VITAL - VITamins to Slow ALzheimer's Disease (Homocysteine Study)

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.

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