Memory Impairment Study (Mild Cognitive Impairment Study)

Alzheimer Disease Clinical Trial

Official title:

A Randomized, Double-Blind, Placebo-Controlled Trial of Vitamin E and Donepezil HCL (Aricept) to Delay Clinical Progression From Mild Cognitive Impairment (MCI) to Alzheimer's Disease (AD)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00000173
• Other study ID #: IA0011
• Secondary ID: 3U01AG010483-08S
• Status: Completed
• Phase: Phase 3
• First received: October 29, 1999
• Last updated: December 10, 2009
• Start date: March 1999
• Est. completion date: January 2004

Study information

• Verified date: June 2009
• Source: National Institute on Aging (NIA)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Federal Government
• Study type: Interventional

Clinical Trial Summary

The National Institute on Aging (NIA) is launching a nationwide treatment study targeting individuals with mild cognitive impairment (MCI), a condition characterized by a memory deficit, but not dementia. An NIA-funded study recently confirmed that MCI is different from both dementia and normal age-related changes in memory. Accurate and early evaluation and treatment of MCI individuals might prevent further cognitive decline, including development of Alzheimer's disease (AD).

The Memory Impairment Study is the first such AD prevention clinical trial carried out by NIH, and will be conducted at 65-80 medical research institutions located in the United States and Canada. This study will test the usefulness of two drugs to slow or stop the conversion from MCI to AD. The trial will evaluate placebo, vitamin E, and donepezil, an investigational agent approved by the Food and Drug Administration for another use. Vitamin E (alpha-tocopherol) is thought to have antioxidant properties, and was shown in a 1997 study to delay important dementia milestones, such as patients' institutionalization or progression to severe dementia, by about seven months.

Description:

This clinical trial will be a multicenter, randomized, double-blind, placebo- controlled, parallel-group study of vitamin E and donepezil in 720 subjects with mild cognitive impairment (MCI). Subjects will be randomized to one of three treatment groups (240 subjects per treatment group): 1) Placebo vitamin E and placebo donepezil plus a multivitamin daily. 2) Vitamin E (2,000 I) and placebo donepezil plus a multivitamin daily.3) Donepezil (10 mg) and placebo vitamin E plus a multivitamin daily.

The study will be conducted over three years, with clinical evaluations every 3 months for the first 6 months and then every 6 months. Subjects randomized to donepezil will start a dose of 5 mg daily. Donepezil will be increased to 10 mg after six weeks. Subjects randomized to vitamin E will start at 1,000 I daily. The dose of Vitamin E will be increased to 2,000 I after six weeks. There will be a 12-month recruitment period. The primary endpoint will be time to development of Probable or Possible AD according to NINCDS-ADRDA criteria. Upon determination of a clinical diagnosis of AD, documentation will be sent to the ADCS Coordinating Center and forwarded to the Central Review Committee for verification. Upon verification, of conversion to diagnosis of AD, subjects will stop taking the donepezil study medication or its corresponding placebo, without breaking the blind, and will be offered open label donepezil at a scheduled visit one month after the prior diagnostic visit. Donepezil will be offered to subjects who convert to AD until the subject completes three years from the baseline visit. Based on an estimated incidence of AD of 15% per year, the study has 85% power to detect a 33% or greater reduction in conversion to AD over 3 years. Secondary outcome measures will include change on the Alzheimer's Disease Assessment Scale (ADAS-COG), the Neuropsychological Battery, the Mini-Mental State Exam (MMSE), Clinical Dementia Rating Scale (CDR), the Global Deterioration Scale (GDS), ADCS- Activities of Daily Living Inventory (ADCS-ADL), a Pharmacoeconomics scale, and a Quality of Life scale. Compliance will be monitored through the measurement of alpha-tocopherol levels and pill counts at each visit.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 0
• Est. completion date: January 2004
• Est. primary completion date: January 2004
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 55 Years to 90 Years

Eligibility

Inclusion Criteria:

• Memory complaints and memory difficulties which are verified by an informant.

• Abnormal memory function documented by scoring below the education adjusted cutoff on the Logical Memory II subscale (Delayed Paragraph Recall) from the Wechsler Memory Scale - Revised (the maximum score is 25): a) less than or equal to 8 for 16 or more years of education, b) less than or equal to 4 for 8-15 years of education, c) less than or equal to 2 for 0-7 years of education.

• Mini-Mental Exam score between 24 and 30 (inclusive) (Exceptions may be made for subjects with less than 8 years of education at the discretion of the project director.).

• Clinical Dementia Rating = 0.5. Memory Box score must be at least 0.5.

• General cognition and functional performance sufficiently preserved such that a diagnosis of Alzheimer's disease cannot be made by the site physician at the time of the screening visit.

• No significant cerebrovascular disease: Modified Hachinski score of less than or equal to 4.

• Age between 55 and 90 (inclusive).

• Permitted medications stable for at least 1 month prior to screening. In particular:

a) Subjects may take stable doses of antidepressants lacking significant anticholinergic side effects (if they are not currently depressed and do not have a history of major depression within the past 2 years). b) Estrogen replacement therapy is permissible. c) Ginkgo biloba is permissible, but discouraged.

• Hamilton Depression rating scale score of less than or equal to 12 on the 17-item scale.

• Informant is available who has frequent contact with the subject (e.g. an average of 10 hours per week or more), agrees to monitor administration of study drug, observe for adverse events, and accompany the subject to all clinic visits for the duration of the protocol.

• CT or MRI scans within 12 months prior to screening without evidence of infection, infarction, or other focal lesions and without clinical symptoms suggestive of intervening neurological disease. A lacune in a non-critical brain area which is not believed to contribute to the subject's cognitive impairment is permissible.

• Adequate visual and auditory acuity to allow neuropsychological testing.

• Good general health with no additional diseases expected to interfere with the study.

• Normal B12, RPR, and Thyroid Function Tests or without any clinically significant abnormalities that would be expected to interfere with the study.

• ECG without clinically significant abnormalities that would be expected to interfere with the study.

• Subject is not pregnant, lactating, or of childbearing potential (i.e. women must be two years post-menopausal or surgically sterile).

• Agreement not to take other vitamin supplements (including Vitamin E), multivitamins, other than those provided by the study.

Exclusion Criteria:

• Any significant neurologic disease other than suspected incipient Alzheimer's disease, such as Parkinson's disease, multi-infarct dementia, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, seizure disorder, subdural hematoma, multiple sclerosis, or history of significant head trauma followed by persistent neurologic defaults or known structural brain abnormalities.

• Major depression or another major psychiatric disorder as described in DSM IV within the past 2 years.

• Psychotic features, agitation or behavioral problems within the last 3 months which could lead to difficulty complying with the protocol.

• History of alcohol or substance abuse or dependence within the past 2 years (DSM IV criteria).

• History of schizophrenia (DSM IV criteria).

• Any significant systemic illness or unstable medical condition which could lead to difficulty complying with the protocol including: a) History of systemic cancer within the last 5 years (non-metastatic skin cancers are acceptable). b) History of myocardial infarction within the past year or unstable or severe cardiovascular disease including angina or CHF with symptoms at rest. c) Clinically significant obstructive pulmonary disease or asthma. d) Clinically significant and unstable gastrointestinal disorder such as ulcer disease or a history of active or occult gastrointestinal bleeding within two years. e) Clinically significant laboratory test abnormalities on the battery of screening tests (hematology, prothrombin time, chemistry, urinalysis, ECG). f) Insulin-requiring diabetes or uncontrolled diabetes mellitus. g) Uncontrolled hypertension (systolic BP greater than 170 or diastolic greater than 100). h) History of clinically significant liver disease, coagulopathy, or vitamin K deficiency within the past 2 years.

• Medications a) Use of centrally active beta-blockers, narcotics, methyldopa and clonidine within 4 weeks prior to screening. b) Use of anti-Parkinsonian medications (e.g. Sinemet, amantadine, bromocriptine, pergolide and selegiline) within 2 months prior to screening. c) Use of neuroleptics or narcotic analgesics within 4 weeks prior to screening. d) Use of long-acting benzodiazepines or barbituates within 4 weeks prior to screening. e) Use of short-acting anxiolytics or sedative hypnotics more frequently than 2 times per week within 4 weeks prior to screening (note: sedative agents should not be used within 72 hours of screening).

f) Initiation or change in dose of an antidepressant lacking significant cholinergic side effects within the 4 weeks prior to screening (use of stable doses of antidepressants for at least 4 weeks prior to screening is acceptable). g) Use of systemic corticosteroids within 3 months prior to screening. h) Medications with significant cholinergic or anticholinergic side effects (e.g. pyridostigmine, tricyclic antidepressants, meclizine, and oxybutynin) within 4 weeks prior to screening. i) Use of anti-convulsants (e.g. Phenytoin, Phenobarbital, Carbamazepine) within 2 months prior to screening. j) Use of warfarin (Coumadin) within 4 weeks prior to screening.

• Vitamin Supplements a) Use of vitamin supplements other than standard multivitamin included as part of the treatment intervention used in this protocol within 2 weeks prior to screening.

• Any prior use of any FDA approved medications for the treatment of Alzheimer's disease (e.g. tacrine, donepezil, or other newly approved medications).

• Use of any investigational drugs within 30 days or 5 half-lives, whichever is longer, prior to screening.

• Subjects who, in the investigator's opinion, will not comply with study procedures.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double-Blind, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Alzheimer Disease
• Cognition Disorders
• Mild Cognitive Impairment

Intervention

Drug:
• Donepezil

• Vitamin E

Locations

Country	Name	City	State
Canada	University of Calgary	Calgary	Alberta
Canada	Fredericton Medical Clinic	Fredericton	New Brunswick
Canada	Geriatric Medicine Research Group	Halifax	Nova Scotia
Canada	St. Joseph's Health Center	London	Ontario
Canada	Jewish General Hospital Memory Clinic	Montreal	Quebec
Canada	Elizabeth Bruyere Centre	Ottawa	Ontario
Canada	Sunnybrook Health Science Center	Toronto	Ontario
Canada	University of British Columbia	Vancouver	British Columbia
Canada	McGill Centre for Studies in Aging	Verdun	Quebec
United States	Univ. of New Mexico	Albuquerque	New Mexico
United States	University of Michigan	Ann Arbor	Michigan
United States	Emory University	Atlanta	Georgia
United States	Augusta VA Medical Center	Augusta	Georgia
United States	Johns Hopkins University	Baltimore	Maryland
United States	Southwestern Vermont Medical Center	Bennington	Vermont
United States	Baumel-Eisner Neuromedical Institute, Boca Raton	Boca Raton	Florida
United States	Massachusetts General Hospital	Boston	Massachusetts
United States	Maimonides Medical Center	Brooklyn	New York
United States	Clinical Neuroscience Research Unit	Burlington	Vermont
United States	Northwestern University	Chicago	Illinois
United States	Rush Presbyterian St. Luke's Medical Center	Chicago	Illinois
United States	University Hospitals of Cleveland	Cleveland	Ohio
United States	Duke University Medical Center	Durham	North Carolina
United States	Baumel-Eisner Neuromedical Institute, Ft. Lauderdale	Ft. Lauderdale	Florida
United States	Baylor College of Medicine	Houston	Texas
United States	Indiana University	Indianapolis	Indiana
United States	UC Irvine Institute for Brain Aging and Dementia	Irvine	California
United States	Mayo Clinic Jacksonville	Jacksonville	Florida
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	Memory Disorders Institute	Lakehurst	New Jersey
United States	University of Nevada	Las Vegas	Nevada
United States	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire
United States	University of Kentucky	Lexington	Kentucky
United States	University of California, Los Angeles	Los Angeles	California
United States	University of Southern California	Los Angeles	California
United States	Marshfield Clinic	Marshfield	Wisconsin
United States	East Bay Institute	Martinez	California
United States	Baumel-Eisner Neuromedical Institute, MiamiBeach	Miami Beach	Florida
United States	Wein Center	Miami Beach	Florida
United States	University of Minnesota	Minneapolis	Minnesota
United States	Vanderbilt University Medical Center	Nashville	Tennessee
United States	Yale University	New Haven	Connecticut
United States	Columbia University	New York	New York
United States	Mount Sinai Medical Center	New York	New York
United States	NYU Medical Center	New York	New York
United States	Medical University of South Carolina	North Charleston	South Carolina
United States	Nathan S. Kline Institute for Psychiatric Research	Orangeburg	New York
United States	Brown University	Pawtucket	Rhode Island
United States	MCP Hahnemann	Philadelphia	Pennsylvania
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	Barrow Neurological Group	Phoenix	Arizona
United States	University of Pittsburgh	Pittsburgh	Pennsylvania
United States	University of Miami	Port Charlotte	Florida
United States	Oregon Health Sciences University	Portland	Oregon
United States	Princeton Biomedical Research, PA	Princeton	New Jersey
United States	Mayo Clinic	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	Sutter Institute for Medical Research	Sacramento	California
United States	Affiliated Research Instiute	San Diego	California
United States	University of California, San Diego	San Diego	California
United States	University of California, San Francisco	San Francisco	California
United States	University of Washington	Seattle	Washington
United States	Southern Illinois University	Springfield	Illinois
United States	Washington University	St. Louis	Missouri
United States	SUNY Stony Brook	Stony Brook	New York
United States	ClinSearch, Inc.	Summit	New Jersey
United States	University of South Florida	Tampa	Florida
United States	Princeton Biomedical - Toms River	Toms River	New Jersey
United States	University of Arizona	Tucson	Arizona
United States	Alzheimer's Research Corp.	West Long Branch	New Jersey
United States	Premiere Research Institute	West Palm Beach	Florida
United States	Burke Medical Research Institute	White Plains	New York

Sponsors (2)

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

Countries where clinical trial is conducted

United States,  Canada, 

References & Publications (4)

Grundman M, Petersen RC, Ferris SH, Thomas RG, Aisen PS, Bennett DA, Foster NL, Jack CR Jr, Galasko DR, Doody R, Kaye J, Sano M, Mohs R, Gauthier S, Kim HT, Jin S, Schultz AN, Schafer K, Mulnard R, van Dyck CH, Mintzer J, Zamrini EY, Cahn-Weiner D, Thal L — View Citation

Petersen RC, Smith GE, Waring SC, Ivnik RJ, Kokmen E, Tangelos EG. Aging, memory, and mild cognitive impairment. Int Psychogeriatr. 1997;9 Suppl 1:65-9. — View Citation

Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Donepezil Study Group. Neurology. 1998 Jan;50(1):136-45. — View Citation

Rubin EH, Morris JC, Grant EA, Vendegna T. Very mild senile dementia of the Alzheimer type. I. Clinical assessment. Arch Neurol. 1989 Apr;46(4):379-82. — View Citation

External Links

•   More information about the study from the Alzheimer's Disease Cooperative Study site at the University of California at San Diego.