Anti-viral Therapy in Alzheimer's Disease

NCT03282916 | Completed Phase 2 Results DMC FDA Drug

• 3 other identifiers: AAAV1800R01AG055422NYSPI 7537
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 3

Brief Summary

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.

Conditions

Alzheimer Disease; Herpes Simplex 1; Herpes Simplex 2

Keywords

Valacyclovir; Anti-viral treatment

Outcome Measures

Primary Outcomes (1)

• Alzheimer's Disease Assessment Scale - Cognition (ADAS-COG11, Modified Version) Score

  The modified ADAS-COG11 is a neuropsychological test used to measure the severity of cognitive dysfunction in Alzheimer's disease. The full range is 0 to 70, where a higher score indicates worse cognition.

  Baseline, Week 78

Secondary Outcomes (3)

• Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) Score

  Baseline, Week 78

• Total 18F-Florbetapir Brain Uptake

  Baseline, Week 78

• Total 18F-MK-6240 Temporal Lobe Brain Uptake

  Baseline, Week 78

Study Arms (2)

Valacyclovir

ACTIVE COMPARATOR

The oral valacyclovir will be distributed in 500mg caplets. Patients will take 8 caplets per day.

Drug: Valacyclovir

Placebo

PLACEBO COMPARATOR

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

Drug: Placebo

Interventions

Valacyclovir DRUG

Valacyclovir hydrochloride 500mg caplet

Also known as: Valtrex

Valacyclovir

Placebo DRUG

Placebo sugar pill 500mg caplet

Placebo

Eligibility Criteria

• Age: 50 Years - 95 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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
• 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
• 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

Sponsors & Collaborators

• Columbia University: lead
• National Institutes of Health (NIH): collaborator
• National Institute on Aging (NIA): collaborator

Study Sites (3)

Banner Alzheimer's Institute (BAI)

Phoenix, Arizona, 85006, United States

Location

New York University School of Medicine

New York, New York, 10016, United States

Location

New York State Psychiatric Institute

New York, New York, 10032, United States

Location

Related Publications (2)

• Devanand DP, Wisniewski T, Razlighi Q, Qian M, Wei R, Andrews HF, Acosta EP, Bell KL, Pelton GH, Deliyannides D, Perrin AC, Caccappolo E, Gershon AA, Prasad KM, Kreisl WC, Mintz A, Huey ED. Valacyclovir Treatment of Early Symptomatic Alzheimer Disease: The VALAD Randomized Clinical Trial. JAMA. 2025 Dec 17:e2521738. doi: 10.1001/jama.2025.21738. Online ahead of print.

  PMID: 41405855 DERIVED

• Devanand DP, Andrews H, Kreisl WC, Razlighi Q, Gershon A, Stern Y, Mintz A, Wisniewski T, Acosta E, Pollina J, Katsikoumbas M, Bell KL, Pelton GH, Deliyannides D, Prasad KM, Huey ED. Antiviral therapy: Valacyclovir Treatment of Alzheimer's Disease (VALAD) Trial: protocol for a randomised, double-blind,placebo-controlled, treatment trial. BMJ Open. 2020 Feb 6;10(2):e032112. doi: 10.1136/bmjopen-2019-032112.

  PMID: 32034019 DERIVED

MeSH Terms

Conditions

Alzheimer Disease

Interventions

Valacyclovir

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

Acyclovir; Guanine; Hypoxanthines; Purinones; Purines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Limitations and Caveats

Limitations included the small sample size. The COVID-19 pandemic contributed to a dropout rate of 24%.

Results Point of Contact

• Title: Dr. Davangere P Devanand
• Organization: Columbia University Irving Medical Center

dpd3@cumc.columbia.edu

646-774-8658

Study Officials

• Davangere Devanand, MD

  Columbia University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Clinical Psychiatry and Neurology

Study Record Dates

• First Submitted: September 12, 2017
• First Posted: September 14, 2017
• Study Start: February 12, 2018
• Primary Completion: September 5, 2024
• Study Completion: September 5, 2024
• Last Updated: September 25, 2025
• Results First Posted: September 8, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)