Official Title: “A Randomized, Double-Blind, Placebo-Controlled Trial of Valproate to Attenuate the Progression of Alzheimer's Disease (AD)”

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 Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: October 2008

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. 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, 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(s) in this Clinical Trial

• Drug: Valproate
  • 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
• Drug: Placebo
  • Placebo tablets beginning with one daily and increasing according to weight and perceived tolerability concerns for two years, followed by a 2-month washout

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
• Placebo Comparator: 2

Primary Measures

• 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: Baseline, 3, 6, 9, 12, 15, 18, 21, 24, and 26 months
    Safety Issue?: No

Secondary Measures

• Cognitive performance assessed by the Alzheimer's disease Assessment Scale-cognitive subtest (ADAS-cog) and the MMSE
  • Time Frame: Baseline, 6, 12, 18, 24, and 26 months
    Safety Issue?: No
• Functional performance assessed by the Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) inventory
  • Time Frame: Baseline, 6, 12, 18, 24, and 26 months
    Safety Issue?: No
• Global severity of dementia using the CDR Sum of Boxes
  • Time Frame: Baseline, 6, 12, 18, 24, and 26 months
    Safety Issue?: No
• Agitation measured by the Cohen-Mansfield Agitation Inventory (CMAI), community version
  • Time Frame: Baseline, 3, 6, 9, 12, 15, 18, 21, 24, and 26 months
    Safety Issue?: No
• Change in the participant's clinical condition or endpoint assessed with the ADCS-Clinical Global Impression of Change (ADCS-CGIC)
  • Time Frame: Baseline, 12, and 24 months
    Safety Issue?: No
• Safety and tolerability assessed by recording adverse experiences and comorbid events, vital signs, and laboratory data
  • Time Frame: Baseline, 1.5, 3, 6, 9, 12, 15, 18, 21, 24, and 26 months
    Safety Issue?: Yes

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 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.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 55 Years

Maximum Age for this Clinical Trial: 90 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: National Institute on Aging (NIA)

Overall Clinical Trial Officials and Contacts

Pierre Tariot, MD Study Director University of Rochester Medical Center, Departments of Psychiatry, Medicine, and Neurology, and the Center for Aging and Developmental Biology  

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00071721

Study ID Number: IA0043

ClinicalTrials.gov Identifier: NCT00071721

Health Authority: United States: Food and Drug Administration