Valacyclovir for Mild Cognitive Impairment (VALMCI)

Anti-viral treatment in Mild Cognitive Impairment (MCI) is a Phase II, placebo-controlled, 52-week trial using oral valacyclovir 4 g/day in 50 HSV seropositive, AD biomarker-positive, amnestic mild cognitive impairment (MCI) patients (eMCI and lMCI). The trial will directly address the long-standing viral etiology hypothesis of Alzheimer's disease (AD) which posits that viruses, particularly the very common herpes simplex virus-1 (HSV1) and herpes simplex virus-2 (HSV2), may be etiologic or contribute to the pathology of AD. This trial will intervene at an earlier stage (MCI). We will compare the repurposed drug valacyclovir to placebo in patients with amnestic MCI (eMCI and lMCI) in a randomized, double-blind, two-arm parallel group 52-week pilot trial. Our Phase II trial will be the first antiviral drug trial conducted in MCI.

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.This trial will intervene at an earlier stage (MCI). In AD biomarker positive patients with Mild Cognitive Impairment (eMCI and lMCI) who test positive for serum antibodies to HSV1 or HSV2, the generic antiviral drug valacyclovir will be compared at oral doses of 4 grams per day, to matching placebo in the treatment of 50 patients (25 valacyclovir, 25 placebo) in a randomized, double-blind, 52-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 52-week trial. We will explore apolipoprotein E e4 genotype as a moderator, and changes in global clinical status, viral antibodies and proteomic assays, AD signature of MRI regional and whole brain cortical thinning, and plasma total tau, p-tau epitopes and neurofilament light (Nfl) protein markers for neurodegeneration as exploratory hypotheses. Apolipoprotein biomarker testing will be completed preferably at Week 0 (may be completed at any alternative site visit if necessary), MRI scans at Week 0 and Week 52, PET scans at Screening and Week 52. This innovative Phase II proof of concept trial clearly has exceptionally high reward potential for the treatment of MCI.

Oral valacyclovir will be distributed in 500mg caplets. Patients will take 8 caplets per day (total dose: 4 grams per day) for 52 weeks.

The oral placebo (sugar pill) will be distributed in 500mg caplets. Patients will take 8 caplets per day for 52 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.

Change in Alzheimer's Disease Cooperative Study- Preclinical Alzheimer Cognitive Composite (PAAC) cognitive composite score from Week 0 to Week 52.

The ADCS-PACC combines four widely used paper-and-pencil cognitive tests. These include the list- learning task from the Free and Cued Selective Reminding Test (FCSRT), as well as a paragraph- recall test from the Wechsler Memory Scale, both of which measure episodic memory. The Digit Symbol Substitution Test from the Wechsler Adult Intelligence Scale tests executive function. The final component, the Mini-Mental State Examination (MMSE), assesses global functioning and mental status. Scores range from -5 to +5 with higher scores indicating less deficit and lower scores indicating greater deficit.

Change in Alzheimer's Disease Cooperative Study-Activities of Daily Living scale-PI (ADCS-ADL-PI) score from Week 0 to Week 52.

The ADCS-ADL-PI will be administered to the patient, for the assessment of impairments of complex Activities of Daily Living for patients with MCI. Scores range from 0-45 with lower scores indicating greater deficit and higher scores indicating less deficit.

Inclusion Criteria: Males and females ages 50-95. Females must be postmenopausal, defined as 12 consecutive months without menstruation. (Patient Report) Diagnosis of MCI (includes eMCI and lMCI by ADNI criteria)(Neuropsychological Evaluation) Folstein Mini Mental State (MMSE) greater than or equal to 23/30. (Neuropsychological Evaluation) Patient retains capacity to consent for him/herself. (Physician Evaluation) At screening, patients must test positive for serum antibodies to HSV1 or HSV2. (Laboratory Tests) Use of cholinesterase inhibitors or memantine is not required but will be permitted. If already prescribed, doses of these medications must be stable for 1 month prior to study entry. Patients are permitted to receive cholinesterase inhibitors and/or memantine throughout the duration of the study. Any changes to the medication will be documented in the participant research chart. Medications given for other medical reasons, e.g., antidiabetic or anti-hypertensive 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.(Patient Report) Either PET amyloid scan positivity at screening, or prior CSF biomarker positive for AD. (Medical Records or through completing a PET scan as part of screening) Exclusion Criteria: 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. (Physician Evaluation) Active suicidal intent or plan based on clinical assessment. (SRMP Assessment by Study Physician) 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 clinical 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. (Laboratory Report) Serum vitamin B12 levels below the normal range. (Laboratory Report) Patients with thyroid stimulating hormone (TSH) levels above 4.94 mlU/L. (Laboratory Report) Use of benzodiazepines in lorazepam equivalent doses equal to or greater than 2 mg daily. (Patient Report) For MRI, metal implants and pacemaker, and claustrophobia such that the patient refuses MRI. (Patient Report) Radiation exposure in the prior 12 months that, together with 18F- Florbetapir will be above the FDA annual radiation exposure threshold. (Patient Report and 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)