Valproate in Dementia (VALID)
Information source: Alzheimer's Disease Cooperative Study (ADCS)
ClinicalTrials.gov processed this data on August 20, 2015
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Alzheimer Disease
Intervention: Valproate (Drug); Placebo (Drug)
Phase: Phase 3
Status: Completed
Sponsored by: Alzheimer's Disease Cooperative Study (ADCS) Official(s) and/or principal investigator(s):
Pierre Tariot, MD, Study Director, Affiliation: University of Rochester Medical Center, Departments of Psychiatry, Medicine, and Neurology, and the Center for Aging and Developmental Biology
Summary
The purpose of this trial is to demonstrate whether valproate therapy delays the emergence
of agitation and/or psychosis in outpatients with probable Alzheimer's disease (AD) who have
not experienced agitation and psychosis in their illness. A secondary aim is to determine
whether valproate therapy delays the progression of cognitive and functional measures of the
illness. This trial will also assess the tolerability and safety of low-dose, long-term
valproate therapy. Valproate, an anticonvulsant drug, was selected because of its possible
symptomatic efficacy for agitation in AD, known safety profile in numerous clinical
populations, and in view of recent data supporting its neuroprotective potential in AD.
Clinical Details
Official title: A Randomized, Double-Blind, Placebo-Controlled Trial of Valproate to Attenuate the Progression of Alzheimer's Disease (AD)
Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
Primary outcome: Presence of Agitation and/or Psychosis Measured by the Neuropsychiatric Inventory (NPI) Combined With an Assessment of the Clinical Significance of Behavioral Change Rated by the Study Clinician
Secondary outcome: Cognitive Performance Assessed by the Alzheimer's Disease Assessment Scale-cognitive Subtest (ADAS-cog)Functional Performance Assessed by the Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Inventory Global Severity of Dementia Using the CDR Sum of Boxes Agitation Measured by the Cohen-Mansfield Agitation Inventory (CMAI), Community Version Participant's Clinical Condition or Endpoint Assessed With the ADCS-Clinical Global Impression of Change (ADCS-CGIC)
Detailed description:
This study represents a novel clinical trial strategy designed to assess both prospective
"prophylactic" therapy for psychopathology in Alzheimer's disease (AD) and to assess an
approach that may alter several aspects of the pathophysiology of AD, and perhaps result in
alteration of clinical progression of illness. Interpretation of these results will be
supported by study of relevant biomarkers and imaging data. Valproate was selected because
of its possible symptomatic efficacy for agitation in AD, known safety profile in numerous
clinical populations, and in view of recent data supporting its neuroprotective potential in
AD. The primary hypothesis is that chronic valproate administration to participants with AD
who lack agitation and psychosis at baseline will delay the emergence of agitation and/or
psychosis. An effect of this nature may have significant public health implications, for
instance, by delaying institutionalization.
This is a randomized, placebo-controlled, double blind, multicenter 26-month trial of
valproate therapy at a target dose of 10-12 mg/kg/day in 300 outpatients with mild to
moderate Alzheimer's Disease (AD) who lack agitation and psychosis at baseline and since
onset of illness. Participants will have regular clinic visits as well as telephone contacts
for assessment of behavior, cognition, function, safety and tolerability. The chief
secondary aim is to determine whether valproate administration to participants with AD will
attenuate clinical progression of illness measured by a reduced rate of cognitive or
functional decline. In addition, issues related to safety and tolerability with low-dose
(10-12 mg/kg/day) therapy will be addressed. Biological specimens will be obtained to study
markers selected for their relevance to the disease as well as the postulated mechanism of
action of the valproate therapy. Magnetic resonance imaging (MRI) scans will be performed
prior to experimental treatment and after one year in a subset of participants in order to
address possible drug-placebo differences in brain volume measures.
Approximately 300 participants from 25-35 clinical trial centers in the United States will
be enrolled. Participation will include men and women with a diagnosis of probable
Alzheimer's disease, age 55 or older, weighing at least 40 kg (88. 2 lbs.), residing in the
community at baseline, Mini Mental State Examination (MMSE) 10-20 inclusive, who have not
experienced agitation or psychosis since the onset of their illness and who do not require
treatment with psychotropic medications with the exception of antidepressants used only for
treatment of depressive symptoms and limited use of sedatives for sleep. Participants, their
relatives, guardians or authorized representatives and informants will be given ample
opportunity to inquire about details of the study. Informed consent forms covering consent
for the trial itself as well as the genetic research and biological sample storage and MRI
scans will be provided to protect the patient's rights and confidentiality.
Eligibility
Minimum age: 55 Years.
Maximum age: 90 Years.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- Probable AD by National Institute of Neurological Disorders and Stroke
(NINDS)-Alzheimer's Disease and Related Disorder Association (ADRDA) criteria.
- Males or females.
- > 55 and < 90 years of age.
- Weight > 40 kg (88. 2 lbs.).
- Residing in the community at Screen and Baseline. Participants may reside in
assisted living facilities, but not in long-term care nursing facilities or assisted
living facilities that provide intensive support for people with dementia nor may
they reside in a secure unit necessary for behavioral management.
- Mini Mental State Examination (MMSE) at Screen and Baseline 12-20 inclusive.
- Computed tomography (CT) or magnetic resonance imaging (MRI) since onset of dementia
consistent with the diagnosis of probable AD. Single lacunes in non-critical areas
and non-specific white matter changes that are interpreted as age-related are not
grounds for exclusion. Any ambiguous scan results must be reviewed with the Project
Director.
- Fluent in English or Spanish.
- Supervision available for study medication.
- Study partner to accompany subject to all visits.
- Study partner must have in-person contact with the participant > 2 days/week.
- Able to ingest oral medication.
- Total Neuropsychiatric Inventory (NPI) score for previous 4 weeks < 8 at Screening,
and for the period between Screening and Baseline.
- NPI item score for the items assessing delusions, hallucinations,
agitation/aggression all greater than or equal to 1 for 4 weeks prior to Screening
(less than once/week and mild severity at most) and for the period between Screening
and Baseline.
- Scores of greater than or equal to 1 for items rating delusions, hallucinations, and
agitation/aggression taken from the NPI, modified to assess these features since
onset of illness. This will be derived from a second interview with the modified
NPI. (Agitation/psychosis during episodes of delirium are not considered
exclusionary.).
Exclusion Criteria:
Exceptions to these criteria may be considered on a case-by-case basis at the discretion
of the Project Director:
- Non-AD dementia.
- Females of child-bearing potential.
- Residence in a long-term care facility or equivalent at Baseline.
- Presence or previous history of agitation or psychosis requiring active psychotropic
medication since the illness began.
- History of clinically significant stroke.
- Current evidence or history in past two years of: focal brain lesion, head injury
with loss of consciousness or Diagnostic and Statistical Manual of Mental Disorders,
4th Edition (DSM-IV) criteria for any major psychiatric disorder including psychosis,
major depression, bipolar disorder, alcohol or substance abuse.
- Sensory impairment that would prevent subject from participating in or cooperating
with the protocol.
- Medical contraindications to study participation.
- Use of another investigational agent within two months prior to Screening.
- Evidence of any significant clinical disorder or laboratory finding that renders the
subject unsuitable for receiving an investigational new drug including clinically
significant or unstable hematologic, hepatic, cardiovascular, pulmonary,
gastrointestinal, endocrine, metabolic, renal, or other systemic disease or
laboratory abnormality.
- Clinical contraindication to the use of valproate (e. g., known hypersensitivity or
allergic reactions, severe neutropenia, severe hepatic disease, or urea cycle
disorder. A urea cycle disorder should be considered in patients with history of
unexplained encephalopathy following protein meals, or family history of urea cycle
disorder).
- History of seizure within past 5 years prior to Screening.
- Platelet count < 100,000/mm^3.
- International Normalized Ratio (INR) > 1. 2 or partial thromboplastin time (PTT) > 40
seconds.
- Active neoplastic disease. Exceptions: skin tumors other than melanoma are not
excluded; patients with stable prostate cancer may be included at the discretion of
the Project Director; women who have been treated for breast cancer and have no
metastases and whose survival is expected to exceed 2 years may be considered for
inclusion on a case-by-case basis in consultation with the Project Director; patients
with purely localized bladder wall cancers may be included at the discretion of the
Project Director.
Excluded Medications:
- Use of psychotropics for treatment of agitation or psychosis. Antidepressants used
in stable doses for 3 months prior to Screening to treat depression or anxiety, but
not agitation, will be permitted. Low dose sedatives for sleep, but not agitation,
will be permitted. Cholinesterase inhibitors used in stable doses for at least 3
months prior to Screening are permitted.
- Regular use of narcotic analgesics within 3 months of Screening.
- Anti-parkinsonian medications (e. g. levodopa, selegiline, pergolide, bromocriptine,
pramipexole) within 2 months of Screening.
- Use of drugs with significant central anticholinergic or antihistaminic effects (eg,
benztropine, trihexyphenidyl, dicyclomine, diphenhydramine, cyproheptadine,
diphenoxylate, hydroxyzine, meclizine, prochlorperazine, promethazine) within 2
months of Screening.
- Use of other investigational drug studies within two months prior to Screening.
- Use of other anticonvulsants within 5 years prior to Screening.
- Use of zidovudine at any time.
- Use of tricyclic antidepressants within 1 month prior to Screening.
- Regular use of high doses of salicylates at Screening (> 1,300 mg/d).
- Vitamin E > 2,100 IU/d within 1 month prior to Screening.
- Warfarin use is permitted when approved by the Project Director and INR and PTT
criteria are met.
Locations and Contacts
Sun Health Research Institute, Sun City, Arizona 85351, United States
University of Arizona, Tucson, Arizona 85724, United States
University of California, Irvine, Irvine, California 92697-4540, United States
University of California, ADRC, San Diego, La Jolla, California 92093-0624, United States
VA Healthcare System Long Beach, Long Beach, California 90822, United States
University of California ADRC, Los Angeles, California 90095-1769, United States
University of California, LA (Olive View), Los Angeles, California 90095, United States
University of Southern California, Los Angeles, California 90089-0191, United States
Pacific Research Network, San Diego, California 32103, United States
Stanford University, VA Aging Clinical Research Center, Stanford, California 94304, United States
Yale University School of Medicine, New Haven, Connecticut 06511, United States
Georgetown University Medical Center, Washington, DC, District of Columbia 20057, United States
Howard University, Washington, District of Columbia 20060, United States
Mayo Clinic, Jacksonville, Florida 32224, United States
Wein Center, Mount Sinai Medical Center, Miami, Florida 33140, United States
Byrd Institute, Tampa, Florida 33647, United States
University of South Florida, Tampa, Florida 33617, United States
Premier Research Institute, West Palm Beach, Florida 33407, United States
Emory University, Atlanta, Georgia 30329, United States
Northwestern University, Chicago, Illinois 60611, United States
Southern Illinois University, Springfield, Illinois 62794, United States
Indiana University School of Medicine, Indianapolis, Indiana 46202-5120, United States
University of Kansas, Kansas City, Kansas 66160, United States
Lahey Clinic, Research Neurology, Burlington, Massachusetts 01805, United States
University of Michigan, Ann Arbor, Michigan 48109-0489, United States
Saint Mary's Health Care, Grand Rapids, Michigan 49503, United States
St. Louis University, St. Louis, Missouri 63103, United States
University of Nevada, Las Vegas, Nevada 89154-5084, United States
Albany Medical Center, Albany, New York 12208, United States
Dent Neurologic Institute, Amherst, New York 14226, United States
Columbia University, New York, New York 10032, United States
New York University Medical Center, New York, New York 10016, United States
Global Research and Consulting, Olean, New York 14760, United States
University of Rochester, Rochester, New York 14642, United States
Syracuse VA Medical Center, Syracuse, New York 13210, United States
North East Ohio Health Services, Beachwood, Ohio 44122, United States
Case Western Reserve University, University Hospitals of Cleveland, Cleveland, Ohio 44120, United States
University of Pennsylvania, Philadelphia, Pennsylvania 19104-4283, United States
Brown University, Memorial Hospital of Rhode Island, Providence, Rhode Island 02860, United States
Medical University of South Carolina-Columbia, Columbia, South Carolina 29203, United States
Medical University of South Carolina-Florence, Florence, South Carolina 29502, United States
Medical University of South Carolina, North Charleston, South Carolina 29406-6076, United States
Psychiatric Consultants, Nashville, Tennessee 37203, United States
University of Texas Southwestern Medical Center, Dallas, Texas 75390-9070, United States
Southwestern Vermont Medical Center, Bennington, Vermont 05201, United States
University of Virginia, Charlottesville, Virginia 22908, United States
Additional Information
Related publications: Tariot PN, Loy R, Ryan JM, Porsteinsson A, Ismail S. Mood stabilizers in Alzheimer's disease: symptomatic and neuroprotective rationales. Adv Drug Deliv Rev. 2002 Dec 7;54(12):1567-77. Review. Manji HK, Moore GJ, Rajkowska G, Chen G. Neuroplasticity and cellular resilience in mood disorders. Mol Psychiatry. 2000 Nov;5(6):578-93. Review. Chen G, Huang LD, Jiang YM, Manji HK. The mood-stabilizing agent valproate inhibits the activity of glycogen synthase kinase-3. J Neurochem. 1999 Mar;72(3):1327-30.
Starting date: October 2003
Last updated: September 15, 2014
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