Valproic Acid in Subjects With Intact Cognition - Proof of Concept Study
| Status: | Completed |
|---|---|
| Conditions: | Alzheimer Disease |
| Therapuetic Areas: | Neurology |
| Healthy: | No |
| Age Range: | 65 - 90 |
| Updated: | 10/14/2017 |
| Start Date: | April 2012 |
| End Date: | October 2014 |
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
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.
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.
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.
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.
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
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