Clinical trial NCT00056225: VITAL - VITamins to Slow ALzheimer's Disease (Homocysteine Study)
Official title: High Dose Supplements to Reduce Homocysteine and Slow the Rate of Cognitive Decline in Alzheimer's Disease (Vitamins to Slow Alzheimer's - VITAL)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Alzheimer's Disease
Keywords: homocysteine
Lead sponsor: National Institute on Aging (NIA)
Sponsor class: NIH
Collaborators: name: Alzheimer's Disease Cooperative Study (ADCS)
First posted: 2003-03-10
Enrollment: 340
Sex: ALL
Minimum age (years): 55
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine whether reduction of homocysteine levels with high-dose folate (folic acid), B6, and B12 supplementation will slow the rate of cognitive decline in persons with Alzheimer's disease.

Detailed description: Blood levels of homocysteine are elevated in Alzheimer's disease (AD), and hyperhomocysteinemia may contribute to disease pathophysiology by vascular and direct neurotoxic mechanisms. Homocysteine levels can be reduced by administration of high dose supplements of folate (folic acid) and vitamins B6 and B12. The proposed study is for a multicenter, randomized, controlled clinical trial to determine whether reduction of homocysteine levels with high-dose folate/B6/B12 supplementation will slow the rate of cognitive decline in subjects with AD.

This will be a parallel design study, including two groups of unequal size: 60% of subjects will receive daily high-dose supplements (folate 5mg, vitamin B6 25mg, vitamin B12 1 mg), and 40% will receive an identical looking placebo. The duration of treatment will be 18 months, and participants will make eight visits to the assigned study site for safety and efficacy assessments of the medications. The primary outcome measure will be the longitudinal decline in the ADAScog, a psychometric instrument that evaluates memory, attention, reasoning, language, orientation and praxis (Rosen et al 1984). To power the trial to detect a 25% reduction in rate of ADAScog decline (80% power, alpha=0.05, drop-out estimate 20%, drop-in estimate 10%), it will enroll a total of 400 participants. Persons of minority racial groups are also being recruited, although all participants must be able to speak either English or Spanish.

Eligibility criteria: Inclusion Criteria:

* National Institute of Neurological Disorders and Stroke (NINDS)/Alzheimer's Disease and Related Disorders Association (ADRDA) criteria for probable Alzheimer's disease.
* Mini-Mental Status Examination (MMSE) score between 14 and 26, inclusive
* Stable medical condition for 3 months
* Stable medications for 4 weeks prior to the screening visit
* Physically acceptable for this study as confirmed by medical history, physical exam, neurologic exam and clinical laboratory tests
* Supervision available for administration of study medications
* Study partner to accompany subject to all scheduled visits
* Fluent in English or Spanish
* Modified Hachinski equal to or less than 4 CT or magnetic resonance imaging (MRI) since onset of memory impairment demonstrating absence of clinically significant focal lesion
* Able to complete baseline assessments
* 6 years of education or work history sufficient to exclude mental retardation
* Able to ingest oral medication

Exclusion Criteria:

* B12 or folate deficiency
* Renal insufficiency (serum creatinine \>=2.0)
* Active neoplastic disease (skin tumors other than melanoma are not exclusionary; patients with stable prostate cancer may be included at the discretion of the project director)
* Use of another investigational agent within 2 months
* History of clinically significant stroke
* Current evidence or history in the past 2 years of epilepsy, focal brain lesion, head injury with loss of consciousness and/or immediate confusion after the injury, or DSM-IV criteria for any major psychiatric disorder including psychosis, major depression, bipolar disorder, alcohol or substance abuse
* Blindness, deafness, language difficulties or any other disability which may prevent the subject from participating or cooperating in the protocol

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama
state: Alabama
city: Scottsdale
country: United States
facility: Mayo Clinic, Scottsdale
state: Arizona
city: Sun City
country: United States
facility: Sun Health Research Institute
state: Arizona
city: Tucson
country: United States
facility: University of Arizona, Arizona Health Sciences Center
state: Arizona
city: Irvine
country: United States
facility: University of California, Irvine, Institute for Brain Aging and Dementia
state: California
city: La Jolla
country: United States
facility: University of California, San Diego
state: California
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Los Angeles
country: United States
facility: University of California, Los Angeles
state: California
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: Sacramento
country: United States
facility: University of California, Davis
state: California
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Washington, DC
country: United States
facility: Georgetown University
state: District of Columbia
city: Washington, DC
country: United States
facility: Howard University
state: District of Columbia
city: Jacksonville
country: United States
facility: Mayo Clinic
state: Florida
city: Tampa
country: United States
facility: University of South Florida
state: Florida
city: Atlanta
country: United States
facility: Emory University
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: Rush Presbyterian/St. Lukes Medical Center, Rush Alzheimer's Disease Center
state: Illinois
city: Springfield
country: United States
facility: Southern Illinois University
state: Illinois
city: Indianapolis
country: United States
facility: Indiana University
state: Indiana
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
city: Boston
country: United States
facility: Boston University School of Medicine
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Las Vegas
country: United States
facility: University of Nevada School of Medicine, Center for Cognitive Aging
state: Nevada
city: Kenilworth
country: United States
facility: ClinSearch
state: New Jersey
city: New York
country: United States
facility: New York University Medical Center
state: New York
city: New York
country: United States
facility: Mt. Sinai School of Medicine
state: New York
city: New York
country: United States
facility: Columbia University
state: New York
city: Rochester
country: United States
facility: University of Rochester Medical Center, Alzheimer's Disease Center
state: New York
city: Cleveland
country: United States
facility: University Memory and Aging Center, Case Western Reserve University/University Hospitals of Cleveland
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University, Oregon Aging and Alzheimer's Disease Center
state: Oregon
city: Philadelphia
country: United States
facility: University of Pennsylvania
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh
state: Pennsylvania
city: Pawtucket
country: United States
facility: Memorial Hospital of Rhode Island, Alzheimer's Disease and Memory Disorder Clinic
state: Rhode Island
city: North Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Dallas
country: United States
facility: University of Texas, Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Seattle
country: United States
facility: University of Washington
state: Washington
Study officials:
affiliation: Georgetown University, Department of Neurology
name: Paul Aisen, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, Wilson PW, Wolf PA. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med. 2002 Feb 14;346(7):476-83. doi: 10.1056/NEJMoa011613.
citation: Aisen PS, Egelko S, Andrews H, Diaz-Arrastia R, Weiner M, DeCarli C, Jagust W, Miller JW, Green R, Bell K, Sano M. A pilot study of vitamins to lower plasma homocysteine levels in Alzheimer disease. Am J Geriatr Psychiatry. 2003 Mar-Apr;11(2):246-9.
citation: Kruman II, Kumaravel TS, Lohani A, Pedersen WA, Cutler RG, Kruman Y, Haughey N, Lee J, Evans M, Mattson MP. Folic acid deficiency and homocysteine impair DNA repair in hippocampal neurons and sensitize them to amyloid toxicity in experimental models of Alzheimer's disease. J Neurosci. 2002 Mar 1;22(5):1752-62. doi: 10.1523/JNEUROSCI.22-05-01752.2002.
citation: Aisen PS, Schneider LS, Sano M, Diaz-Arrastia R, van Dyck CH, Weiner MF, Bottiglieri T, Jin S, Stokes KT, Thomas RG, Thal LJ; Alzheimer Disease Cooperative Study. High-dose B vitamin supplementation and cognitive decline in Alzheimer disease: a randomized controlled trial. JAMA. 2008 Oct 15;300(15):1774-83. doi: 10.1001/jama.300.15.1774.