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Anti-viral Therapy in Alzheimer's Disease

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ClinicalTrials.gov Identifier: NCT03282916
Recruitment Status : Recruiting
First Posted : September 14, 2017
Last Update Posted : September 26, 2018
Sponsor:
Collaborators:
National Institutes of Health (NIH)
National Institute on Aging (NIA)
Information provided by (Responsible Party):
Davangere P. Devanand, New York State Psychiatric Institute

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 at 2 g to 4 g 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 HSV2. The study will be a randomized, double-blind, 18-month Phase II proof of concept trial.

Condition or disease Intervention/treatment Phase
Alzheimer Disease Herpes Simplex 1 Herpes Simplex 2 Drug: Valacyclovir Drug: Placebo Phase 2

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. 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 2 to 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)
Estimated Enrollment : 130 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Treatment
Official Title: Anti-viral Therapy in Alzheimer's Disease
Actual Study Start Date : February 12, 2018
Estimated Primary Completion Date : August 2022
Estimated Study Completion Date : August 2022


Arm Intervention/treatment
Active Comparator: Valacyclovir
The oral valacyclovir will be distributed in 500mg caplets. Patients will take 4-8 caplets per day.
Drug: Valacyclovir
Valacyclovir hydrochloride 500g caplet
Other Name: Valtrex

Placebo Comparator: Placebo
The oral placebo sugar pill will be distributed in 500mg caplets. Patients will take 4-8 caplets per day.
Drug: Placebo
Placebo sugar pill 500mg caplet




Primary Outcome Measures :
  1. 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.


Secondary Outcome Measures :
  1. 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.

    It includes a large section on Instrumental Activities of Daily Living that are affected in mild AD.


  2. 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.

  3. 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.



Information from the National Library of Medicine

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Ages Eligible for Study:   55 Years to 95 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Males and females. Females must be postmenopausal defined as 12 consecutive months without menstruation. Patient Report
  2. Diagnosis of probable AD by NIA clinical diagnostic criteria. Physician Evaluation
  3. Folstein Mini Mental State (MMSE) score 20 to 28 (inclusive) out of 30. Neuropsychological Evaluation
  4. Clinical Dementia Rating (CDR) score of 1 (mild dementia). Physician Evaluation
  5. A family member or other individual who is in contact with the patient and consents to serve as informant during the study Patient Report
  6. 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
  7. 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.
  8. Use of cholinesterase inhibitors and memantine, and concomitant psychotropic medications (other than highdose benzodiazepines), will be permitted throughout the trial. Doses of these medications will need to be stable for at least 2 months 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.

Exclusion Criteria:

  1. Caregiver is unwilling or unable, in the opinion of the investigator, to comply with study instructions. Physician Evaluation
  2. Patient has dementia predominantly of non-Alzheimer's type, including vascular dementia, frontotemporal dementia, Lewy body dementia, substance-induced dementia. Physician Evaluation
  3. Modified Hachinski scale score greater than 4. Physician Evaluation
  4. Current clinical diagnosis of schizophrenia, schizoaffective disorder, other psychosis, bipolar disorder or current major depression by DSM-5 criteria. Prior history of major depression will not be exclusionary (25% of older adults have a lifetime history of major depression). Physician Evaluation
  5. Active suicidal intent or plan based on clinical assessment. Physician Evaluation
  6. Current or recent (past 6 months) alcohol or substance use disorder (DSM-5 criteria). Physician Evaluation
  7. Current diagnosis of other major neurological disorders, including Parkinson's disease, multiple sclerosis, CNS infection, Huntington's disease, and amyotrophic lateral sclerosis. Physician Evaluation
  8. Clinical stroke with residual neurological deficits. MRI findings of cerebrovascular disease (small infarcts, lacunes, periventricular disease) in the absence of clinical stroke with residual neurological deficits will not lead to exclusion. Physician Evaluation
  9. Acute, severe, unstable medical illness. For cancer, patients with active illness or metastases in the last 12 months will be excluded, but past history of successfully treated cancer will not lead to exclusion. Physician Evaluation
  10. Sitting blood pressure > 160/100 mm Hg. Physician Evaluation
  11. Renal failure as determined by an estimated Glomerular Filtration Rate (GFR) < 44 ml/min/1.73m2 (see 4.3.b.). Physician Evaluation/ Laboratory Report
  12. Serum vitamin B12 levels below the normal range. Physician Evaluation/ Laboratory Report
  13. Patients with thrombotic thrombocytopenic purpura/hemolytic uremic syndrome will be excluded. Physician Evaluation
  14. Use of benzodiazepines in lorazepam equivalent doses equal to or greater than 2 mg daily. Physician Evaluation
  15. 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
  16. For MRI, metal implants and pacemaker, and claustrophobia such that the patient refuses MRI. In the investigators' experience, these exclusions occur in less than 5% of patients with mild AD. MRI is required for VALAD. Patient Report/ Physician Evaluation
  17. 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
  18. 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
  19. Olfaction component: current upper respiratory infection (patient tested as soon as this improves), current smoker > 1 pack daily (past smoking has been shown not to affect UPSIT scores, UPSIT score < 12/40 (10 out of 40 is scored by chance in this multiple-choice test) indicating congenital anosmia. In the investigators' experience, less than 3% of cases are excluded for having one or more of these exclusionary criteria. If a patient is excluded from the olfaction component, the patient will still be eligible for the main protocol and all other study procedures. Patient Report/Physician Evaluation
  20. Clinical judgment that past lifetime radiation exposure is extensive enough to make exposure to PET scans in the current study inadvisable.

    Clinical judgment of the evaluating study physician

  21. Serum vitamin B12 levels below the normal range. Physician Evaluation/Laboratory Report

Information from the National Library of Medicine

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


Contacts
Contact: Davangere Devanand, MD 646-774-8658 dpd3@cumc.columbia.edu
Contact: Edward Huey, MD 212-305-6939 edward.huey@nyspi.columbia.edu

Locations
United States, New York
New York State Psychiatric Institute Recruiting
New York, New York, United States, 10032
Contact: Julianna Pollina, BS    646-774-8638    julianna.pollina@nyspi.columbia.edu   
Contact: Mariasofia Katsikoumbas, BS    646-774-8641    mariasofia.katsikoumbas@nyspi.columbia.edu   
Principal Investigator: Davangere Devanand, MD         
Sub-Investigator: Edward Huey, MD         
Sub-Investigator: Yaakov Stern, PhD         
Sponsors and Collaborators
New York State Psychiatric Institute
National Institutes of Health (NIH)
National Institute on Aging (NIA)
Investigators
Principal Investigator: Davangere Devanand, MD Columbia University

Responsible Party: Davangere P. Devanand, Professor of Clinical Psychiatry and Neurology, New York State Psychiatric Institute
ClinicalTrials.gov Identifier: NCT03282916     History of Changes
Other Study ID Numbers: 7537
R01AG055422 ( U.S. NIH Grant/Contract )
First Posted: September 14, 2017    Key Record Dates
Last Update Posted: September 26, 2018
Last Verified: September 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Davangere P. Devanand, New York State Psychiatric Institute:
Valacyclovir
Anti-viral treatment

Additional relevant MeSH terms:
Alzheimer Disease
Herpes Simplex
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Virus Diseases
Skin Diseases, Viral
Skin Diseases, Infectious
Skin Diseases
Dementia
Tauopathies
Herpesviridae Infections
DNA Virus Infections
Valacyclovir
Acyclovir
Antiviral Agents
Anti-Infective Agents