Anti-Viral Clinical Trial for Alzheimer's Disease

  • STATUS
    Recruiting
  • End date
    Aug 22, 2022
Updated on 13 October 2021
cognitive impairment
benzodiazepines
dementia
mini-mental state examination
mild cognitive impairment
amyloid
memantine
cholinesterase inhibitors
cholinesterase
mild dementia

Summary

Viruses may cause or contribute to the pathology of Alzheimer's disease. This research treatment study at the MEMORY DISORDERS CLINIC is the first ever clinical trial to address this hypothesis. This study includes: brain imaging, clinical assessments, anti-viral research treatment with pills.

Description

Many viruses are latent for decades before being reactivated in the brain by stress, immune compromise, or other factors. After the initial oral infection, herpes simplex virus-1 (HSV1) becomes latent in the trigeminal ganglion and can later enter the brain via retrograde axonal transport, often targeting the temporal lobes. HSV1 can also enter the brain via olfactory neurons directly. HSV1 (oral herpes) and HSV2 (genital herpes) are known to trigger amyloid aggregation and their DNA is commonly found in amyloid plaques. Anti-HSV drugs reduce Aβ and p-tau accumulation in brains of infected mice. HSV1 reactivation is associated with tau hyperphosphorylation in mice and may play a role in tau propagation across neurons. In humans, recurrent reactivation with newly produced HSV1 particles, 'drop by drop,' may produce neuronal damage and eventually lead to neurodegeneration and Alzheimer's disease (AD) pathology, partly due to effects on amyloid and tau. Clinical studies show cognitive impairment in HSV seropositive patients in different patient groups and in healthy adults, and antiviral treatments show robust efficacy against peripheral HSV infection. The study team will conduct the first-ever clinical trial to directly address the long-standing viral etiology hypothesis of AD which posits that viruses, particularly the very common HSV1 and HSV2, may be etiologic or contribute to the pathology of AD. In patients with mild AD who test positive for serum antibodies to HSV1 or HSV2, the generic antiviral drug valacyclovir, repurposed as an anti-AD drug, will be compared at oral doses of 4 grams per day, to matching placebo in the treatment of 130 patients (65 valacyclovir, 65 placebo) in a randomized, double-blind, 78-week Phase II proof of concept trial. Patients treated with valacyclovir are hypothesized to show smaller decline in cognition and functioning compared to placebo, and, using 18F-Florbetapir PET imaging, to show less amyloid accumulation than placebo over the 78-week trial. Through the use of tau PET imaging with the tracer 18F-MK-6240 at baseline and 78 weeks, patients treated with valacyclovir are hypothesized to show smaller increases in 18F-MK-6240 binding than patients treated with placebo from baseline to 78 weeks. Apolipoprotein E genotype at baseline, as well as changes in cortical thinning on structural MRI, olfactory identification deficits, and antiviral antibody titers from baseline to 78 weeks, will be evaluated in exploratory analyses. In patients who agree to lumbar puncture, plasma and CSF acyclovir will be assayed to establish the degree of CNS penetration of valacyclovir in mild AD, and the investigators will obtain CSF Aβ42, tau, p-tau for subset exploratory analyses with changes in outcome measures. If this trial is successful, the investigators will apply for funding to conduct a larger, multicenter, Phase III study using a study design that will be informed by the results of this Phase II trial. This innovative Phase II proof of concept trial clearly has exceptionally high reward potential for the treatment of AD.

Details
Condition Alzheimer's Disease, Alzheimer Disease
Clinical Study IdentifierTX280415
Last Modified on13 October 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Females must be postmenopausal defined as 12 consecutive
months without menstruation, Patient Report Diagnosis of probable AD by NIA
clinical diagnostic criteria, Folstein Mini Mental State (MMSE) score 18 to 28
(inclusive) out of 30, Neuropsychological Evaluation Clinical Dementia Rating
(CDR) score of 1 (mild dementia), A family member or other individual who is
in contact with the patient and consents to serve as informant during the
study Patient Report Patient retains capacity to consent for him/herself or
retains the capacity to identify a surrogate who will consent on his/her
behalf, At screening, patients must test positive for serum antibodies to HSV1
or HSV2, Patients that test equivocal (index between 0.90-1.09; < 0.90 is
negative and > 1.09 is positive) will repeat the test within 6 weeks at a
repeat visit, If the results are negative at the second test, the patient will
not enter the study. If the results are equivocal or positive at the second
test (first test was equivocal), we will enroll the patient in the study
because "equivocal" indicates the presence of antibodies that do not reach the
minimum threshold, Use of cholinesterase inhibitors and memantine, and
concomitant psychotropic medications (other than high dose benzodiazepines)
will be permitted throughout the trial, Doses of these medications will need
to be stable for at least 1 month prior to study entry, Any changes to the
medication will be documented in the participant research chart, Medications
given for other medical reasons, e.g., anti-diabetic or antihypertensive
medications, will not be altered for the purposes of this trial and the
patient's primary physician may adjust such medications as medically indicated
throughout the trial, Details of concomitant medication use will be documented
at all visits and will be available for statistical analysis, For patients
diagnosed with Mild Cognitive Impairment and CDR score of 0.5 ( questionable
dementia), if these patients have biomarkers of AD neuropathology with either
a positive amyloid PET scan, positive fluorodeoxyglucose (FDG) PET scan of the
brain, or positive findings for AD in CSF ( low ABeta42 and high tau, p-tau
protein levels) they will be eligible for the study. This applies to patients
who already had an amyloid PET scan, FDG PET scan of the brain, or lumbar

Exclusion Criteria

Caregiver
is unwilling or unable, in the opinion of the investigator, to comply with
study instructions, Patient has dementia predominantly of non-Alzheimer's
type, including vascular dementia, frontotemporal dementia, Lewy body
dementia, substance-induced dementia, Modified Hachinski scale score greater
than 4, Current clinical diagnosis of schizophrenia, schizoaffective disorder
other psychosis, bipolar disorder or current major depression by DSM-5
criteria. Prior history of major depression will not be exclusionary (25% of
older adults have a lifetime history of major depression), Active suicidal
intent or plan based on clinical assessment, Physician Evaluation Current or
recent (past 6 months) alcohol or substance use disorder (DSM-5 criteria)
Current diagnosis of other major neurological disorders, including Parkinson's
disease, multiple sclerosis, CNS infection, Huntington's disease, and
amyotrophic lateral sclerosis, Clinical stroke with residual neurological
deficits. MRI findings of cerebrovascular disease (small infarcts, lacunes
periventricular disease) in the absence of clinical stroke with residual
neurological deficits will not lead to exclusion, Acute, severe, unstable
medical illness. For cancer, patients with active illness or metastases in the
last 12 months will be excluded, but past history of successfully treated
cancer will not lead to exclusion
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