Valacyclovir for Mild Cognitive Impairment

NCT04710030 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: 8089
• Study Type: interventional
• Target: 50
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Mild Cognitive Impairment; Herpes Simplex 1; Herpes Simplex 2

Keywords

Valacyclovir; Anti-viral treatment

Outcome Measures

Primary Outcomes (1)

• Change in Standardized Uptake Value Ratio (SUVR) of (18F-Florbetapir PET) From Week 0 to Week 52.

  18F-Florbetapir PET imaging is hypothesized to show amyloid accumulation in sum of six ROIs (cerebellar gray matter reference) that are known to show increased uptake in AD: medial orbital frontal, anterior cingulate, parietal, temporal, posterior cingulate, precuneus.

  Week 0 to Week 52

Secondary Outcomes (3)

• Change From Week 0 to Week 52 in the Alzheimer's Disease Cooperative Study-Preclinical Alzheimer Cognitive Composite (PACC) Z-score

  Assessed by Change in Least Square Means from Week 0 to Week 52 (measure in Outcome Measure Data Table), covarying for baseline score, age, sex and apolipoprotein E e4 status.

• Change From Week 0 to Week 52 in the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale-Prevention Instrument (ADCS-ADL-PI)

  Assessed by Change in Least Square Means from Week 0 to Week 52 (measure in Outcome Measure Data Table), covarying for baseline score, age, sex and apolipoprotein E e4 status.

• Change From Week 0 to Week 52 in Clinical Dementia Rating (CDR) Sum of Boxes

  Assessed by Change in Least Square Means from Week 0 to Week 52 (measure in Outcome Measure Data Table), covarying for baseline score, age, sex and apolipoprotein E e4 status.

Study Arms (2)

Valacyclovir

ACTIVE COMPARATOR

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

Drug: Valacyclovir hydrochloride 500mg caplet

Placebo

PLACEBO COMPARATOR

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

Drug: Placebo sugar pill caplet

Interventions

Valacyclovir hydrochloride 500mg caplet DRUG

Active Comparator

Also known as: Valtrex

Valacyclovir

Placebo sugar pill caplet DRUG

Placebo Comparator

Also known as: Placebo

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 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)

You may not qualify if:

• 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)
• 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)

Sponsors & Collaborators

• New York State Psychiatric Institute: lead
• Alzheimer's Association: collaborator

Study Sites (1)

New York State Psychiatric Institute

New York, New York, 10032, United States

Location

MeSH Terms

Conditions

Cognitive Dysfunction

Interventions

Valacyclovir

Condition Hierarchy (Ancestors)

Cognition Disorders; Neurocognitive Disorders; Mental Disorders

Intervention Hierarchy (Ancestors)

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

Results Point of Contact

• Title: Dr. Davangere Devanand
• Organization: New York State Psychiatric Institute

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
• Masking Details: Triple (Participant, Care Provider, Investigator)
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Clinical Psychiatry and Neurology

Model Details: Parallel Assignment

Study Record Dates

• First Submitted: January 13, 2021
• First Posted: January 14, 2021
• Study Start: February 1, 2021
• Primary Completion: October 23, 2024
• Study Completion: December 23, 2024
• Last Updated: March 31, 2026
• Results First Posted: March 31, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)