Valproic Acid in Subjects With Intact Cognition - Proof of Concept Study

Study Overview
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Brief Summary
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The purpose of this study is to evaluate the safety of administration and effects of valproic acid on clusterin expression in cognitively-intact, healthy, elderly subjects. Clusterin mutations have recently been identified as a risk factor for the development of Alzheimer's Disease and changes in clusterin expression are seen in the elderly who develop Alzheimer's disease irrespective of whether they carry these genetic mutations or not. Valproic acid may prevent or reverse these changes. Fourteen subjects with normal memory and thinking will participate in this study. Ten of these subjects will receive valproic acid and 4 will receive a placebo capsule with no active medicine. Participants will take study medication or placebo for 28 days and be followed for a total 35 days in this trial.

Detailed Description
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This is a placebo-controlled, single-center, multiple ascending dose study. Seven healthy volunteers will be enrolled into 2 sequential cohorts, for a total of 14 enrolled subjects. The study will be conducted using two doses of valproate (250 mg PO bid, followed by 500 mg PO bid). At each dose level, 7 cognitively intact normal elderly subjects will be entered into the study with two subjects randomly selected to receive placebo while the other five subjects receive the designated dose of valproate. Study procedures will include routine assessment of adverse events, safety labs, baseline MRI, physical and neurological exams, and cerebrospinal fluid collection. Other investigational medication or devices are prohibited during this study.

Official Title
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Safety And Target Engagement Of Clu1 By Valproic Acid In Subjects With Intact Cognition: Proof Of Concept For The Development Of A Prevention Trial For Alzheimer's Disease

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: Valproic Acid
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Men or women aged 65-90, inclusive. English-speaking, to ensure compliance with cognitive testing and study visit procedures. Female participants must not be pregnant or of childbearing potential, i.e. either surgically sterile or postmenopausal for > 1 year. Stable medical condition for three months prior to screening visit, with no clinically significant abnormalities of hepatic, renal, and hematologic function defined as follows: Platelets > 100,000 Serum creatinine ≤ 1.6 mg/dL Liver function tests ≤ 1.5 upper limit of normal No clinically significant abnormalities of other laboratory studies (blood counts, chemistry panel, urinalysis) as determined by the study physician Stable medications for 4 weeks prior to screening visit. Able to ingest oral medications. No history of adverse drug reactions to VPA or similar agents. Physically acceptable for this study as confirmed by medical history, physical exam, neurological exam and clinical tests in the opinion of the study physician. Not demented by Hachinski Ischemic Index (< 4). Exclusion Criteria: Significant neurologic disease such as Parkinson's disease, stroke, brain tumor, multiple sclerosis or seizure disorder. Major depression in past 12 months (DSM-IV criteria), major mental illness such as schizophrenia, or recent (in past 12 months) alcohol or substance abuse by history. History of invasive cancer within the past two years (excluding non-melanoma skin cancer). Contra-indications to lumbar puncture (bleeding disorder, platelet count < 100,000, anticoagulant treatment, major structural abnormality or sepsis in the area of the lumbosacral spine that would make spinal fluid collection technically difficult). Clinically significant MRI abnormalities that contraindicate lumber or suggest central nervous system disease processes that could influence study outcomes in the opinion of the PI. Use of any investigational agents within 30 days prior to screening. Major surgery within eight weeks prior to the Baseline Visit. Severe unstable medical illnesses, including uncontrolled cardiac conditions or heart failure (New York Heart Association Class III or IV) . Antiretroviral therapy for human immunodeficiency virus (HIV). Residence in a skilled nursing facility. Blindness, deafness, language difficulties or any other disability which may prevent the participant from participating or cooperating in the protocol. Excluded Medications Experimental drugs Lamictal Tricyclic antidepressants (amitriptyline/nortryptiline) Carbamazepine/ oxcarbazepine Benzodiazepines Phenobarbital Phenytoin Tolbutamide Topiramate Warfarin Zidovudine

Ages Eligible for Study
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Minimum Age: 65 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Valproic Acid<br>Valproic acid 250 mg or 500mg by mouth twice daily. | Drug: Valproic Acid<br>* generic valproic acid tablets packaged in placebo-matched capsules.<br>* Other names: Depakote;|
| Placebo Comparator: Placebo<br>Placebo capsule by mouth twice daily. | Drug: Placebo<br>* Placebo capsule without active study medication in identical capsules as experimental medicine.<br>* Other names: Sugar pill;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Frequency of Adverse Events Over the Duration of the Study by Study Arm | Safety assessments will be based on medical review of adverse event reports and the results of vital sign measurements, physical examinations, and clinical laboratory tests throughout the study. The incidence of observed toxicities and adverse events will be tabulated, the frequencies compared in participants who receive active medication and those who receive placebo, and reviewed for potential significance and clinical importance. | Day 35 | 
| Change in Cerebrospinal Fluid Amyloid Levels (pg/ml) Over 28 Day Intervention Period by Study Arm | Change in cerebrospinal fluid amyloid-beta 1-42 levels in pg/ml from baseline to end of treatment (day 28) | Baseline and day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Cerebrospinal Fluid P-tau Levels (pg/ml) | Change in cerebrospinal fluid p181-tau levels (pg/ml) from baseline to end of treatment (Day 28) | Baseline and day 28 | 
| Change in Free & Cued Selective Reminding Test- Free Recall (Number of Items Correct) | Change in Free & Cued Selective Reminding Test- delayed free recall from baseline to end of treatment (Day 28) | Baseline and day 28 | 
| Change in Cerebrospinal Fluid Clusterin Levels (pg/ml) | Change in cerebrospinal fluid clusterin levels (pg/ml) from baseline to end of treatment (Day 28) | Baseline and day 28 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cognitively normal elderly population, safety and tolerability