NCT04710030

Valacyclovir for Mild Cognitive Impairment

Anti Viral Treatment in Mild Cognitive Impairment

• Status: Completed
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 50 (actual)
• Sponsor: New York State Psychiatric Institute · Academic / Other
• Sex: All
• Age: 50 Years – 95 Years
• Healthy volunteers: Not accepted

Summary

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.

Detailed 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.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.

Conditions

• Mild Cognitive Impairment
• Herpes Simplex 1
• Herpes Simplex 2

Interventions

Type	Name	Description
DRUG	Valacyclovir hydrochloride 500mg caplet	Active Comparator
DRUG	Placebo sugar pill caplet	Placebo Comparator

Timeline

• Start date: 2021-02-01
• Primary completion: 2024-10-23
• Completion: 2024-12-23
• First posted: 2021-01-14
• Last updated: 2026-03-31
• Results posted: 2026-03-31

Locations

1 site across 1 country: United States

Regulatory

• FDA-regulated drug study