Valproate in Dementia (VALID)

This study has been completed.

Sponsor:

Collaborator:

National Institute on Aging (NIA)

Information provided by (Responsible Party):

Alzheimer's Disease Cooperative Study (ADCS)

ClinicalTrials.gov Identifier:

NCT00071721

First received: October 29, 2003

Last updated: January 10, 2013

Last verified: January 2013

History of Changes

Results First Received: July 6, 2010

Study Type:	Interventional
Study Design:	Allocation: Randomized; Endpoint Classification: Safety/Efficacy Study; Intervention Model: Parallel Assignment; Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition:	Alzheimer Disease
Interventions:	Drug: Valproate Drug: Placebo

Participant Flow

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Recruitment Details

Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
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Pre-Assignment Details

Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups

	Description
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

Participant Flow: Overall Study

	Valproate	Placebo
STARTED	153	160
COMPLETED	81	69
NOT COMPLETED	72	91

Baseline Characteristics

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Reporting Groups

	Description
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
Total	Total of all reporting groups

Baseline Measures

	Valproate	Placebo	Total
Number of Participants [units: participants]	153	160	313
Age [units: years] Mean ± Standard Deviation	74.9 ± 8.2	76.6 ± 7.4	75.7 ± 7.8
Gender [units: participants]
Female	83	101	184
Male	70	59	129
Region of Enrollment [units: participants]
United States	153	160	313
ADAScog ^[1] [units: Units on a scale] Mean ± Standard Deviation	29.4 ± 8.9	30.1 ± 9.8	29.8 ± 9.4
ADCS-ADL ^[2] [units: Units on a scale] Mean ± Standard Deviation	56.9 ± 11.8	54.9 ± 13	55.9 ± 12.4
CDR-SOB ^[3] [units: Units on a scale] Mean ± Standard Deviation	7.1 ± 2.7	7.5 ± 3.1	7.3 ± 2.9
CMAI ^[4] [units: Units on a scale] Mean ± Standard Deviation	10.9 ± 8.9	11.9 ± 10.4	11.4 ± 9.7
NPI ^[5] [units: Units on a scale] Mean ± Standard Deviation	2.6 ± 2.6	3.1 ± 2.6	2.9 ± 2.6

[1]	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.
[2]	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.
[3]	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.
[4]	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.
[5]	The Neuropsychiatric Inventory (NPI) quantifies behavioral changes in dementia, including depression, anxiety, psychosis, agitation, sleep change, appetite change, and others. This is a structured questionnaire administered to the subject's caregiver/study partner. The range of this instrument is 0 to 120 with higher numbers indicating greater impairment.

Outcome Measures

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1. 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 [ Time Frame: 24 months ]

Show Outcome Measure 1

2. Secondary:

Cognitive Performance Assessed by the Alzheimer's Disease Assessment Scale-cognitive Subtest (ADAS-cog) [ Time Frame: 24 months ]

Show Outcome Measure 2

3. Secondary:

Functional Performance Assessed by the Alzheimer’s Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Inventory [ Time Frame: 24 months ]

Show Outcome Measure 3

4. Secondary:

Global Severity of Dementia Using the CDR Sum of Boxes [ Time Frame: 24 months ]

Show Outcome Measure 4

5. Secondary:

Agitation Measured by the Cohen-Mansfield Agitation Inventory (CMAI), Community Version [ Time Frame: 24 months ]

Show Outcome Measure 5

6. Secondary:

Participant’s Clinical Condition or Endpoint Assessed With the ADCS-Clinical Global Impression of Change (ADCS-CGIC) [ Time Frame: 24 months ]

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Measure Type	Secondary
Measure Title	Participant’s Clinical Condition or Endpoint Assessed With the ADCS-Clinical Global Impression of Change (ADCS-CGIC)
Measure Description	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.
Time Frame	24 months
Safety Issue	No

Population Description

Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups

	Description
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

Measured Values

	Valproate	Placebo
Number of Participants Analyzed [units: participants]	153	160
Participant’s Clinical Condition or Endpoint Assessed With the ADCS-Clinical Global Impression of Change (ADCS-CGIC) [units: Units on a scale] Mean ± Standard Deviation	5.7 ± 0.9	5.5 ± 1.1

No statistical analysis provided for Participant’s Clinical Condition or Endpoint Assessed With the ADCS-Clinical Global Impression of Change (ADCS-CGIC)

Serious Adverse Events

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Time Frame	No text entered.
Additional Description	No text entered.

Reporting Groups

	Description
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

Serious Adverse Events

	Valproate	Placebo
Total, serious adverse events
# participants affected / at risk	51/153 (33.33%)	62/160 (38.75%)
Blood and lymphatic system disorders
Anaemia ¹
# participants affected / at risk	1/153 (0.65%)	2/160 (1.25%)
# events	1	2
Cardiac disorders
Angina pectoris ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Angina unstable ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Atrial fibrillation ¹
# participants affected / at risk	3/153 (1.96%)	1/160 (0.63%)
# events	4	2
Bradycardia ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Cardiac disorder ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Cardiac failure ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Cardiac failure congestive ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	2
Myocardial infarction ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Sinus tachycardia ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Endocrine disorders
Hypothyroidism ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Gastrointestinal disorders
Abdominal distension ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Abdominal pain ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Dysphagia ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Faecaloma ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Femoral hernia ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Gastric haemorrhage ¹
# participants affected / at risk	0/153 (0.00%)	0/160 (0.00%)
# events	1	0
Gastric ulcer haemorrhage ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Gastrointestinal haemorrhage ¹
# participants affected / at risk	0/153 (0.00%)	2/160 (1.25%)
# events	0	2
Oesophageal obstruction ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Rectal haemorrhage ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
General disorders
Chest pain ¹
# participants affected / at risk	3/153 (1.96%)	1/160 (0.63%)
# events	3	1
Death ¹
# participants affected / at risk	5/153 (3.27%)	7/160 (4.38%)
# events	5	7
Pyrexia ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Hepatobiliary disorders
Cholecystitis ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Hepatic mass ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Infections and infestations
Bronchitis ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Cellulitis ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Enterococcal bacteraemia ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Infection ¹
# participants affected / at risk	0/153 (0.00%)	2/160 (1.25%)
# events	0	2
Influenza ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Kidney infection ¹
# participants affected / at risk	2/153 (1.31%)	0/160 (0.00%)
# events	2	0
Listeriosis ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Nasopharyngitis ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Pneumonia ¹
# participants affected / at risk	5/153 (3.27%)	6/160 (3.75%)
# events	5	6
Pneumonia bacterial ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Postoperative infection ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Urinary tract infection ¹
# participants affected / at risk	4/153 (2.61%)	3/160 (1.88%)
# events	5	3
Injury, poisoning and procedural complications
Accidental overdose ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Drug toxicity ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Fall ¹
# participants affected / at risk	6/153 (3.92%)	9/160 (5.63%)
# events	6	10
Fractured sacrum ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Head injury ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Hip fracture ¹
# participants affected / at risk	0/153 (0.00%)	2/160 (1.25%)
# events	0	2
Joint dislocation ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Subdural haematoma ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	2	0
Upper limb fracture ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Investigations
Liver function test abnormal ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Metabolism and nutrition disorders
Decreased appetite ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Dehydration ¹
# participants affected / at risk	3/153 (1.96%)	0/160 (0.00%)
# events	3	0
Hypoglycaemia ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Hypokalaemia ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Musculoskeletal and connective tissue disorders
Arthralgia ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Arthritis ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Chondropathy ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Muscular weakness ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Musculoskeletal chest pain ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Spondylolisthesis ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Colon cancer ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Mantle cell lymphoma ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Metastatic neoplasm ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Prostate cancer ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Rectal cancer ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Nervous system disorders
Cerebral artery occlusion ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Cerebral infarction ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Cerebrovascular accident ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Convulsion ¹
# participants affected / at risk	0/153 (0.00%)	4/160 (2.50%)
# events	0	4
Coordination abnormal ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Depressed level of consciousness ¹
# participants affected / at risk	1/153 (0.65%)	1/160 (0.63%)
# events	1	1
Dizziness ¹
# participants affected / at risk	2/153 (1.31%)	1/160 (0.63%)
# events	2	1
Loss of consciousness ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Lumbar radiculopathy ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Subdural haematoma ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Subdural haemorrhage ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Syncope ¹
# participants affected / at risk	4/153 (2.61%)	2/160 (1.25%)
# events	4	2
Transient ischaemic attack ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Psychiatric disorders
Abnormal behaviour ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Agitation ¹
# participants affected / at risk	0/153 (0.00%)	2/160 (1.25%)
# events	0	2
Confusional state ¹
# participants affected / at risk	2/153 (1.31%)	0/160 (0.00%)
# events	2	0
Delirium ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Hallucination ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Lethargy ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Mental disorder ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Renal and urinary disorders
Haematuria ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Urinary incontinence ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Urinary retention ¹
# participants affected / at risk	1/153 (0.65%)	1/160 (0.63%)
# events	1	1
Reproductive system and breast disorders
Breast swelling ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea ¹
# participants affected / at risk	1/153 (0.65%)	3/160 (1.88%)
# events	1	3
Pneumonia aspiration ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Pulmonary embolism ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Respiratory distress ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Skin and subcutaneous tissue disorders
Hyperhidrosis ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Skin ulcer ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Surgical and medical procedures
Bladder repair ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Breast reconstruction ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Cardiac pacemaker replacement ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Cholecystectomy ¹
# participants affected / at risk	1/153 (0.65%)	1/160 (0.63%)
# events	1	1
Gallbladder operation ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Hip arthroplasty ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Hospitalisation ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Joint arthroplasty ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Knee operation ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Leg amputation ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Lesion excision ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Surgery ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	1	0
Uterine prolapse repair ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Ventriculo-peritoneal shunt ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Whole blood transfusion ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Vascular disorders
Deep vein thrombosis ¹
# participants affected / at risk	1/153 (0.65%)	0/160 (0.00%)
# events	2	0
Hypertension ¹
# participants affected / at risk	1/153 (0.65%)	1/160 (0.63%)
# events	1	1
Hypotension ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Pulmonary embolism ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1
Thrombosis ¹
# participants affected / at risk	0/153 (0.00%)	1/160 (0.63%)
# events	0	1

1	Term from vocabulary, MedDRA (8.0)

Other Adverse Events

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More Information

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Certain Agreements:

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.

Results Point of Contact:

Name/Title: Paul Aisen
Organization: Alzheimer's Disease Cooperative Study
phone: 858-622-2028
e-mail: paisen@ucsd.edu

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. Review.

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

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.

Publications automatically indexed to this study:

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.

Responsible Party:	Alzheimer's Disease Cooperative Study (ADCS)
ClinicalTrials.gov Identifier:	NCT00071721 History of Changes
Other Study ID Numbers:	IA0043, 1RC2AG036535, IND 67,222, ADCS Protocol ADC-022-VN
Study First Received:	October 29, 2003
Results First Received:	July 6, 2010
Last Updated:	January 10, 2013
Health Authority:	United States: Food and Drug Administration

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