Antiviral therapy: Valacyclovir Treatment of Alzheimer's Disease (VALAD) Trial: protocol for a randomised, double-blind,placebo-controlled, treatment trial.

Introduction: After infection, herpes simplex virus-1 (HSV1) becomes latent in the trigeminal ganglion and can enter the brain via retrograde axonal transport. Recurrent reactivation of HSV1 may lead to neurodegeneration and Alzheimer's disease (AD) pathology. HSV1 (oral herpes) and HSV2 (genital herpes) can trigger amyloid beta-protein (Aβ) aggregation and HSV1 DNA is common in amyloid plaques. Anti-HSV drugs reduce Aβ and phosphorylated tau accumulation in cell-culture models. Cognitive impairment is greater in patients with HSV seropositive, and antiviral drugs show robust efficacy against peripheral HSV infection. Recent studies of electronic health records databases demonstrate that HSV infections increase dementia risk, and that antiviral medication treatment reduces this risk. The generic antiviral drug valacyclovir was superior to placebo in improving memory in a schizophrenia pilot trial but has not been tested in AD.
Methods and Analysis: In patients with mild AD who test positive for HSV1 or HSV2 serum antibodies, valacyclovir, repurposed as an anti-AD drug, will be compared with placebo (lactose pills) in 130 patients (65 valacyclovir and 65 placebo) in a randomised, double-blind, 78-week phase II proof-of-concept trial. Patients on valacyclovir, dose-titrated from 2 g to a targeted oral dose of 4 g daily, compared with placebo, are hypothesised to show smaller cognitive and functional decline, and, using ¹⁸ F-Florbetapir positron emission tomography (PET) and ¹⁸ F-MK-6240 PET imaging, to show less amyloid and tau accumulation, respectively. In the lumbar puncture subsample, cerebrospinal fluid acyclovir will be assayed to assess central nervous system valacyclovir penetration.
Ethics and Dissemination: The trial is being overseen by the New York State Psychiatric Institute Institutional Review Board (protocol 7537), the National Institute on Ageing, and the Data Safety Monitoring Board. Written informed consent is obtained for all subjects. Results will be disseminated via publication, clinicaltrials.gov, media and conferences.
Trial Registration Number: ClinicalTrials.gov identifier (NCT03282916) Pre-results.
Competing Interests: Competing interests: AM, QR, KMP, DAD, WCK, EA, HA, JP, MK have no competing interests. DPD is a consultant to Acadia, Eisai, Genentech, Avanir, Neuronix, Grifols and BXcel Therapeutics and has grant support from the National Institute of Aging. EDH is a consultant to Biogen and Ionis. TW is a consultant to Alzemend Neuro, Inc. and Grifols and has grant support from the National Institute of Health and the National Institute on Aging. KLB has grant support from Lilly, Amylx and Biohaven. AAG is contracted with Merck. GHP has grant support from the National Institute on Aging. YS is a consultant to Eli Lilly, Axovant, Takeda, and AbbVie, has donated to Piramal Imaging Limited, has grant support from California Walnut Commission, and has a license for the Dependence Scale.
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