Valproate in Dementia (VALID)
Condition: Alzheimer Disease
MeSH terms: Alzheimer Disease
Intervention: Valproate; Placebo
Intervention description: 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
Intervention MeSH terms: Valproic Acid
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 313.0
Sex: All
Minimum age: 55 Years
Maximum age: 90 Years
Healthy volunteers: No
Keywords: Alzheimer disease; Agitation; Psychosis

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.
    

Eligibility 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.