DORA and LP in Alzheimer's Disease Biomarkers

Alzheimer Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06274528
• Other study ID #: 202301150
• Status: Recruiting
• Phase: Phase 2
• Start date: March 11, 2024
• Est. completion date: March 11, 2029

Study information

• Verified date: March 2024
• Source: Washington University School of Medicine
• Contact: Chloe Meehan, MA
• Phone: 314-273-0878
• Email: cmeehan[@]wustl.edu
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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 fluid around the brain known as cerebrospinal fluid (CSF). Amyloid-beta and tau are proteins involved in the disease process leading to Alzheimer's disease.

Description:

The overall goal of this project is to conduct an adaptive 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 cerebrospinal fluid (CSF) and blood plasma 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 ratio in CSF 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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 201
• Est. completion date: March 11, 2029
• Est. primary completion date: March 11, 2029
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: All
• Age group: 65 Years and older

Eligibility

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.
• Untreated sleep apnea AHI>15
• Poorly treated sleep apnea with <4 hours/night <70% of the nights for 30 days prior to enrollment or undertreated OSA defined as an AHI =10.
• Negative plasma amyloid-beta and tau test
• Contraindication to lumbar puncture (anticoagulants; bleeding disorder; allergy to lidocaine or disinfectant; prior central nervous system or lower back surgery).
• Stroke.
• History of renal impairment
• Defined as patients with markers of kidney damage or eGFR = 60 ml/min/1.73m2.
• Normal Limits > 60.0 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.
• Body mass index >35.
• History of substance abuse or alcoholism 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.

Related Conditions & MeSH terms

• Alzheimer Disease

Intervention

Drug:
• Lemborexant 10 mg
Within FDA approved dose 10 mg; capsule; QD, 6 month duration
• Lemborexant 20mg
20 mg; capsule; QD; 6 month duration
• Placebo
0 mg; capsule; QD; 6 month duration

Locations

Country	Name	City	State
United States	Washington University in St. Louis, School of Medicine	Saint Louis	Missouri

Sponsors (1)

Lead Sponsor	Collaborator
Washington University School of Medicine

Country where clinical trial is conducted

United States, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Measure changes of cerebrospinal TREM2 (exploratory)	CSF	6 months
Other	Measure changes of cerebrospinal NPTX2 (exploratory)	CSF	6 months
Other	Measure changes of cerebrospinal NfL (exploratory)	CSF	6 months
Other	Measure changes of blood plasma NfL (exploratory)	Blood	6 months
Primary	Changes CSF pT181/T181 ratio of lemborexant 10 and 20 mg compared to Placebo	CSF collection	6 months
Secondary	Number of participants with treatment-related adverse events	Adverse events	6 months
Secondary	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
Secondary	Measure changes on blood plasma amyloid-beta isoforms (Aß38, Aß40, Aß42)	Blood collection	6 months
Secondary	Measure changes of CSF amyloid beta isoforms (Aß38, Aß40, Aß42)	CSF collection	6 months
Secondary	Measure changes of blood plasma p-tau/tau forms (T181, pT181, S202, pS202, pS202/S202, T217, pT217, pT217/T217).	Blood collection	6 months
Secondary	Measure changes of cerebrospinal fluid p-tau/tau forms (T181, pT181, S202, pS202, pS202/S202, T217, pT217, pT217/T217).	CSF collection	6 months