Valproate in Dementia (VALID)

NCT00071721 | Completed Phase 3 Results DMC

• 4 other identifiers: IA00431RC2AG036535IND 67,222ADCS Protocol ADC-022-VN
• Study Type: interventional
• Target: 313
• Locations: 1 country
• Sites: 46

Brief 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.

Conditions

Alzheimer Disease

Keywords

Alzheimer disease; Agitation; Psychosis

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (5)

• Cognitive Performance Assessed by the Alzheimer's Disease Assessment Scale-cognitive Subtest (ADAS-cog)

  24 months

• Functional Performance Assessed by the Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Inventory

  24 months

• Global Severity of Dementia Using the CDR Sum of Boxes

  24 months

• Agitation Measured by the Cohen-Mansfield Agitation Inventory (CMAI), Community Version

  24 months

• Participant's Clinical Condition or Endpoint Assessed With the ADCS-Clinical Global Impression of Change (ADCS-CGIC)

  24 months

Study Arms (2)

1

EXPERIMENTAL

Drug: Valproate

2

PLACEBO COMPARATOR

Drug: Placebo

Interventions

Valproate DRUG

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

Also known as: Depakene, Depakote

1

Placebo DRUG

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

2

Eligibility Criteria

• Age: 55 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Alzheimer's Disease Cooperative Study (ADCS): lead
• National Institute on Aging (NIA): collaborator

Study Sites (46)

Sun Health Research Institute

Sun City, Arizona, 85351, United States

Location

University of Arizona

Tucson, Arizona, 85724, United States

Location

University of California, Irvine

Irvine, California, 92697-4540, United States

Location

University of California, ADRC, San Diego

La Jolla, California, 92093-0624, United States

Location

VA Healthcare System Long Beach

Long Beach, California, 90822, United States

Location

University of Southern California

Los Angeles, California, 90089-0191, United States

Location

University of California ADRC

Los Angeles, California, 90095-1769, United States

Location

University of California, LA (Olive View)

Los Angeles, California, 90095, United States

Location

Pacific Research Network

San Diego, California, 32103, United States

Location

Stanford University, VA Aging Clinical Research Center

Stanford, California, 94304, United States

Location

Yale University School of Medicine

New Haven, Connecticut, 06511, United States

Location

Georgetown University Medical Center

Washington D.C., District of Columbia, 20057, United States

Location

Howard University

Washington D.C., District of Columbia, 20060, United States

Location

Mayo Clinic

Jacksonville, Florida, 32224, United States

Location

Wein Center, Mount Sinai Medical Center

Miami, Florida, 33140, United States

Location

University of South Florida

Tampa, Florida, 33617, United States

Location

Byrd Institute

Tampa, Florida, 33647, United States

Location

Premier Research Institute

West Palm Beach, Florida, 33407, United States

Location

Emory University

Atlanta, Georgia, 30329, United States

Location

Northwestern University

Chicago, Illinois, 60611, United States

Location

Southern Illinois University

Springfield, Illinois, 62794, United States

Location

Indiana University School of Medicine

Indianapolis, Indiana, 46202-5120, United States

Location

University of Kansas

Kansas City, Kansas, 66160, United States

Location

Lahey Clinic, Research Neurology

Burlington, Massachusetts, 01805, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109-0489, United States

Location

Saint Mary's Health Care

Grand Rapids, Michigan, 49503, United States

Location

St. Louis University

St Louis, Missouri, 63103, United States

Location

University of Nevada

Las Vegas, Nevada, 89154-5084, United States

Location

Albany Medical Center

Albany, New York, 12208, United States

Location

Dent Neurologic Institute

Amherst, New York, 14226, United States

Location

New York University Medical Center

New York, New York, 10016, United States

Location

Columbia University

New York, New York, 10032, United States

Location

Global Research and Consulting

Olean, New York, 14760, United States

Location

University of Rochester

Rochester, New York, 14642, United States

Location

Syracuse VA Medical Center

Syracuse, New York, 13210, United States

Location

North East Ohio Health Services

Beachwood, Ohio, 44122, United States

Location

Case Western Reserve University, University Hospitals of Cleveland

Cleveland, Ohio, 44120, United States

Location

University of Pennsylvania

Philadelphia, Pennsylvania, 19104-4283, United States

Location

Brown University, Memorial Hospital of Rhode Island

Providence, Rhode Island, 02860, United States

Location

Medical University of South Carolina-Columbia

Columbia, South Carolina, 29203, United States

Location

Medical University of South Carolina-Florence

Florence, South Carolina, 29502, United States

Location

Medical University of South Carolina

North Charleston, South Carolina, 29406-6076, United States

Location

Psychiatric Consultants

Nashville, Tennessee, 37203, United States

Location

University of Texas Southwestern Medical Center

Dallas, Texas, 75390-9070, United States

Location

Southwestern Vermont Medical Center

Bennington, Vermont, 05201, United States

Location

University of Virginia

Charlottesville, Virginia, 22908, United States

Location

Related Publications (4)

• 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. doi: 10.1016/s0169-409x(02)00153-9.

  PMID: 12453674 BACKGROUND

• Manji HK, Moore GJ, Rajkowska G, Chen G. Neuroplasticity and cellular resilience in mood disorders. Mol Psychiatry. 2000 Nov;5(6):578-93. doi: 10.1038/sj.mp.4000811.

  PMID: 11126389 BACKGROUND

• 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. doi: 10.1046/j.1471-4159.2000.0721327.x.

  PMID: 10037507 BACKGROUND

• Tariot PN, Schneider LS, Cummings J, Thomas RG, Raman R, Jakimovich LJ, Loy R, Bartocci B, Fleisher A, Ismail MS, Porsteinsson A, Weiner M, Jack CR Jr, Thal L, Aisen PS; Alzheimer's Disease Cooperative Study Group. Chronic divalproex sodium to attenuate agitation and clinical progression of Alzheimer disease. Arch Gen Psychiatry. 2011 Aug;68(8):853-61. doi: 10.1001/archgenpsychiatry.2011.72.

  PMID: 21810649 DERIVED

MeSH Terms

Conditions

Alzheimer Disease; Psychomotor Agitation; Psychotic Disorders

Interventions

Valproic Acid

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Dyskinesias; Neurologic Manifestations; Psychomotor Disorders; Neurobehavioral Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Aberrant Motor Behavior in Dementia; Behavioral Symptoms; Behavior; Schizophrenia Spectrum and Other Psychotic Disorders

Intervention Hierarchy (Ancestors)

Pentanoic Acids; Valerates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Fatty Acids, Volatile; Fatty Acids; Lipids

Results Point of Contact

• Title: Paul Aisen
• Organization: Alzheimer's Disease Cooperative Study

paisen@ucsd.edu

858-622-2028

Study Officials

• Pierre Tariot, MD

  University of Rochester Medical Center, Departments of Psychiatry, Medicine, and Neurology, and the Center for Aging and Developmental Biology

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 29, 2003
• First Posted: October 31, 2003
• Study Start: October 1, 2003
• Primary Completion: February 1, 2009
• Study Completion: December 1, 2009
• Last Updated: September 25, 2014
• Results First Posted: October 20, 2010

Record last verified: 2014-09

Locations

US (46)