hypertension.
  • Pulmonary disease.
  • Type I diabetes.
  • Neurologic or psychiatric disorder requiring medication.
  • Untreated depression
  • Tobacco use.
  • Use of sedating medications.
  • Use of medications that interact with lemborexant (if cannot be discontinued).
  • Abnormal safety labs.
• History of current suicidal ideations.
• Inability to speak and understand English.
• Currently pregnant or breast-feeding.
• In the opinion of the PI, the participant should be excluded due to an abnormal physical examination.
• Must not have participated in any clinical trial involving a study drug or device within the 30-days prior to study enrollment.
• Must not participate in another drug or device study prior to the end of this study participation.

Optional assessment exclusion criteria:

• Contraindication to lumbar puncture (anticoagulants; bleeding disorder; allergy to lidocaine or disinfectant; prior central nervous system or lower back surgery).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lemborexant 10 mg; Lemborexant is a capsule, taken by mouth once a night, approximately 30 minutes prior to bed for 6 months.	Drug: Lemborexant 10 mg; Within FDA approved dose 10 mg; capsule; QD, 6 month duration; Other Names: DAYVIGO
Experimental: Lemborexant 20 mg; Lemborexant is a capsule, taken by mouth once a night, approximately 30 minutes prior to bed for 6 months.	Drug: Lemborexant 20mg; 20 mg; capsule; QD; 6 month duration; Other Names: DAYVIGO
Placebo Comparator: Placebo; Placebo is in capsule form and contains an inactive substance. It is taken by mouth once a night, approximately 30 minutes prior to bed for 6 months.	Drug: Placebo; 0 mg; capsule; QD; 6 month duration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Changes plasma pT181/T181 ratio of lemborexant 10 and 20 mg compared to Placebo	plasma collection	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of participants with treatment-related adverse events	Adverse events	6 months
Measure the blood concentration of lemborexant 10 mg and 20 mg and determine the dose-response relationship with CSF pT181/T181	Blood collection	6 months
Measure changes of cerebrospinal fluid p-tau/tau forms (T181, pT181, S202, pS202, pS202/S202, T217, pT217, pT217/T217).	CSF collection	6 months
Measure changes on blood plasma amyloid-beta isoforms (Aβ38, Aβ40, Aβ42, Aβ42/Aβ40)	Blood collection	6 months
Measure changes of CSF amyloid beta isoforms (Aβ38, Aβ40, Aβ42,Aβ42/Aβ40 )	CSF collection	6 months
Measure changes of blood plasma p-tau/tau forms (T181, pT181, pT181/T181, S202, pS202, pS202/S202, T217, pT217, pT217/T217).	Blood collection	6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Measure changes of cerebrospinal TREM2 (exploratory)	CSF	6 months
Measure changes of cerebrospinal NPTX2 (exploratory)	CSF	6 months
Measure changes of cerebrospinal NfL (exploratory)	CSF	6 months
Measure changes of blood plasma NfL (exploratory)	Blood	6 months

Collaborators and Investigators

• Sponsor: Washington University School of Medicine
• Collaborators: National Institutes of Health (NIH); National Institute on Aging (NIA); Eisai Inc.
• Investigators: Principal Investigator: Brendan Lucey, MD, Washington University School of Medicine

Study record dates

Study Major Dates

• Study Start (Actual): March 11, 2024
• Primary Completion (Estimated): March 31, 2030
• Study Completion (Estimated): March 31, 2030

Study Registration Dates

• First Submitted: January 29, 2024
• First Submitted That Met QC Criteria: February 15, 2024
• First Posted (Actual): February 23, 2024

Study Record Updates

• Last Update Posted (Actual): May 5, 2026
• Last Update Submitted That Met QC Criteria: April 29, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: Sleep; Older Adults; DORA
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Mental Disorders; Neurocognitive Disorders; Dementia; Tauopathies; Neurodegenerative Diseases; Alzheimer Disease; Sleep Aids, Pharmaceutical; Orexin Receptor Antagonists; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Neurotransmitter Agents; Hypnotics and Sedatives; lemborexant
• Other Study ID Numbers: 202301150; R01AG080551 (U.S. NIH Grant/Contract)

Drug and device information, study documents

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