Age-Related Eye Disease Study 2 (AREDS2)

• To study the effects of high supplemental doses of dietary xanthophylls (lutein and zeaxanthin)and omega-3 long-chain polyunsaturated fatty acids (LCPUFAs)(DHA and EPA)on the development of advanced AMD.
• To study the effects of these supplements on cataract and moderate vision loss.
• To study the effects of eliminating beta-carotene from the original AREDS formulation on the development and progression of AMD.
• To study the effects of reducing zinc in the original AREDS formulation on the development and progression of AMD.
• To contribute data for validation of the photographic AMD scales developed from the Age-Related Eye Disease Study.

The Retinal Diseases Panel (RDP) of the National Plan for Eye and Vision Research identified characterization of environmental effects on AMD etiology and the development of new AMD treatments as two of the four key programmatic goals for AMD research.

The RDP stated: "The leading cause of visual loss among elderly persons is AMD, which has an increasingly important social and economic impact in the United States. As the size of the elderly population increases in this country, AMD will become a more prevalent cause of blindness than both diabetic retinopathy and glaucoma combined. Although laser treatment has been shown to reduce the risk of extensive macular scarring from the "wet" or neovascular form of the disease, there are currently no effective treatments for the vast majority of patients with AMD."

Nutrient-based preventive interventions for AMD development and progression were examined in The Age-Related Eye Disease Study (AREDS). AREDS includes a completed randomized clinical trial designed to evaluate the effect of pharmacologic doses of zinc and/or an antioxidant formulation (vitamin C, vitamin E, and beta-carotene) on the rate of progression to advanced AMD and on visual acuity outcomes. The use of the combination of antioxidants and zinc reduced the likelihood of developing advanced AMD by approximately 25% among participants who had at least a moderate risk of developing AMD. Overall risk of moderate vision loss (> 15 letters on the ETDRS chart) was reduced by 19% at 5 years.

The evidence base suggests that lutein and zeaxanthin and omega-3 LCPUFAs may act as modifiable factors capable of modulating processes implicated in AMD pathogenesis and progression. Intake of these compounds may also show merit as a well-tolerated preventive intervention. Biochemical and biophysical properties of these compounds demonstrate a capacity to modulate factors and processes that activate and are activated by exposures associated with aging. These exposures include developmental changes associated with aging, chronic light exposure, alterations in energy metabolism, and cellular signaling pathways.

An inverse relationship of dietary omega-3 LCPUFA intake with advanced AMD has been reported in all studies examining the issue. For prevalent disease, the magnitude of odds ratios for highest versus lowest omega-3 LCPUFA intake ranged from 0.4 to 0.9. Among these studies, the one containing the largest number of subjects with neovascular AMD yielded a significantly lower likelihood of having the disease among participants reporting the highest consumption of omega-3 LCPUFAs. Five of six studies examining the association of dietary lutein/zeaxanthin intake with advanced AMD have yielded inverse relationships that are statistically significant. The magnitude of odd ratios in these studies ranged from 0.1 to 0.7. Both sets of findings are germane in guiding applied clinical research on prevention and treatment of retinal disease, since: (1) tissue concentrations of DHA (an omega-3 LCPUFA), lutein, and zeaxanthin per unit area are substantially higher in the retina than elsewhere in the body; and (2) retinal tissue status of these compounds is modifiable and dependent upon intake.

There is a compelling need to implement a clinical trial on nutrients that are both concentrated in the retina and implicated in modulation of pathogenic factors and processes of AMD.

AREDS2 is a multi-center randomized trial of 4,000 participants designed to assess the effects of oral supplementation of high doses of macular xanthophylls (lutein and zeaxanthin) and omega-3 LCPUFAs (DHA and EPA) on the progression to advanced AMD. The study will enroll participants aged 50 to 85 years, with sufficiently clear ocular media to allow accurate assessment of AMD from fundus photographs.Participants should have either bilateral large drusen (>125 microns) or large drusen in one eye and advanced AMD in the fellow eye. All participants will be offered additional treatment with the original AREDS formulation (now considered standard of care) and 3 variations of this formula. These are: (1) no beta-carotene; (2) lower amounts of zinc; and (3) no beta-carotene and lower amounts of zinc. Eligible participants will be followed for a minimum of five years.

Men and women between the ages of 50 and 85 years whose macular status ranges from large drusen in both eyes or large drusen in one eye and advanced AMD (neovascular AMD or geographic atrophy) in the fellow eye are eligible for the study provided that their ocular media are clear enough to allow good fundus photography.

No longer recruiting. Comments: Enrollment began in the summer of 2006 and concluded June 30, 2008. All AREDS2 clinical centers are located in the United States.

Ongoing. Comments: AREDS2 is in the follow-up phase with follow-up participant visits scheduled to occur through December 2012.

None at this time.