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

Primary Purpose

Alzheimer's Disease

Status

Completed

Phase

Early Phase 1

Locations

United States

Study Type

Interventional

Intervention

Valproic Acid

Placebo

About this trial

This is an interventional basic science trial for Alzheimer's Disease focused on measuring cognitively normal elderly population, safety and tolerability

Eligibility Criteria

65 Years - 90 Years (Older Adult)All SexesAccepts Healthy Volunteers

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

Sites / Locations

Sander's Brown Center on Aging

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Valproic Acid

Placebo

Arm Description

Valproic acid 250 mg or 500mg by mouth twice daily.

Placebo capsule by mouth twice daily.

Outcomes

Primary Outcome Measures

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.

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)

Secondary Outcome Measures

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)

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)

Change in Cerebrospinal Fluid Clusterin Levels (pg/ml)

Change in cerebrospinal fluid clusterin levels (pg/ml) from baseline to end of treatment (Day 28)

Full Information

NCT ID

NCT01729598

First Posted

May 14, 2012

Last Updated

October 7, 2019

Sponsor

Gregory Jicha, 323-5550

Collaborators

University of Kentucky, Kentucky Alzheimer's Center

1. Study Identification

Unique Protocol Identification Number

NCT01729598

Brief Title

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

Acronym

VPA

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

2. Study Status

Record Verification Date

October 2019

Overall Recruitment Status

Completed

Study Start Date

April 2012 (undefined)

Primary Completion Date

October 2014 (Actual)

Study Completion Date

October 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Gregory Jicha, 323-5550

Collaborators

University of Kentucky, Kentucky Alzheimer's Center

4. Oversight

Data Monitoring Committee

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Alzheimer's Disease

Keywords

cognitively normal elderly population, safety and tolerability

7. Study Design

Primary Purpose

Basic Science

Study Phase

Early Phase 1

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

14 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Valproic Acid

Arm Type

Experimental

Arm Description

Valproic acid 250 mg or 500mg by mouth twice daily.

Arm Title

Placebo

Arm Type

Placebo Comparator

Arm Description

Placebo capsule by mouth twice daily.

Intervention Type

Drug

Intervention Name(s)

Valproic Acid

Other Intervention Name(s)

VPA, Depakote

Intervention Description

generic valproic acid tablets packaged in placebo-matched capsules.

Intervention Type

Drug

Intervention Name(s)

Placebo

Other Intervention Name(s)

Sugar pill

Intervention Description

Placebo capsule without active study medication in identical capsules as experimental medicine.

Primary Outcome Measure Information:

Title

Frequency of Adverse Events Over the Duration of the Study by Study Arm

Description

Time Frame

Day 35

Title

Change in Cerebrospinal Fluid Amyloid Levels (pg/ml) Over 28 Day Intervention Period by Study Arm

Description

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

Secondary Outcome Measure Information:

Title

Change in Cerebrospinal Fluid P-tau Levels (pg/ml)

Description

Change in cerebrospinal fluid p181-tau levels (pg/ml) from baseline to end of treatment (Day 28)

Time Frame

Baseline and day 28

Title

Change in Free & Cued Selective Reminding Test- Free Recall (Number of Items Correct)

Description

Change in Free & Cued Selective Reminding Test- delayed free recall from baseline to end of treatment (Day 28)

Time Frame

Baseline and day 28

Title

Change in Cerebrospinal Fluid Clusterin Levels (pg/ml)

Description

Change in cerebrospinal fluid clusterin levels (pg/ml) from baseline to end of treatment (Day 28)

Time Frame

Baseline and day 28

10. Eligibility

Sex

All

Minimum Age & Unit of Time

65 Years

Maximum Age & Unit of Time

90 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Steve Estus, PhD

Organizational Affiliation

University of Kentucky

Official's Role

Principal Investigator

First Name & Middle Initial & Last Name & Degree

Gregory Jicha, MD

Organizational Affiliation

University of Kentucky

Official's Role

Principal Investigator

Facility Information:

Facility Name

Sander's Brown Center on Aging

City

Lexington

State/Province

Kentucky

ZIP/Postal Code

40536

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

Yes

IPD Sharing 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

IPD Sharing Time Frame

1/1/19 to 12/31/28

IPD Sharing 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.

IPD Sharing URL

http://www.uky.edu/coa/adc/investigators-research-resources

Learn more about this trial

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

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