Efavirenz for Patients With Alzheimer's Disease

• Status: Active, not recruiting
• Trial end date: 2021-12-31
• Target enrollment: 0
• Participant gender: All

Summary

This will be a two-center, placebo controlled blinded clinical trial to evaluate the safety and tolerability of efavirenz (EFV) in 36 clinically stable subjects with mild cognitive impairment/early dementia due to Alzheimer's Disease (AD) age ≥55 years. Of these 36 total subjects, 18 will be recruited by MGH and 18 will be recruited by UH. A subset of the subjects at MGH only will also participate in a Stable Isotope Labeling Kinetics (SILK) protocol with deuterated water (a nonhazardous substance), designed to more precisely measure EFV effects on CNS cholesterol turnover.

Each respective site's 18 total recruited individuals will be divided into 3 groups: these 3 groups will represent two particular dosages of EFV and a placebo group, respectively. In a double-blind fashion, participants will be receiving either a capsule of EFV or placebo daily for 20 weeks. At MGH only, 12 individuals (4 from each of the two EFV groups and placebo) will participate in the unique "heavy water" SILK protocol assessing the kinetics of deuterium enrichment in plasma 24-hydroxycholesterol (24-OHC). All study participants at both sites will have their blood, cerebral spinal fluid, and urine analyzed at various points throughout the study. All participants will have their DNA genotyped for APOE isoforms (E2, E3 or E4) and single nucleotide polymorphisms (SNPs) in CYP46A1 (rs754203) and CYP2B6 (rs3745274) to be used for post-hoc analysis.

• Phase: Phase 1
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Case Western Reserve University
• Collaborators: Massachusetts General Hospital; University Hospitals Cleveland Medical Center
• Treatments: Efavirenz

Criteria

Inclusion Criteria:

• Between the ages of 55-85

• Either male or female

• Diagnosis of (a) as per below:

a) Mild Cognitive Impairment (MCI) or early dementia due to AD as defined by (1) complaint of cognitive decline, (2) MMSE Total=16-30, (3) CDR=0.5-1

• Fluent in English

• Education >8 years, literate, and/or good working history that precludes consideration of mental retardation

• Visual and auditory acuity sufficient for neuropsychological testing

• Modified Hachinski Ischemic Score<4

• No major health issues or diseases expected to interfere with the study

• Willing to complete all assessments and study procedures

• Not pregnant, lactating or of child-bearing potential (women must be >2 years post- menopausal or surgically sterile)

• If cognitively impaired, study partner with frequent contact with patient willing to accompany patient to visits and complete partner study forms

• No contraindication or hypersensitivity to EFV

• Screening laboratory testing must be within normal limits or, if abnormal, must be judged to be clinically insignificant by the investigators

• Stable use of cholinesterase inhibitor is permitted if doses are stable for 3 months prior to enrollment

Exclusion Criteria:

• Any CNS disease other than suspected prodromal or early AD, such as clinical stroke, brain tumor, normal pressure hydrocephalus, brain tumor, multiple sclerosis, significant head trauma with persistent neurological or cognitive deficits or complaints, Parkinson's Disease, frontotemporal dementia, or other neurodegenerative diseases

• Ongoing major and active psychiatric disorder and/or other concurrent medical condition that, in the opinion of the investigator, might compromise safety and/or compliance with study requirements.

• History of alcohol or other substance abuse or dependence within the past two years

• Any significant systemic illness or unstable medical condition that could affect study compliance, including a history of prolonged QTc

• Laboratory abnormalities in B12, TSH, or other common laboratory parameters that might contribute to cognitive dysfunction

• Current use of medications with psychoactive properties that may deleteriously affect cognition (e.g., anticholinergics, antihistamines, antipsychotics, sedative hypnotics, anxiolytics) that, in the opinion of the investigator, may deleteriously affect cognition. Use of other investigational agents one month prior to entry and for the duration of the study

• Treatment with any of the following agents/classes within the past 3 months:

simvastatin, antiepileptic agents, clopidogrel, voriconazole, systemic ketoconazole, cyclosporine, St. John's Wort.