Valproate in Dementia (VALID)

• Sponsor: Alzheimer's Disease Cooperative Study (ADCS) (Other)
• Overall Status: Completed
• CT.gov ID: NCT00071721
• Collaborator: National Institute on Aging (NIA) (NIH)
• Enrollment: 313
• Locations: 46
• Arms: 2
• Duration (Months): 74
• Patients Per Site: 6.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Alzheimer Disease	Drug: Valproate; Drug: Placebo	Phase 3

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

• Study Type: Interventional
• Actual Enrollment: 313 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Placebo-Controlled Trial of Valproate to Attenuate the Progression of Alzheimer's Disease (AD)
• Study Start Date: Oct 1, 2003
• Actual Primary Completion Date: Feb 1, 2009
• Actual Study Completion Date: Dec 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1	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; Other Names: Depakene, Depakote
Placebo Comparator: 2	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

Outcome Measures

Primary Outcome Measures

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 [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.

Secondary Outcome Measures

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

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

   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. Global Severity of Dementia Using the CDR Sum of Boxes [24 months]

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

   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. Participant's Clinical Condition or Endpoint Assessed With the ADCS-Clinical Global Impression of Change (ADCS-CGIC) [24 months]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 55 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sun Health Research Institute	Sun City	Arizona	United States	85351
2	University of Arizona	Tucson	Arizona	United States	85724
3	University of California, Irvine	Irvine	California	United States	92697-4540
4	University of California, ADRC, San Diego	La Jolla	California	United States	92093-0624
5	VA Healthcare System Long Beach	Long Beach	California	United States	90822
6	University of Southern California	Los Angeles	California	United States	90089-0191
7	University of California ADRC	Los Angeles	California	United States	90095-1769
8	University of California, LA (Olive View)	Los Angeles	California	United States	90095
9	Pacific Research Network	San Diego	California	United States	32103
10	Stanford University, VA Aging Clinical Research Center	Stanford	California	United States	94304
11	Yale University School of Medicine	New Haven	Connecticut	United States	06511
12	Georgetown University Medical Center	Washington, DC	District of Columbia	United States	20057
13	Howard University	Washington	District of Columbia	United States	20060
14	Mayo Clinic	Jacksonville	Florida	United States	32224
15	Wein Center, Mount Sinai Medical Center	Miami	Florida	United States	33140
16	University of South Florida	Tampa	Florida	United States	33617
17	Byrd Institute	Tampa	Florida	United States	33647
18	Premier Research Institute	West Palm Beach	Florida	United States	33407
19	Emory University	Atlanta	Georgia	United States	30329
20	Northwestern University	Chicago	Illinois	United States	60611
21	Southern Illinois University	Springfield	Illinois	United States	62794
22	Indiana University School of Medicine	Indianapolis	Indiana	United States	46202-5120
23	University of Kansas	Kansas City	Kansas	United States	66160
24	Lahey Clinic, Research Neurology	Burlington	Massachusetts	United States	01805
25	University of Michigan	Ann Arbor	Michigan	United States	48109-0489
26	Saint Mary's Health Care	Grand Rapids	Michigan	United States	49503
27	St. Louis University	St. Louis	Missouri	United States	63103
28	University of Nevada	Las Vegas	Nevada	United States	89154-5084
29	Albany Medical Center	Albany	New York	United States	12208
30	Dent Neurologic Institute	Amherst	New York	United States	14226
31	New York University Medical Center	New York	New York	United States	10016
32	Columbia University	New York	New York	United States	10032
33	Global Research and Consulting	Olean	New York	United States	14760
34	University of Rochester	Rochester	New York	United States	14642
35	Syracuse VA Medical Center	Syracuse	New York	United States	13210
36	North East Ohio Health Services	Beachwood	Ohio	United States	44122
37	Case Western Reserve University, University Hospitals of Cleveland	Cleveland	Ohio	United States	44120
38	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104-4283
39	Brown University, Memorial Hospital of Rhode Island	Providence	Rhode Island	United States	02860
40	Medical University of South Carolina-Columbia	Columbia	South Carolina	United States	29203
41	Medical University of South Carolina-Florence	Florence	South Carolina	United States	29502
42	Medical University of South Carolina	North Charleston	South Carolina	United States	29406-6076
43	Psychiatric Consultants	Nashville	Tennessee	United States	37203
44	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390-9070
45	Southwestern Vermont Medical Center	Bennington	Vermont	United States	05201
46	University of Virginia	Charlottesville	Virginia	United States	22908

Sponsors and Collaborators

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

Investigators

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

Study Documents (Full-Text)

None provided.

More Information

Publications

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

• Responsible Party: Alzheimer's Disease Cooperative Study (ADCS)
• ClinicalTrials.gov Identifier: NCT00071721
• Other Study ID Numbers: IA0043; 1RC2AG036535; IND 67,222; ADCS Protocol ADC-022-VN
• First Posted: Oct 31, 2003
• Last Update Posted: Sep 25, 2014
• Last Verified: Sep 1, 2014

• Keywords provided by Alzheimer's Disease Cooperative Study (ADCS): Alzheimer disease; Agitation; Psychosis
• Additional relevant MeSH terms: Alzheimer Disease; Valproic Acid

Study Results

Participant Flow

Arm/Group Title	Valproate	Placebo
Arm/Group Description	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 tablets beginning with one daily and increasing according to weight and perceived tolerability concerns for two years, followed by a 2-month washout
Period Title: Overall Study
STARTED	153	160
COMPLETED	81	69
NOT COMPLETED	72	91

Baseline Characteristics

Arm/Group Title	Valproate	Placebo	Total
Arm/Group Description	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 tablets beginning with one daily and increasing according to weight and perceived tolerability concerns for two years, followed by a 2-month washout	Total of all reporting groups
Overall Participants	153	160	313
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	74.9 (8.2)	76.6 (7.4)	75.7 (7.8)
Sex: Female, Male (Count of Participants)
Female	83 54.2%	101 63.1%	184 58.8%
Male	70 45.8%	59 36.9%	129 41.2%
Region of Enrollment (participants) [Number]
United States	153 100%	160 100%	313 100%
ADAScog (Units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Units on a scale]	29.4 (8.9)	30.1 (9.8)	29.8 (9.4)
ADCS-ADL (Units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Units on a scale]	56.9 (11.8)	54.9 (13)	55.9 (12.4)
CDR-SOB (Units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Units on a scale]	7.1 (2.7)	7.5 (3.1)	7.3 (2.9)
CMAI (Units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Units on a scale]	10.9 (8.9)	11.9 (10.4)	11.4 (9.7)
NPI (Units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Units on a scale]	2.6 (2.6)	3.1 (2.6)	2.9 (2.6)

Outcome Measures

1. Primary Outcome

Title	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
Description	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.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Valproate	Placebo
Arm/Group Description	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 tablets beginning with one daily and increasing according to weight and perceived tolerability concerns for two years, followed by a 2-month washout
Measure Participants	153	160
Number [Participants]	25 16.3%	29 18.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Valproate, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.88
	Comments
	Method	Cox Proportional Hazards
	Comments
Method of Estimation	Estimation Parameter	Cox Proportional Hazard
	Estimated Value	0.958
	Confidence Interval	() 95%; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Cognitive Performance Assessed by the Alzheimer's Disease Assessment Scale-cognitive Subtest (ADAS-cog)
Description	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.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Valproate	Placebo
Arm/Group Description	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 tablets beginning with one daily and increasing according to weight and perceived tolerability concerns for two years, followed by a 2-month washout
Measure Participants	153	160
Mean (Standard Deviation) [Units on a scale]	42.3 (14.3)	41.9 (14.4)

3. Secondary Outcome

Title	Functional Performance Assessed by the Alzheimer's Disease Cooperative Study Activities of Daily Living (ADCS-ADL) Inventory
Description	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.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Valproate	Placebo
Arm/Group Description	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 tablets beginning with one daily and increasing according to weight and perceived tolerability concerns for two years, followed by a 2-month washout
Measure Participants	153	160
Mean (Standard Deviation) [Units on a scale]	35.1 (20.3)	41.0 (14.81)

4. Secondary Outcome

Title	Global Severity of Dementia Using the CDR Sum of Boxes
Description	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.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Valproate	Placebo
Arm/Group Description	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 tablets beginning with one daily and increasing according to weight and perceived tolerability concerns for two years, followed by a 2-month washout
Measure Participants	153	160
Mean (Standard Deviation) [Units on a scale]	12.0 (4.1)	11.5 (3.7)

5. Secondary Outcome

Title	Agitation Measured by the Cohen-Mansfield Agitation Inventory (CMAI), Community Version
Description	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.
Time Frame	24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Valproate	Placebo
Arm/Group Description	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 tablets beginning with one daily and increasing according to weight and perceived tolerability concerns for two years, followed by a 2-month washout
Measure Participants	153	160
Mean (Standard Deviation) [Units on a scale]	10.6 (11.6)	12.1 (10.9)

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Valproate	Placebo
Arm/Group Description	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 tablets beginning with one daily and increasing according to weight and perceived tolerability concerns for two years, followed by a 2-month washout
Measure Participants	153	160
Mean (Standard Deviation) [Units on a scale]	5.7 (0.9)	5.5 (1.1)

Adverse Events

Arm/Group Title	Valproate		Placebo
Arm/Group Description	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 tablets beginning with one daily and increasing according to weight and perceived tolerability concerns for two years, followed by a 2-month washout
All Cause Mortality
	Valproate		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Valproate		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	51/153 (33.3%)		62/160 (38.8%)
Blood and lymphatic system disorders
Anaemia	1/153 (0.7%)	1	2/160 (1.3%)	2
Cardiac disorders
Angina pectoris	0/153 (0%)	0	1/160 (0.6%)	1
Angina unstable	1/153 (0.7%)	1	0/160 (0%)	0
Atrial fibrillation	3/153 (2%)	4	1/160 (0.6%)	2
Bradycardia	0/153 (0%)	0	1/160 (0.6%)	1
Cardiac disorder	1/153 (0.7%)	1	0/160 (0%)	0
Cardiac failure	0/153 (0%)	0	1/160 (0.6%)	1
Cardiac failure congestive	0/153 (0%)	0	1/160 (0.6%)	2
Myocardial infarction	0/153 (0%)	0	1/160 (0.6%)	1
Sinus tachycardia	0/153 (0%)	0	1/160 (0.6%)	1
Endocrine disorders
Hypothyroidism	0/153 (0%)	0	1/160 (0.6%)	1
Gastrointestinal disorders
Abdominal distension	1/153 (0.7%)	1	0/160 (0%)	0
Abdominal pain	1/153 (0.7%)	1	0/160 (0%)	0
Dysphagia	1/153 (0.7%)	1	0/160 (0%)	0
Faecaloma	1/153 (0.7%)	1	0/160 (0%)	0
Femoral hernia	0/153 (0%)	0	1/160 (0.6%)	1
Gastric haemorrhage	1/153 (0.7%)	1	0/160 (0%)	0
Gastric ulcer haemorrhage	0/153 (0%)	0	1/160 (0.6%)	1
Gastrointestinal haemorrhage	0/153 (0%)	0	2/160 (1.3%)	2
Oesophageal obstruction	1/153 (0.7%)	1	0/160 (0%)	0
Rectal haemorrhage	0/153 (0%)	0	1/160 (0.6%)	1
General disorders
Chest pain	3/153 (2%)	3	1/160 (0.6%)	1
Death	5/153 (3.3%)	5	7/160 (4.4%)	7
Pyrexia	1/153 (0.7%)	1	0/160 (0%)	0
Hepatobiliary disorders
Cholecystitis	0/153 (0%)	0	1/160 (0.6%)	1
Hepatic mass	1/153 (0.7%)	1	0/160 (0%)	0
Infections and infestations
Bronchitis	1/153 (0.7%)	1	0/160 (0%)	0
Cellulitis	0/153 (0%)	0	1/160 (0.6%)	1
Enterococcal bacteraemia	0/153 (0%)	0	1/160 (0.6%)	1
Infection	0/153 (0%)	0	2/160 (1.3%)	2
Influenza	1/153 (0.7%)	1	0/160 (0%)	0
Kidney infection	2/153 (1.3%)	2	0/160 (0%)	0
Listeriosis	1/153 (0.7%)	1	0/160 (0%)	0
Nasopharyngitis	0/153 (0%)	0	1/160 (0.6%)	1
Pneumonia	5/153 (3.3%)	5	6/160 (3.8%)	6
Pneumonia bacterial	0/153 (0%)	0	1/160 (0.6%)	1
Postoperative infection	0/153 (0%)	0	1/160 (0.6%)	1
Urinary tract infection	4/153 (2.6%)	5	3/160 (1.9%)	3
Injury, poisoning and procedural complications
Accidental overdose	1/153 (0.7%)	1	0/160 (0%)	0
Drug toxicity	1/153 (0.7%)	1	0/160 (0%)	0
Fall	6/153 (3.9%)	6	9/160 (5.6%)	10
Fractured sacrum	0/153 (0%)	0	1/160 (0.6%)	1
Head injury	1/153 (0.7%)	1	0/160 (0%)	0
Hip fracture	0/153 (0%)	0	2/160 (1.3%)	2
Joint dislocation	0/153 (0%)	0	1/160 (0.6%)	1
Subdural haematoma	1/153 (0.7%)	2	0/160 (0%)	0
Upper limb fracture	0/153 (0%)	0	1/160 (0.6%)	1
Investigations
Liver function test abnormal	1/153 (0.7%)	1	0/160 (0%)	0
Metabolism and nutrition disorders
Decreased appetite	0/153 (0%)	0	1/160 (0.6%)	1
Dehydration	3/153 (2%)	3	0/160 (0%)	0
Hypoglycaemia	1/153 (0.7%)	1	0/160 (0%)	0
Hypokalaemia	1/153 (0.7%)	1	0/160 (0%)	0
Musculoskeletal and connective tissue disorders
Arthralgia	1/153 (0.7%)	1	0/160 (0%)	0
Arthritis	0/153 (0%)	0	1/160 (0.6%)	1
Chondropathy	1/153 (0.7%)	1	0/160 (0%)	0
Muscular weakness	1/153 (0.7%)	1	0/160 (0%)	0
Musculoskeletal chest pain	0/153 (0%)	0	1/160 (0.6%)	1
Spondylolisthesis	1/153 (0.7%)	1	0/160 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer	0/153 (0%)	0	1/160 (0.6%)	1
Colon cancer	0/153 (0%)	0	1/160 (0.6%)	1
Mantle cell lymphoma	0/153 (0%)	0	1/160 (0.6%)	1
Metastatic neoplasm	0/153 (0%)	0	1/160 (0.6%)	1
Prostate cancer	1/153 (0.7%)	1	0/160 (0%)	0
Rectal cancer	0/153 (0%)	0	1/160 (0.6%)	1
Nervous system disorders
Cerebral artery occlusion	1/153 (0.7%)	1	0/160 (0%)	0
Cerebral infarction	0/153 (0%)	0	1/160 (0.6%)	1
Cerebrovascular accident	0/153 (0%)	0	1/160 (0.6%)	1
Convulsion	0/153 (0%)	0	4/160 (2.5%)	4
Coordination abnormal	0/153 (0%)	0	1/160 (0.6%)	1
Depressed level of consciousness	1/153 (0.7%)	1	1/160 (0.6%)	1
Dizziness	2/153 (1.3%)	2	1/160 (0.6%)	1
Loss of consciousness	0/153 (0%)	0	1/160 (0.6%)	1
Lumbar radiculopathy	0/153 (0%)	0	1/160 (0.6%)	1
Subdural haematoma	1/153 (0.7%)	1	0/160 (0%)	0
Subdural haemorrhage	1/153 (0.7%)	1	0/160 (0%)	0
Syncope	4/153 (2.6%)	4	2/160 (1.3%)	2
Transient ischaemic attack	1/153 (0.7%)	1	0/160 (0%)	0
Psychiatric disorders
Abnormal behaviour	1/153 (0.7%)	1	0/160 (0%)	0
Agitation	0/153 (0%)	0	2/160 (1.3%)	2
Confusional state	2/153 (1.3%)	2	0/160 (0%)	0
Delirium	0/153 (0%)	0	1/160 (0.6%)	1
Hallucination	1/153 (0.7%)	1	0/160 (0%)	0
Lethargy	0/153 (0%)	0	1/160 (0.6%)	1
Mental disorder	0/153 (0%)	0	1/160 (0.6%)	1
Renal and urinary disorders
Haematuria	1/153 (0.7%)	1	0/160 (0%)	0
Urinary incontinence	1/153 (0.7%)	1	0/160 (0%)	0
Urinary retention	1/153 (0.7%)	1	1/160 (0.6%)	1
Reproductive system and breast disorders
Breast swelling	1/153 (0.7%)	1	0/160 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/153 (0.7%)	1	3/160 (1.9%)	3
Pneumonia aspiration	0/153 (0%)	0	1/160 (0.6%)	1
Pulmonary embolism	0/153 (0%)	0	1/160 (0.6%)	1
Respiratory distress	0/153 (0%)	0	1/160 (0.6%)	1
Skin and subcutaneous tissue disorders
Hyperhidrosis	0/153 (0%)	0	1/160 (0.6%)	1
Skin ulcer	1/153 (0.7%)	1	0/160 (0%)	0
Surgical and medical procedures
Bladder repair	0/153 (0%)	0	1/160 (0.6%)	1
Breast reconstruction	0/153 (0%)	0	1/160 (0.6%)	1
Cardiac pacemaker replacement	1/153 (0.7%)	1	0/160 (0%)	0
Cholecystectomy	1/153 (0.7%)	1	1/160 (0.6%)	1
Gallbladder operation	1/153 (0.7%)	1	0/160 (0%)	0
Hip arthroplasty	1/153 (0.7%)	1	0/160 (0%)	0
Hospitalisation	0/153 (0%)	0	1/160 (0.6%)	1
Joint arthroplasty	0/153 (0%)	0	1/160 (0.6%)	1
Knee operation	0/153 (0%)	0	1/160 (0.6%)	1
Leg amputation	0/153 (0%)	0	1/160 (0.6%)	1
Lesion excision	1/153 (0.7%)	1	0/160 (0%)	0
Surgery	1/153 (0.7%)	1	0/160 (0%)	0
Uterine prolapse repair	0/153 (0%)	0	1/160 (0.6%)	1
Ventriculo-peritoneal shunt	0/153 (0%)	0	1/160 (0.6%)	1
Whole blood transfusion	0/153 (0%)	0	1/160 (0.6%)	1
Vascular disorders
Deep vein thrombosis	1/153 (0.7%)	2	0/160 (0%)	0
Hypertension	1/153 (0.7%)	1	1/160 (0.6%)	1
Hypotension	0/153 (0%)	0	1/160 (0.6%)	1
Pulmonary embolism	0/153 (0%)	0	1/160 (0.6%)	1
Thrombosis	0/153 (0%)	0	1/160 (0.6%)	1
Other (Not Including Serious) Adverse Events
	Valproate		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	145/153 (94.8%)		151/160 (94.4%)
Eye disorders
Vision blurred	10/153 (6.5%)	11	8/160 (5%)	8
Gastrointestinal disorders
Abdominal discomfort	16/153 (10.5%)	19	13/160 (8.1%)	13
Constipation	26/153 (17%)	28	13/160 (8.1%)	16
Diarrhoea	38/153 (24.8%)	45	19/160 (11.9%)	24
Dry mouth	16/153 (10.5%)	16	15/160 (9.4%)	15
Faecal incontinence	8/153 (5.2%)	8	5/160 (3.1%)	5
Nausea	14/153 (9.2%)	16	10/160 (6.3%)	11
Vomiting	9/153 (5.9%)	10	7/160 (4.4%)	7
General disorders
Asthenia	48/153 (31.4%)	52	35/160 (21.9%)	37
Chest pain	7/153 (4.6%)	9	8/160 (5%)	8
Oedema peripheral	10/153 (6.5%)	12	7/160 (4.4%)	7
Infections and infestations
Bronchitis	7/153 (4.6%)	8	5/160 (3.1%)	6
Nasopharyngitis	11/153 (7.2%)	12	9/160 (5.6%)	13
Urinary tract infection	15/153 (9.8%)	19	17/160 (10.6%)	28
Injury, poisoning and procedural complications
Fall	54/153 (35.3%)	85	42/160 (26.3%)	86
Investigations
Weight decreased	11/153 (7.2%)	12	11/160 (6.9%)	11
Metabolism and nutrition disorders
Decreased appetite	8/153 (5.2%)	9	7/160 (4.4%)	8
Musculoskeletal and connective tissue disorders
Arthralgia	20/153 (13.1%)	21	12/160 (7.5%)	14
Back pain	21/153 (13.7%)	21	20/160 (12.5%)	20
Joint swelling	14/153 (9.2%)	15	10/160 (6.3%)	12
Muscular weakness	28/153 (18.3%)	32	14/160 (8.8%)	14
Myalgia	11/153 (7.2%)	12	11/160 (6.9%)	12
Nervous system disorders
Disturbance in attention	40/153 (26.1%)	40	39/160 (24.4%)	39
Dizziness	23/153 (15%)	25	30/160 (18.8%)	36
Gait disturbance	51/153 (33.3%)	64	30/160 (18.8%)	35
Headache	16/153 (10.5%)	19	13/160 (8.1%)	16
Tremor	44/153 (28.8%)	51	22/160 (13.8%)	23
Psychiatric disorders
Agitation	43/153 (28.1%)	50	54/160 (33.8%)	74
Anxiety	24/153 (15.7%)	29	38/160 (23.8%)	47
Apathy	9/153 (5.9%)	9	9/160 (5.6%)	9
Confusional state	76/153 (49.7%)	114	79/160 (49.4%)	111
Crying	23/153 (15%)	27	22/160 (13.8%)	24
Delusion	10/153 (6.5%)	11	14/160 (8.8%)	20
Depressed mood	35/153 (22.9%)	37	23/160 (14.4%)	26
Depression	18/153 (11.8%)	19	10/160 (6.3%)	11
Hallucination	9/153 (5.9%)	11	5/160 (3.1%)	5
Insomnia	20/153 (13.1%)	23	16/160 (10%)	18
Restlessness	28/153 (18.3%)	34	31/160 (19.4%)	39
Somnolence	66/153 (43.1%)	80	46/160 (28.8%)	51
Renal and urinary disorders
Pollakiuria	23/153 (15%)	25	17/160 (10.6%)	19
Urinary incontinence	15/153 (9.8%)	18	15/160 (9.4%)	16
Respiratory, thoracic and mediastinal disorders
Cough	21/153 (13.7%)	24	18/160 (11.3%)	22
Dyspnoea	19/153 (12.4%)	20	9/160 (5.6%)	9
Skin and subcutaneous tissue disorders
Hyperhidrosis	4/153 (2.6%)	4	9/160 (5.6%)	9
Rash	7/153 (4.6%)	7	15/160 (9.4%)	17

Limitations/Caveats

[Not Specified]

More Information

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.