Valproate in Dementia (VALID)
Condition: Alzheimer Disease
MeSH terms: Alzheimer Disease
Study type: Interventional
Phase: Phase 3

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.
    

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.
    

Intervention name(s): Valproate; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): 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; Placebo tablets beginning with one daily and increasing according to weight and perceived tolerability concerns for two years, followed by a 2-month washout
Other intervention name(s): Depakene, Depakote
Intervention MeSH terms: Valproic Acid
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: Alzheimer disease; Agitation; Psychosis