Clinical trial NCT01729598: Valproic Acid in Subjects With Intact Cognition - Proof of Concept Study
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: EARLY_PHASE1
Conditions: Alzheimer's Disease
Keywords: cognitively normal elderly population
safety and tolerability
Lead sponsor: University of Kentucky
Sponsor class: OTHER
Collaborators: name: University of Kentucky
name: Kentucky Alzheimer's Center
First posted: 2012-11-20
Enrollment: 14
Sex: ALL
Minimum age (years): 65
Maximum age (years): 90
Standard ages: OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

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.

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.

Eligibility 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

Primary outcomes:
measure: Frequency of Adverse Events Over the Duration of the Study by Study Arm
timeFrame: Day 35
measure: Change in Cerebrospinal Fluid Amyloid Levels (pg/ml) Over 28 Day Intervention Period by Study Arm
timeFrame: Baseline and day 28
Secondary outcomes:
measure: Change in Cerebrospinal Fluid P-tau Levels (pg/ml)
timeFrame: Baseline and day 28
measure: Change in Free & Cued Selective Reminding Test- Free Recall (Number of Items Correct)
timeFrame: Baseline and day 28
measure: Change in Cerebrospinal Fluid Clusterin Levels (pg/ml)
timeFrame: Baseline and day 28
Other outcomes:
Locations:
city: Lexington
country: United States
facility: Sander's Brown Center on Aging
state: Kentucky
Study officials:
affiliation: University of Kentucky
name: Steve Estus, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Kentucky
name: Gregory Jicha, MD
role: PRINCIPAL_INVESTIGATOR
References: