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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01729598
Recruitment Status : Completed
First Posted : November 20, 2012
Results First Posted : October 9, 2019
Last Update Posted : October 9, 2019
Sponsor:
Collaborators:
University of Kentucky
Kentucky Alzheimer's Center
Information provided by (Responsible Party):
Gregory Jicha, 323-5550, University of Kentucky

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Alzheimer's Disease Drug: Valproic Acid Drug: Placebo Early Phase 1

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 14 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary Purpose: Basic Science
Official Title: 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
Study Start Date : April 2012
Actual Primary Completion Date : October 2014
Actual Study Completion Date : October 2014


Arm Intervention/treatment
Experimental: Valproic Acid
Valproic acid 250 mg or 500mg by mouth twice daily.
Drug: Valproic Acid
generic valproic acid tablets packaged in placebo-matched capsules.
Other Names:
  • VPA
  • Depakote

Placebo Comparator: Placebo
Placebo capsule by mouth twice daily.
Drug: Placebo
Placebo capsule without active study medication in identical capsules as experimental medicine.
Other Name: Sugar pill




Primary Outcome Measures :
  1. Frequency of Adverse Events Over the Duration of the Study by Study Arm [ Time Frame: Day 35 ]
    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.

  2. Change in Cerebrospinal Fluid Amyloid Levels (pg/ml) Over 28 Day Intervention Period by Study Arm [ Time Frame: Baseline and day 28 ]
    Change in cerebrospinal fluid amyloid-beta 1-42 levels in pg/ml from baseline to end of treatment (day 28)


Secondary Outcome Measures :
  1. Change in Cerebrospinal Fluid P-tau Levels (pg/ml) [ Time Frame: Baseline and day 28 ]
    Change in cerebrospinal fluid p181-tau levels (pg/ml) from baseline to end of treatment (Day 28)

  2. Change in Free & Cued Selective Reminding Test- Free Recall (Number of Items Correct) [ Time Frame: Baseline and day 28 ]
    Change in Free & Cued Selective Reminding Test- delayed free recall from baseline to end of treatment (Day 28)

  3. Change in Cerebrospinal Fluid Clusterin Levels (pg/ml) [ Time Frame: Baseline and day 28 ]
    Change in cerebrospinal fluid clusterin levels (pg/ml) from baseline to end of treatment (Day 28)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   65 Years to 90 Years   (Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  1. Men or women aged 65-90, inclusive.
  2. English-speaking, to ensure compliance with cognitive testing and study visit procedures.
  3. Female participants must not be pregnant or of childbearing potential, i.e. either surgically sterile or postmenopausal for > 1 year.
  4. 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
  5. Stable medications for 4 weeks prior to screening visit.
  6. Able to ingest oral medications.
  7. No history of adverse drug reactions to VPA or similar agents.
  8. Physically acceptable for this study as confirmed by medical history, physical exam, neurological exam and clinical tests in the opinion of the study physician.
  9. Not demented by Hachinski Ischemic Index (< 4).

Exclusion Criteria:

  1. Significant neurologic disease such as Parkinson's disease, stroke, brain tumor, multiple sclerosis or seizure disorder.
  2. 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.
  3. History of invasive cancer within the past two years (excluding non-melanoma skin cancer).
  4. 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).
  5. 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.
  6. Use of any investigational agents within 30 days prior to screening.
  7. Major surgery within eight weeks prior to the Baseline Visit.
  8. Severe unstable medical illnesses, including uncontrolled cardiac conditions or heart failure (New York Heart Association Class III or IV) .
  9. Antiretroviral therapy for human immunodeficiency virus (HIV).
  10. Residence in a skilled nursing facility.
  11. Blindness, deafness, language difficulties or any other disability which may prevent the participant from participating or cooperating in the protocol.

Excluded Medications

  1. Experimental drugs
  2. Lamictal
  3. Tricyclic antidepressants (amitriptyline/nortryptiline)
  4. Carbamazepine/ oxcarbazepine
  5. Benzodiazepines
  6. Phenobarbital
  7. Phenytoin
  8. Tolbutamide
  9. Topiramate
  10. Warfarin
  11. Zidovudine

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): NCT01729598


Locations
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United States, Kentucky
Sander's Brown Center on Aging
Lexington, Kentucky, United States, 40536
Sponsors and Collaborators
Gregory Jicha, 323-5550
University of Kentucky
Kentucky Alzheimer's Center
Investigators
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Principal Investigator: Steve Estus, PhD University of Kentucky
Principal Investigator: Gregory Jicha, MD University of Kentucky

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Responsible Party: Gregory Jicha, 323-5550, Professor, University of Kentucky
ClinicalTrials.gov Identifier: NCT01729598    
Other Study ID Numbers: 12-0068-F6A
First Posted: November 20, 2012    Key Record Dates
Results First Posted: October 9, 2019
Last Update Posted: October 9, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: IPD will be shared with interested investigators that submit a data request to the UK Alzheimer Center Biostatistics Group upon publication of the primary manuscript from this study. The request will be reviewed for scientific validity and human subjects protection issues prior to approval for release. IPD that may be released includes all clinical data stripped of identifying information. Clinical Information will be assigned a blinded subject number that protects the identity and HIPAA protected information collected as part of this study. To request data, follow the instructions at the following link: http://www.uky.edu/coa/adc/investigators-research-resources
Supporting Materials: Study Protocol
Statistical Analysis Plan (SAP)
Informed Consent Form (ICF)
Clinical Study Report (CSR)
Time Frame: 1/1/19 to 12/31/28
Access Criteria: Access will be granted to any investigator upon provision of an acceptable project hypothesis and specification of data desired. Oversight by the project team will ensure that redundant projects do not result in competitive use of the resources. Project data access will be determined by the PI and investigator team at UK within these broad access terms. There will be no cost for data access. We stipulate that the parent grant UL1TR001998 should be cited by those with whom data is shared.
URL: http://www.uky.edu/coa/adc/investigators-research-resources
Keywords provided by Gregory Jicha, 323-5550, University of Kentucky:
cognitively normal elderly population
safety and tolerability
Additional relevant MeSH terms:
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Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Valproic Acid
Anticonvulsants
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
GABA Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs