DORA and LP in Alzheimer's Disease Biomarkers

NCT ID: NCT06274528

Last Updated: 2025-11-05

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE2
• Total Enrollment: 201 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2024-03-11
• Study Completion Date: 2029-03-11

Brief Summary

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.

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.

Conditions

Alzheimer Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Lemborexant 10 mg

Lemborexant is a capsule, taken by mouth once a night, approximately 30 minutes prior to bed for 6 months.

Group Type: EXPERIMENTAL

Lemborexant 10 mg

Intervention Type: DRUG

Within FDA approved dose 10 mg; capsule; QD, 6 month duration

Lemborexant 20 mg

Lemborexant is a capsule, taken by mouth once a night, approximately 30 minutes prior to bed for 6 months.

Group Type: EXPERIMENTAL

Lemborexant 20mg

Intervention Type: DRUG

20 mg; capsule; QD; 6 month duration

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.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

0 mg; capsule; QD; 6 month duration

Interventions

Lemborexant 10 mg

Within FDA approved dose 10 mg; capsule; QD, 6 month duration

Intervention Type: DRUG

Lemborexant 20mg

20 mg; capsule; QD; 6 month duration

Intervention Type: DRUG

Placebo

0 mg; capsule; QD; 6 month duration

Intervention Type: DRUG

Other Intervention Names

DAYVIGO; DAYVIGO

Eligibility Criteria

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.

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

• Minimum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

National Institutes of Health (NIH)

NIH

Sponsor Role: collaborator

Eisai Inc.

INDUSTRY

Sponsor Role: collaborator

National Institute on Aging (NIA)

NIH

Sponsor Role: collaborator

Washington University School of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Brendan Lucey

Professor of Neurology

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Brendan Lucey, MD

Role: PRINCIPAL_INVESTIGATOR

Washington University School of Medicine

Locations

Washington University in St. Louis, School of Medicine

St Louis, Missouri, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Chloe Meehan, MA

Role: CONTACT

cmeehan@wustl.edu

314-273-0878

Crirstina Toedebusch

Role: CONTACT

toedebuschc@wustl.edu

314-747-0646

Facility Contacts

Cristina Toedebusch, BS

Role: primary

toedebuschc@wustl.edu

314-747-0646

Chloe Meehan, BS, MA

Role: backup

cmeehan@wustl.edu

314-273-0878

Other Identifiers

R01AG080551

Identifier Type: NIH

Identifier Source: secondary_id

View Link

202301150

Identifier Type: -

Identifier Source: org_study_id