Alzheimer's Disease
Conditions
Keywords
cognitively normal elderly population, safety and tolerability
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.
Interventions
DRUGValproic Acid
generic valproic acid tablets packaged in placebo-matched capsules.
DRUGPlacebo
Placebo capsule without active study medication in identical capsules as experimental medicine.
Sponsors
University of Kentucky
Kentucky Alzheimer's Center
Gregory Jicha, 323-5550
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
65 Years to 90 Years
Healthy volunteers
Yes
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Frequency of Adverse Events Over the Duration of the Study by Study Arm | 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. |
| Change in Cerebrospinal Fluid Amyloid Levels (pg/ml) Over 28 Day Intervention Period by Study Arm | 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
| Measure | Time frame | Description |
|---|---|---|
| Change in Cerebrospinal Fluid P-tau Levels (pg/ml) | Baseline and day 28 | Change in cerebrospinal fluid p181-tau levels (pg/ml) from baseline to end of treatment (Day 28) |
| Change in Free & Cued Selective Reminding Test- Free Recall (Number of Items Correct) | Baseline and day 28 | Change in Free & Cued Selective Reminding Test- delayed free recall from baseline to end of treatment (Day 28) |
| Change in Cerebrospinal Fluid Clusterin Levels (pg/ml) | Baseline and day 28 | Change in cerebrospinal fluid clusterin levels (pg/ml) from baseline to end of treatment (Day 28) |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Valproic Acid Valproic acid 250 mg or 500mg by mouth twice daily.
Valproic Acid: generic valproic acid tablets packaged in placebo-matched capsules. | 10 |
| Placebo Placebo capsule by mouth twice daily.
Placebo: Placebo capsule without active study medication in identical capsules as experimental medicine. | 4 |
| Total | 14 |
Baseline characteristics
| Characteristic | Valproic Acid | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 10 Participants | 4 Participants | 14 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 76 years STANDARD_DEVIATION 7.3 | 81 years STANDARD_DEVIATION 12.2 | 78 years STANDARD_DEVIATION 8.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 4 Participants | 14 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 4 Participants | 14 Participants |
| Sex: Female, Male Female | 4 Participants | 2 Participants | 6 Participants |
| Sex: Female, Male Male | 6 Participants | 2 Participants | 8 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 4 |
| other Total, other adverse events | 8 / 10 | 1 / 4 |
| serious Total, serious adverse events | 0 / 10 | 0 / 4 |
Outcome results
Primary
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)
Time frame: Baseline and day 28
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Valproic Acid | Change in Cerebrospinal Fluid Amyloid Levels (pg/ml) Over 28 Day Intervention Period by Study Arm | 57.1 pg/ml | Standard Deviation 28.4 |
| Placebo | Change in Cerebrospinal Fluid Amyloid Levels (pg/ml) Over 28 Day Intervention Period by Study Arm | 44.7 pg/ml | Standard Deviation 24.9 |
p-value: 0.55t-test, 2 sided
Primary
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.
Time frame: Day 35
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Valproic Acid | Frequency of Adverse Events Over the Duration of the Study by Study Arm | 8 Participants |
| Placebo | Frequency of Adverse Events Over the Duration of the Study by Study Arm | 1 Participants |
Secondary
Change in Cerebrospinal Fluid Clusterin Levels (pg/ml)
Change in cerebrospinal fluid clusterin levels (pg/ml) from baseline to end of treatment (Day 28)
Time frame: Baseline and day 28
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Valproic Acid | Change in Cerebrospinal Fluid Clusterin Levels (pg/ml) | 2610 pg/ml | Standard Deviation 4373 |
| Placebo | Change in Cerebrospinal Fluid Clusterin Levels (pg/ml) | 201 pg/ml | Standard Deviation 871 |
p-value: 0.31t-test, 2 sided
Secondary
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)
Time frame: Baseline and day 28
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Valproic Acid | Change in Cerebrospinal Fluid P-tau Levels (pg/ml) | -5.7 pg/ml | Standard Deviation 11.9 |
| Placebo | Change in Cerebrospinal Fluid P-tau Levels (pg/ml) | 11.0 pg/ml | Standard Deviation 25.7 |
p-value: 0.19t-test, 2 sided
Secondary
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)
Time frame: Baseline and day 28
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Valproic Acid | Change in Free & Cued Selective Reminding Test- Free Recall (Number of Items Correct) | 1.4 number of items recalled | Standard Deviation 3.5 |
| Placebo | Change in Free & Cued Selective Reminding Test- Free Recall (Number of Items Correct) | -4.5 number of items recalled | Standard Deviation 3.4 |
p-value: 0.02t-test, 2 sided