Valproate in Dementia (VALID)

Alzheimer Disease Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00071721
• Other study ID #: IA0043
• Secondary ID: 1RC2AG036535IND
• Status: Completed
• Phase: Phase 3
• First received: October 29, 2003
• Last updated: September 15, 2014
• Start date: October 2003
• Est. completion date: December 2009

Study information

• Verified date: September 2014
• Source: Alzheimer's Disease Cooperative Study (ADCS)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 313
• Est. completion date: December 2009
• Est. primary completion date: February 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 55 Years to 90 Years

Eligibility

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.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Alzheimer Disease

Intervention

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
• 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

Locations

Country	Name	City	State
United States	Albany Medical Center	Albany	New York
United States	Dent Neurologic Institute	Amherst	New York
United States	University of Michigan	Ann Arbor	Michigan
United States	Emory University	Atlanta	Georgia
United States	North East Ohio Health Services	Beachwood	Ohio
United States	Southwestern Vermont Medical Center	Bennington	Vermont
United States	Lahey Clinic, Research Neurology	Burlington	Massachusetts
United States	University of Virginia	Charlottesville	Virginia
United States	Northwestern University	Chicago	Illinois
United States	Case Western Reserve University, University Hospitals of Cleveland	Cleveland	Ohio
United States	Medical University of South Carolina-Columbia	Columbia	South Carolina
United States	University of Texas Southwestern Medical Center	Dallas	Texas
United States	Medical University of South Carolina-Florence	Florence	South Carolina
United States	Saint Mary's Health Care	Grand Rapids	Michigan
United States	Indiana University School of Medicine	Indianapolis	Indiana
United States	University of California, Irvine	Irvine	California
United States	Mayo Clinic	Jacksonville	Florida
United States	University of Kansas	Kansas City	Kansas
United States	University of California, ADRC, San Diego	La Jolla	California
United States	University of Nevada	Las Vegas	Nevada
United States	VA Healthcare System Long Beach	Long Beach	California
United States	University of California ADRC	Los Angeles	California
United States	University of California, LA (Olive View)	Los Angeles	California
United States	University of Southern California	Los Angeles	California
United States	Wein Center, Mount Sinai Medical Center	Miami	Florida
United States	Psychiatric Consultants	Nashville	Tennessee
United States	Yale University School of Medicine	New Haven	Connecticut
United States	Columbia University	New York	New York
United States	New York University Medical Center	New York	New York
United States	Medical University of South Carolina	North Charleston	South Carolina
United States	Global Research and Consulting	Olean	New York
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Brown University, Memorial Hospital of Rhode Island	Providence	Rhode Island
United States	University of Rochester	Rochester	New York
United States	Pacific Research Network	San Diego	California
United States	Southern Illinois University	Springfield	Illinois
United States	St. Louis University	St. Louis	Missouri
United States	Stanford University, VA Aging Clinical Research Center	Stanford	California
United States	Sun Health Research Institute	Sun City	Arizona
United States	Syracuse VA Medical Center	Syracuse	New York
United States	Byrd Institute	Tampa	Florida
United States	University of South Florida	Tampa	Florida
United States	University of Arizona	Tucson	Arizona
United States	Howard University	Washington	District of Columbia
United States	Georgetown University Medical Center	Washington, DC	District of Columbia
United States	Premier Research Institute	West Palm Beach	Florida

Sponsors (2)

Lead Sponsor	Collaborator
Alzheimer's Disease Cooperative Study (ADCS)	National Institute on Aging (NIA)

Country where clinical trial is conducted

United States, 

References & Publications (3)

Chen G, Huang LD, Jiang YM, Manji HK. The mood-stabilizing agent valproate inhibits the activity of glycogen synthase kinase-3. J Neurochem. 1999 Mar;72(3):1327-30. — View Citation

Manji HK, Moore GJ, Rajkowska G, Chen G. Neuroplasticity and cellular resilience in mood disorders. Mol Psychiatry. 2000 Nov;5(6):578-93. Review. — View Citation

Tariot PN, Loy R, Ryan JM, Porsteinsson A, Ismail S. Mood stabilizers in Alzheimer's disease: symptomatic and neuroprotective rationales. Adv Drug Deliv Rev. 2002 Dec 7;54(12):1567-77. Review. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	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.	24 months	No
Secondary	Cognitive Performance Assessed by the Alzheimer's Disease Assessment Scale-cognitive Subtest (ADAS-cog)	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.	24 months	No
Secondary	Functional Performance Assessed by the Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Inventory	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.	24 months	No
Secondary	Global Severity of Dementia Using the CDR Sum of Boxes	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.	24 months	No
Secondary	Agitation Measured by the Cohen-Mansfield Agitation Inventory (CMAI), Community Version	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.	24 months	No
Secondary	Participant's Clinical Condition or Endpoint Assessed With the ADCS-Clinical Global Impression of Change (ADCS-CGIC)	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.	24 months	No