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The Age-Related Eye Disease Study (AREDS) was initially conceived as a long-term multicenter, prospective study of the clinical course of age-related macular degeneration (AMD) and age-related cataract. Data on progression rates and risk factors from the study will increase understanding of the clinical course of both conditions, generate hypotheses about etiology, and aid in the design of clinical trials of potential interventions. In addition to collecting natural history data, AREDS includes a clinical trial of high-dose vitamin and mineral supplements for AMD and a clinical trial of high-dose vitamin supplements for cataract. The clinical trials were initiated largely because of the widespread public use in the United States of commercially available pharmacologic doses of vitamins and minerals to treat these two eye conditions and the absence of definitive studies on the safety and efficacy of their use. Important design issues for the clinical trials include: defining cataract and AMD, estimating event rates, determining the type and dosage of vitamins and minerals to be tested for each condition, and identifying the parameters necessary for monitoring safety and efficacy. This paper describes the AREDS design, including the study rationale and operational structure, and the approach adopted to combine, for two diseases, clinical trials with a natural history study. Control Clin Trials 1999;20:573–600

Experimental and observational data suggest that micronutrients with antioxidant capabilities may retard the development of age-related cataract.To evaluate the effect of a high-dose antioxidant formulation on the development and progression of age-related lens opacities and visual acuity loss.The 11-center Age-Related Eye Disease Study (AREDS) was a double-masked clinical trial. Participants were randomly assigned to receive daily oral tablets containing either antioxidants (vitamin C, 500 mg; vitamin E, 400 IU; and beta carotene, 15 mg) or no antioxidants. Participants with more than a few small drusen were also randomly assigned to receive tablets with or without zinc (80 mg of zinc as zinc oxide) and copper (2 mg of copper as cupric oxide) as part of the age-related macular degeneration trial. Baseline and annual (starting at year 2) lens photographs were graded at a reading center for the severity of lens opacities using the AREDS cataract grading scale.Primary outcomes were (1) an increase from baseline in nuclear, cortical, or posterior subcapsular opacity grades or cataract surgery, and (2) at least moderate visual acuity loss from baseline (/=15 letters). Primary analyses used repeated-measures logistic regression with a statistical significance level of P =.01. Serum level measurements, medical histories, and mortality rates were used for safety monitoring.Of 4757 participants enrolled, 4629 who were aged from 55 to 80 years had at least 1 natural lens present and were followed up for an average of 6.3 years. No statistically significant effect of the antioxidant formulation was seen on the development or progression of age-related lens opacities (odds ratio = 0.97, P =.55). There was also no statistically significant effect of treatment in reducing the risk of progression for any of the 3 lens opacity types or for cataract surgery. For the 1117 participants with no age-related macular degeneration at baseline, no statistically significant difference was noted between treatment groups for at least moderate visual acuity loss. No statistically significant serious adverse effect was associated with treatment.Use of a high-dose formulation of vitamin C, vitamin E, and beta carotene in a relatively well-nourished older adult cohort had no apparent effect on the 7-year risk of development or progression of age-related lens opacities or visual acuity loss.

Observational and experimental data suggest that antioxidant and/or zinc supplements may delay progression of age-related macular degeneration (AMD) and vision loss.To evaluate the effect of high-dose vitamins C and E, beta carotene, and zinc supplements on AMD progression and visual acuity.The Age-Related Eye Disease Study, an 11-center double-masked clinical trial, enrolled participants in an AMD trial if they had extensive small drusen, intermediate drusen, large drusen, noncentral geographic atrophy, or pigment abnormalities in 1 or both eyes, or advanced AMD or vision loss due to AMD in 1 eye. At least 1 eye had best-corrected visual acuity of 20/32 or better. Participants were randomly assigned to receive daily oral tablets containing: (1) antioxidants (vitamin C, 500 mg; vitamin E, 400 IU; and beta carotene, 15 mg); (2) zinc, 80 mg, as zinc oxide and copper, 2 mg, as cupric oxide; (3) antioxidants plus zinc; or (4) placebo.(1) Photographic assessment of progression to or treatment for advanced AMD and (2) at least moderate visual acuity loss from baseline (or =15 letters). Primary analyses used repeated-measures logistic regression with a significance level of.01, unadjusted for covariates. Serum level measurements, medical histories, and mortality rates were used for safety monitoring.Average follow-up of the 3640 enrolled study participants, aged 55-80 years, was 6.3 years, with 2.4% lost to follow-up. Comparison with placebo demonstrated a statistically significant odds reduction for the development of advanced AMD with antioxidants plus zinc (odds ratio [OR], 0.72; 99% confidence interval [CI], 0.52-0.98). The ORs for zinc alone and antioxidants alone are 0.75 (99% CI, 0.55-1.03) and 0.80 (99% CI, 0.59-1.09), respectively. Participants with extensive small drusen, nonextensive intermediate size drusen, or pigment abnormalities had only a 1.3% 5-year probability of progression to advanced AMD. Odds reduction estimates increased when these 1063 participants were excluded (antioxidants plus zinc: OR, 0.66; 99% CI, 0.47-0.91; zinc: OR, 0.71; 99% CI, 0.52-0.99; antioxidants: OR, 0.76; 99% CI, 0.55-1.05). Both zinc and antioxidants plus zinc significantly reduced the odds of developing advanced AMD in this higher-risk group. The only statistically significant reduction in rates of at least moderate visual acuity loss occurred in persons assigned to receive antioxidants plus zinc (OR, 0.73; 99% CI, 0.54-0.99). No statistically significant serious adverse effect was associated with any of the formulations.Persons older than 55 years should have dilated eye examinations to determine their risk of developing advanced AMD. Those with extensive intermediate size drusen, at least 1 large druse, noncentral geographic atrophy in 1 or both eyes, or advanced AMD or vision loss due to AMD in 1 eye, and without contraindications such as smoking, should consider taking a supplement of antioxidants plus zinc such as that used in this study.