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.
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
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
201
Within FDA approved dose 10 mg; capsule; QD, 6 month duration
20 mg; capsule; QD; 6 month duration
0 mg; capsule; QD; 6 month duration
Washington University in St. Louis, School of Medicine
St Louis, Missouri, United States
RECRUITINGChanges plasma pT181/T181 ratio of lemborexant 10 and 20 mg compared to Placebo
plasma collection
Time frame: 6 months
Number of participants with treatment-related adverse events
Adverse events
Time frame: 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
Time frame: 6 months
Measure changes on blood plasma amyloid-beta isoforms (Aβ38, Aβ40, Aβ42, Aβ42/Aβ40)
Blood collection
Time frame: 6 months
Measure changes of CSF amyloid beta isoforms (Aβ38, Aβ40, Aβ42,Aβ42/Aβ40 )
CSF collection
Time frame: 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
Time frame: 6 months
Measure changes of cerebrospinal fluid p-tau/tau forms (T181, pT181, S202, pS202, pS202/S202, T217, pT217, pT217/T217).
CSF collection
Time frame: 6 months
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