Anti-viral Therapy in Alzheimer's Disease
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|ClinicalTrials.gov Identifier: NCT03282916|
Recruitment Status : Active, not recruiting
First Posted : September 14, 2017
Last Update Posted : December 19, 2022
|Condition or disease||Intervention/treatment||Phase|
|Alzheimer Disease Herpes Simplex 1 Herpes Simplex 2||Drug: Valacyclovir Drug: Placebo||Phase 2|
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. In patients with mild AD who test positive for serum antibodies to HSV1 or HSV2, the generic antiviral drug valacyclovir, repurposed as an anti-AD drug, will be compared at oral doses of 4 grams per day, to matching placebo in the treatment of 130 patients (65 valacyclovir, 65 placebo) in a randomized, double-blind, 78-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 78-week trial. Through the use of tau PET imaging with the tracer 18F-MK-6240 at baseline and 78 weeks, patients treated with valacyclovir are hypothesized to show smaller increases in 18F-MK-6240 binding than patients treated with placebo from baseline to 78 weeks. Apolipoprotein E genotype at baseline, as well as changes in cortical thinning on structural MRI, olfactory identification deficits, and antiviral antibody titers from baseline to 78 weeks, will be evaluated in exploratory analyses. In patients who agree to lumbar puncture, plasma and CSF acyclovir will be assayed to establish the degree of CNS penetration of valacyclovir in mild AD, and the investigators will obtain CSF Aβ42, tau, p-tau for subset exploratory analyses with changes in outcome measures. If this trial is successful, the investigators will apply for funding to conduct a larger, multicenter, Phase III study using a study design that will be informed by the results of this Phase II trial. This innovative Phase II proof of concept trial clearly has exceptionally high reward potential for the treatment of AD.
|Study Type :||Interventional (Clinical Trial)|
|Actual Enrollment :||120 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||Triple (Participant, Care Provider, Investigator)|
|Official Title:||Anti-viral Therapy in Alzheimer's Disease|
|Actual Study Start Date :||February 12, 2018|
|Estimated Primary Completion Date :||December 2023|
|Estimated Study Completion Date :||December 2023|
Active Comparator: Valacyclovir
The oral valacyclovir will be distributed in 500mg caplets. Patients will take 8 caplets per day.
Valacyclovir hydrochloride 500mg caplet
Other Name: Valtrex
Placebo Comparator: Placebo
The oral placebo (sugar pill) will be distributed in 500mg caplets. Patients will take 8 caplets per day.
Placebo sugar pill 500mg caplet
- Change in Alzheimer's Disease Assessment Scale - Cognition (ADAS-COG11, modified version) scores from baseline to 78 weeks. [ Time Frame: Week 0, Week 12, Week 26, Week 52, Week 78 ]The modified ADAS-COG11 is a cognitive battery that assesses attention, category fluency, episodic verbal memory, non-verbal memory, and naming. ADAS-cog has been used in virtually all FDA registration trials in AD. ADAS-cog has three different/equivalent word list versions that will be given sequentially to reduce practice effects.
- Change in Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) scores from baseline to 78 weeks. [ Time Frame: Week 0, Week 12, Week 26, Week 52, Week 78 ]
Measure of daily functioning in Alzheimer's disease that has been used in several major AD trials.
ADCS-ADL includes a large section on Instrumental Activities of Daily Living, that are affected in mild AD.
- Change in total 18F-Florbetapir brain uptake from baseline to 78 weeks. [ Time Frame: Week 0, Week 78 ]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 total 18F-MK-6240 brain uptake from baseline to 78 weeks. [ Time Frame: Week 0, Week 78 ]18F-MK-6240 tau PET imaging will show tau accumulation, SUVR: combining medial temporal, lateral temporal, prefrontal, parietal, and occipital regions of interest, ROIs, with cerebellar reference.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03282916
|United States, Arizona|
|Banner Alzheimer's Institute (BAI)|
|Phoenix, Arizona, United States, 85006|
|United States, New York|
|New York University School of Medicine|
|New York, New York, United States, 10016|
|New York State Psychiatric Institute|
|New York, New York, United States, 10032|
|Principal Investigator:||Davangere Devanand, MD||Columbia University|