O1‐04‐03: The ADCS valproate neuroprotection trial: Primary efficacy and safety results

Abstract

Background: Alzheimer's disease (AD) is characterized by cognitive and functional decline as well as frequent neuropsychiatric symptoms that are associated with considerable morbidity. These include agitation, aggression and psychosis, which often co-occur and have a particularly high persistence rate. This trial represented a novel design and new clinical trials methodology to address whether emergence of agitation and/or psychosis can be delayed or prevented by agents twith psychotropic as well as possible neuroprotective properties. Methods: This NIA-ADCS conducted study was a randomized, placebo-controlled, double blind, multicenter, two-year trial of low-dose (10 mg/kg/d) sodium valproate therapy in 300 outpatients with mild to moderate AD who lacked agitation and psychosis at baseline. Participants were followed regularly with clinic visits as well as telephone contacts providing assessments of behavior, cognition, function, safety and tolerability. Valproate was selected because of its possible symptomatic efficacy for agitation in AD, known safety profile in numerous clinical samples, and because of recent preclinical and basic science evidence supporting its neuroprotective potential in AD. The primary hypothesis was that chronic valproate administration to patients with AD who lacked agitation and psychosis at baseline would delay the emergence of agitation and/or psychosis. An effect of this kind could have significant public health implications by delaying institutionalization or maintaining health-related quality of life. We hypothesized that chronic valproate therapy would also attenuate clinical progression of AD, measured by reduced cognitive or functional decline. Safety and tolerability of chronic low-dose therapy was addressed. Biological specimens were obtained to study markers selected for their relevance to the disease as well as the postulated mechanism of action of valproate. A subset of participants had repeated MRI scans to address possible volumetric changes associated with treatment. After the double-blind phase, there was a two-month single-blind placebo-controlled washout phase to address possible emergence of psychopathology that previously might have been suppressed by active therapy. Results: Enrollment for the trial was completed in December, 2006. The last subject completed in 2/09. Data analysis will be conducted this Spring. Conclusions: This represented a novel approach to secondary prevention of psychopathology associated with AD. Primary efficacy and safety results will be presented at the meeting.