Alzheimer DiseasePhase 3NCT00071721
Valproate in Dementia (VALID)
A Phase 3 study testing Valproate in people with Alzheimer Disease, run by Alzheimer's Disease Cooperative Study (ADCS) at 46 sites in United States.
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. Read more about this study
- Who is it for?
- Ages 55 to 90 years
- Conditions the study is for
- Alzheimer Disease
- What is being tested?
- Valproate
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 313 participants
- Where
- 46 sitesUnited States
- Study dates
- Oct 2003to Dec 2009
- Phase
- Phase 3
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 55 to 90 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Show all 15Show fewer
- 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.).
Who cannot join
- 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.
Show all 28Show fewer
- 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.
Trial locations and contacts
46 sites in 1 country.
46 sites in 1 country
United States46 sites
Albany Medical Center
Albany, New York, 12208
Dent Neurologic Institute
Amherst, New York, 14226
University of Michigan
Ann Arbor, Michigan, 48109-0489
Emory University
Atlanta, Georgia, 30329
North East Ohio Health Services
Beachwood, Ohio, 44122
Southwestern Vermont Medical Center
Bennington, Vermont, 05201
Lahey Clinic, Research Neurology
Burlington, Massachusetts, 01805
University of Virginia
Charlottesville, Virginia, 22908
Northwestern University
Chicago, Illinois, 60611
Case Western Reserve University, University Hospitals of Cleveland
Cleveland, Ohio, 44120
Medical University of South Carolina-Columbia
Columbia, South Carolina, 29203
University of Texas Southwestern Medical Center
Dallas, Texas, 75390-9070
Medical University of South Carolina-Florence
Florence, South Carolina, 29502
Saint Mary's Health Care
Grand Rapids, Michigan, 49503
Indiana University School of Medicine
Indianapolis, Indiana, 46202-5120
University of California, Irvine
Irvine, California, 92697-4540
Mayo Clinic
Jacksonville, Florida, 32224
University of Kansas
Kansas City, Kansas, 66160
University of California, ADRC, San Diego
La Jolla, California, 92093-0624
University of Nevada
Las Vegas, Nevada, 89154-5084
VA Healthcare System Long Beach
Long Beach, California, 90822
University of Southern California
Los Angeles, California, 90089-0191
University of California ADRC
Los Angeles, California, 90095-1769
University of California, LA (Olive View)
Los Angeles, California, 90095
Wein Center, Mount Sinai Medical Center
Miami, Florida, 33140
Psychiatric Consultants
Nashville, Tennessee, 37203
Yale University School of Medicine
New Haven, Connecticut, 06511
New York University Medical Center
New York, New York, 10016
Columbia University
New York, New York, 10032
Medical University of South Carolina
North Charleston, South Carolina, 29406-6076
Global Research and Consulting
Olean, New York, 14760
University of Pennsylvania
Philadelphia, Pennsylvania, 19104-4283
Brown University, Memorial Hospital of Rhode Island
Providence, Rhode Island, 02860
University of Rochester
Rochester, New York, 14642
Pacific Research Network
San Diego, California, 32103
Southern Illinois University
Springfield, Illinois, 62794
St. Louis University
St Louis, Missouri, 63103
Stanford University, VA Aging Clinical Research Center
Stanford, California, 94304
Sun Health Research Institute
Sun City, Arizona, 85351
Syracuse VA Medical Center
Syracuse, New York, 13210
University of South Florida
Tampa, Florida, 33617
Byrd Institute
Tampa, Florida, 33647
University of Arizona
Tucson, Arizona, 85724
Georgetown University Medical Center
Washington D.C., District of Columbia, 20057
Howard University
Washington D.C., District of Columbia, 20060
Premier Research Institute
West Palm Beach, Florida, 33407
About this study
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.
Read the 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.
- Conditions
- Alzheimer Disease
- Being tested
- Valproate, Placebo
- Keywords
- Alzheimer disease, Agitation, Psychosis
- Medical subject headings
- Alzheimer Disease, Psychomotor Agitation, Psychotic Disorders
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
ValproateDrug
Also called Depakene, Depakote
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
PlaceboDrug
Placebo tablets beginning with one daily and increasing according to weight and perceived tolerability concerns for two years, followed by a 2-month washout
| Study group | Role | What they receive |
|---|---|---|
| 1 | Experimental | Not described Receives: Drug: Valproate |
| 2 | Placebo comparator | Not described Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 24 months
Secondary outcomes (5)
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.
Measured: 24 months
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.
Measured: 24 months
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.
Measured: 24 months
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.
Measured: 24 months
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.
Measured: 24 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted31 Oct 2003 (estimated)
- Study startOct 2003
- Primary completionFeb 2009
- Study completionDec 2009
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for Alzheimer DiseaseStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 3
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 313 participants (actual)
Sponsor and investigators
- Lead sponsor
- Alzheimer's Disease Cooperative Study (ADCS)
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute on Aging (NIA)
- Responsible party
- Sponsor
- Investigators
- Pierre Tariot, MD, Study director, University of Rochester Medical Center, Departments of Psychiatry, Medicine, and Neurology, and the Center for Aging and Developmental Biology
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00071721
- Sponsor's protocol ID
- IA0043
- Other IDs
- 1RC2AG036535, IND 67,222, ADCS Protocol ADC-022-VN
- Status last verified
- Sep 2014
- First submitted
- 29 Oct 2003
- Last updated
- 25 Sep 2014
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
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.
PubMed 12453674Manji 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.
PubMed 11126389Chen 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.
PubMed 10037507Jimenez-Maggiora GA, Donohue MC, Rafii MS, Raman R, Aisen PS. Artificial intelligence-enabled safety monitoring in Alzheimer's disease clinical trials. J Prev Alzheimers Dis. 2025 Jan;12(1):100002. doi: 10.1016/j.tjpad.2024.100002. Epub 2025 Jan 1.
PubMed 39800465Tariot 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.
PubMed 21810649
Study at a glance
From the registry record, last updated by the sponsor on 25 Sep 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Randomized, Double-Blind, Placebo-Controlled Trial of Valproate to Attenuate the Progression of Alzheimer's Disease (AD)
- ClinicalTrials.gov ID
- NCT00071721
- Acronym / sponsor ID
- IA0043
- Conditions
- Alzheimer Disease
- Keywords
- Alzheimer disease, Agitation, Psychosis
- Phase
- Phase 3
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 313 participants (actual)
- Lead sponsor
- Alzheimer's Disease Cooperative Study (ADCS)University, hospital or other
- Collaborators
- National Institute on Aging (NIA)
- Study start
- Oct 2003
- Primary completion
- Feb 2009 (actual)
- Study completion
- Dec 2009 (actual)
- First posted
- 31 Oct 2003 (estimated)
- Results
- Posted 20 Oct 2010
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| 1 | Experimental | Drug: Valproate |
| 2 | Placebo comparator | Drug: Placebo |
Who may qualify
- Ages
- 55 to 90 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (15 listed)
- 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.
Key exclusion criteria (28 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| ValproateAlso: Depakene, Depakote250mg 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 | 1 |
| PlaceboPlacebo tablets beginning with one daily and increasing according to weight and perceived tolerability concerns for two years, followed by a 2-month washout | Drug | 2 |
Primary outcome
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: 24 months
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.
5 secondary outcomes
Cognitive Performance Assessed by the Alzheimer's Disease Assessment Scale-cognitive Subtest (ADAS-cog)
Time frame: 24 months
Functional Performance Assessed by the Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Inventory
Time frame: 24 months
Global Severity of Dementia Using the CDR Sum of Boxes
Time frame: 24 months
Agitation Measured by the Cohen-Mansfield Agitation Inventory (CMAI), Community Version
Time frame: 24 months
Participant's Clinical Condition or Endpoint Assessed With the ADCS-Clinical Global Impression of Change (ADCS-CGIC)
Time frame: 24 months
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Sep 2014.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 12453674Tariot 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.
- Background: PubMed 11126389Manji 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.
- Background: PubMed 10037507Chen 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.
- Derived from this study: PubMed 39800465Jimenez-Maggiora GA, Donohue MC, Rafii MS, Raman R, Aisen PS. Artificial intelligence-enabled safety monitoring in Alzheimer's disease clinical trials. J Prev Alzheimers Dis. 2025 Jan;12(1):100002. doi: 10.1016/j.tjpad.2024.100002. Epub 2025 Jan 1.
- Derived from this study: PubMed 21810649Tariot 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.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Pierre Tariot, MD study director
University of Rochester Medical Center, Departments of Psychiatry, Medicine, and Neurology, and the Center for Aging and Developmental Biology
46 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 3 study testing Valproate in people with Alzheimer Disease, run by Alzheimer's Disease Cooperative Study (ADCS) at 46 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 15 inclusion and 28 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 25 Sep 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 46 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 20 Oct 2010). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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: 24 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00071721, which also lists 5 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Sep 2014.