Anti-viral Therapy in Alzheimer's Disease

Study Overview
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Brief Summary
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Anti-viral therapy in Alzheimer's disease will investigate the efficacy of treating patients with mild Alzheimer's disease with the U.S.A marketed generic anti-viral drug Valtrex (valacyclovir, 500mg oral tablet). Valacyclovir, titrated to 4 grams per day, repurposed to treat Alzheimer's disease, will be compared to matching placebo in the treatment of 130 mild AD patients (65 valacyclovir, 65 placebo) who test positive for herpes simplex virus-1 (HSV1) or herpes simplex virus-2 (HSV2). The study will be a randomized, double-blind, 18-month Phase II proof of concept trial.

Detailed Description
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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.

Official Title
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Anti-viral Therapy in Alzheimer's Disease

Conditions
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Alzheimer Disease, Herpes Simplex 1, Herpes Simplex 2

Intervention / Treatment
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* Drug: Valacyclovir
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females. Females must be postmenopausal defined as 12 consecutive months without menstruation. Patient Report Diagnosis of probable AD by NIA clinical diagnostic criteria. Physician Evaluation Folstein Mini Mental State (MMSE) score 18 to 28 (inclusive) out of 30. Neuropsychological Evaluation Clinical Dementia Rating (CDR) score of 1 (mild dementia). Physician Evaluation 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. Patient Report 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 puncture, prior to recruitment into the protocol. Physical Evaluation Exclusion Criteria: Caregiver is unwilling or unable, in the opinion of the investigator, to comply with study instructions. Physician Evaluation Patient has dementia predominantly of non-Alzheimer's type, including vascular dementia, frontotemporal dementia, Lewy body dementia, substance-induced dementia. Physician Evaluation Modified Hachinski scale score greater than 4. Physician Evaluation 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). Physician Evaluation 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). Physician Evaluation Current diagnosis of other major neurological disorders, including Parkinson's disease, multiple sclerosis, CNS infection, Huntington's disease, and amyotrophic lateral sclerosis. Physician Evaluation 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. Physician Evaluation 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. Physician Evaluation Sitting blood pressure > 160/100 mm Hg. Physician Evaluation Renal failure as determined by an estimated Glomerular Filtration Rate (GFR) < 44 ml/min/1.73m2 (see 4.3.b.). Physician Evaluation/ Laboratory Report Serum vitamin B12 levels below the normal range. Physician Evaluation/ Laboratory Report Patients with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome will be excluded. Physician Evaluation Use of benzodiazepines in lorazepam equivalent doses equal to or greater than 2 mg daily. Physician Evaluation For patients consenting to lumbar puncture (40% of sample), this procedure will be conducted if there is no lower spinal malformation or other contraindication to lumbar puncture. Physician Evaluation For MRI, metal implants and pacemaker, and claustrophobia such that the patient refuses MRI. In the investigators' experience, these exclusions occur in less than 5% of patients with mild AD. MRI is required for VALAD. Patient Report/ Physician Evaluation Radiation exposure in the prior 12 months that, together with 18F-Florbetapir and 18F--MK-6240 PET, will be above the FDA annual radiation exposure threshold. This will be determined through study staff ( i.e. Principal Investigator, Study Physician) discussion with potential subjects at Screening, documenting inquiry about radiation history. If there is any history of additional radiation exposure in the past year; it will be reviewed with PET Center staff for their approval before proceeding. The combined radiation exposure from the maximum doses used for 18F-Florbetapir and 18F-MK- 6240 is within the FDA limits for annual radiation exposure and the second scan in each patient will be done 18 months after the initial PET scan (for both radioligands). Patient Report/Physician Evaluation Severe vision or hearing impairment that would prevent the participant from performing the psychometric tests accurately. This will be a clinical determination by the study physician without formal testing or audiometry Physician Evaluation Olfaction component: current upper respiratory infection (patient tested as soon as this improves), current smoker > 1 pack daily (past smoking has been shown not to affect UPSIT scores, UPSIT score < 12/40 (10 out of 40 is scored by chance in this multiple-choice test) indicating congenital anosmia. In the investigators' experience, less than 3% of cases are excluded for having one or more of these exclusionary criteria. If a patient is excluded from the olfaction component, the patient will still be eligible for the main protocol and all other study procedures. Patient Report/Physician Evaluation

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 95 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Valacyclovir<br>The oral valacyclovir will be distributed in 500mg caplets. Patients will take 8 caplets per day. | Drug: Valacyclovir<br>* Valacyclovir hydrochloride 500mg caplet<br>* Other names: Valtrex;|
| Placebo Comparator: Placebo<br>The oral placebo (sugar pill) will be distributed in 500mg caplets. Patients will take 8 caplets per day. | Drug: Placebo<br>* Placebo sugar pill 500mg caplet<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Alzheimer's Disease Assessment Scale - Cognition (ADAS-COG11, modified version) scores from baseline to 78 weeks. | The modified ADAS-COG11 is a cognitive battery that assesses attention, category fluency, episodic verbal memory, non-verbal memory, and naming. ADAS-cog has been used in virtually all FDA registration trials in AD. ADAS-cog has three different/equivalent word list versions that will be given sequentially to reduce practice effects. | Week 0, Week 12, Week 26, Week 52, Week 78 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scores from baseline to 78 weeks. | Measure of daily functioning in Alzheimer's disease that has been used in several major AD trials. ADCS-ADL includes a large section on Instrumental Activities of Daily Living, that are affected in mild AD. | Week 0, Week 12, Week 26, Week 52, Week 78 | 
| Change in total 18F-Florbetapir brain uptake from baseline to 78 weeks. | 18F-Florbetapir PET imaging will show amyloid accumulation in sum of six ROIs (cerebellar reference) that show increased uptake in AD: medial orbital frontal, anterior cingulate, parietal, temporal, posterior cingulate, precuneus. | Week 0, Week 78 | 
| Change in total 18F-MK-6240 brain uptake from baseline to 78 weeks. | 18F-MK-6240 tau PET imaging will show tau accumulation, SUVR: combining medial temporal, lateral temporal, prefrontal, parietal, and occipital regions of interest, ROIs, with cerebellar reference. | Week 0, Week 78 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Valacyclovir, Anti-viral treatment