Valproate in Dementia (VALID)
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.
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||A Randomized, Double-Blind, Placebo-Controlled Trial of Valproate to Attenuate the Progression of Alzheimer's Disease (AD)|
- 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 [ Time Frame: 24 months ] [ Designated as safety issue: No ]NPI quantifies behavioral changes in dementia, including depression, anxiety, psychosis, agitation, and others. This is a questionnaire administered to the subject's study partner. The range of this instrument is 0 to 120 with higher numbers indicating greater impairment. To determine whether or not psychosis or agitation is present, there is no cutoff score but is based on the clinician's judgment. In the NPI, the subject responds to 'Yes' or 'No' questions. Then it is determined how often psychosis or agitation occurs and if it is mild, moderate or severe.
- Cognitive Performance Assessed by the Alzheimer's Disease Assessment Scale-cognitive Subtest (ADAS-cog) [ Time Frame: 24 months ] [ Designated as safety issue: No ]Alzheimer's Disease Assessment Scale, cognitive sub-scale in points per year (ADAS-cog) is a psychometric measure sensitive to change in mild to moderate AD. The range of this instrument is 0 to 70 with higher numbers indicating greater impairment.
- Functional Performance Assessed by the Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Inventory [ Time Frame: 24 months ] [ Designated as safety issue: No ]Alzheimer's Disease Cooperative Study Activities of Daily Living Score (ADCS-ADL) is a structured questionnaire about activities of daily living, administered to the subject's caregiver/study partner. The range of this instrument is 0 to 78 with lower numbers indicating greater impairment.
- Global Severity of Dementia Using the CDR Sum of Boxes [ Time Frame: 24 months ] [ Designated as safety issue: No ]Clinical Dementia Rating, Sum of Boxes (CDR-SOB) is a global rating of dementia severity based on the clinician's interpretation of the history and examination. The range of this instrument is 0 to 18 with higher numbers indicating greater impairment.
- Agitation Measured by the Cohen-Mansfield Agitation Inventory (CMAI), Community Version [ Time Frame: 24 months ] [ Designated as safety issue: No ]The Cohen-Mansfield Agitation Inventory (CMAI) is a 29-item caregiver rating questionnaire for the assessment of agitation in older persons. It includes descriptions of 29 agitated behaviors, each rated on a 7-point scale of frequency. The range of this instrument is 29 to 203 with higher numbers indicating greater impairment.
- Participant's Clinical Condition or Endpoint Assessed With the ADCS-Clinical Global Impression of Change (ADCS-CGIC) [ Time Frame: 24 months ] [ Designated as safety issue: No ]ADCS-Clinical Global Impression of Change (ADCS-CGIC) provides a means to reliably assess global change from baseline. It provides a semi-structured format to allow clinicians to gather necessary clinical information from both the participant and informant, in order to make an overall impression of clinical change. The range of this instrument is 1 to 7 with lower numbers indicating improvement and higher numbers indicating a worsened state.
|Study Start Date:||October 2003|
|Study Completion Date:||December 2009|
|Primary Completion Date:||February 2009 (Final data collection date for primary outcome measure)|
250mg tablets beginning with one daily for one week, then two daily for one week, then titrated according to body weight and tolerability to achieve 10-12 mg/kg daily for 2 years, followed by a 2-month washout
Other Name: Depakene, Depakote
|Placebo Comparator: 2||
Placebo tablets beginning with one daily and increasing according to weight and perceived tolerability concerns for two years, followed by a 2-month washout
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.
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|Study Director:||Pierre Tariot, MD||University of Rochester Medical Center, Departments of Psychiatry, Medicine, and Neurology, and the Center for Aging and Developmental Biology|