Multicenter Vitamin E Trial in Aging Persons With Down Syndrome

Alzheimer disease (AD) continues to be the most serious health problem faced by aging persons with Down syndrome. AD is also a major public health concern in the aging general population. With increasing life expectancy there will be a dramatic increase in the prevalence of AD cases, which will pose a significant increased burden on the health care system and individual providers of care. Persons with Down syndrome are uniquely vulnerable to a form of Alzheimer disease indistinguishable from the sporadic variety that affects aging individuals from the general population. Oxidative damage is a highly plausible mechanism in the pathogenesis of this disease due to the overexpression of superoxide dismutase, associated with a gene located on chromosome 21, which is present in triplicate in the Down syndrome genotype. For the last six years, we have been conducting a clinical trial to determine the safety and efficacy of the anti-oxidant Vitamin E in slowing the cognitive and functional decline associated with the dementia of AD among individuals with DS. The study is a randomized, double-blind trial, stratified in a two-arm parallel design. The subjects are medically stable individuals who are 50 years of age or older at the time of screening. Among those randomized to the treatment arm, vitamin E is taken in the form of 1000 IU capsules for 36 months. Each subject is evaluated every 6 months for 3 years. The primary outcome is is the Brief Praxis Test (BPT), which is well-suited to quantifying cognitive decline in this population. The target enrollment of 350 persons is estimated to be sufficient to provide adequate statistical power to detect a slowing by one-third in the rate of cognitive decline with vitamin E treatment. The Data and Safety Monitoring Board (DSMB) for this trial includes 4 physicians, and a statistician with expertise in clinical trials. Each DSMB member receives a report on each serious adverse event (SAE) on a flow basis, and statistically summaries of unblinded safety data--including deaths, adverse events and vital signs--prior to each meeting of the DSMB. The most recent DSMB meeting took place on February 23,2010. The timeline for study completion is: recruitment of the study sample (N=350) was completed on 12/31/2008; the final 36-month evaluation will take place in 04/2010; statistical analysis and final report of results is expected to be completed by 12/31/2010.

Inclusion criteria

• presence of clinically determined Down syndrome (karyotypes optional)
• appropriately signed and witnessed consent form
• age of 50 years or older at the start of the protocol
• medically stable
• medications stable more than 1 month
• involvement/cooperation of informant/caregiver

Exclusion criteria

• medical/neurological condition (other than Alzheimer disease) associated with dementia
• inability to adequately perform the Brief Praxis Test, as demonstrated by a score <20
• in the presence of dementia, modified Hachinski score > 4 at Screening Visit
• major depression within 3 months
• history of coagulopathy (inherited or acquired)
• current use of anticoagulants
• use of experimental medications within 2 months
• regular use of vitamin E greater than 50 units per day during the previous 6 months
• allergy to vitamin E