The Age-Related Eye Disease Study: A Clinical Trial of Zinc and Antioxidants—Age-Related Eye Disease Study Report No. 2^,

Abstract

The Age-Related Eye Disease Study includes a clinical trial of high dose antioxidant and zinc supplements for age-related macular degeneration and a clinical trial of high dose antioxidants for cataract. The clinical trials were initiated largely because of the widespread public use in the United States of commercially available pharmacological 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. This report focuses on the clinical trial of zinc and the possibility that this elderly study cohort, who were randomly assigned in a factorial design to receive zinc, antioxidants and placebo, could be assessed for zinc effects other than those currently addressed by the trial.

The common causes of blindness in the United States are associated with increasing age. Because older people compose the fastest growing segment of the U.S. population, age-related eye disorders will become increasingly prevalent in the coming decades. The Age-Related Eye Disease Study (AREDS)⁴ was designed to assess two of these disorders: age-related macular degeneration (AMD) and cataract. The study will provide descriptive data on the clinical course of the conditions, attempt to identify factors that influence their development and progression and evaluate the potential efficacy of high dose vitamins and zinc in arresting or retarding their progression. Details concerning the study design are available elsewhere (The Age-Related Eye Disease Study Research Group 2000), and a portion of the description of the study design is republished in part herein. The main outcome variable for the randomized comparison of zinc and placebo is the progression of AMD. Age-related macular degeneration is a collection of clinically recognizable ocular findings and a leading cause of registered blindness in both England (Sorsby 1966) and the United States (Kahn and Moorhead 1973, National Advisory Eye Council 1984). Clinical findings associated with AMD include drusen, retinal pigment epithelial (RPE) abnormalities, geographic atrophy, RPE detachment, choroidal neovascularization (CNV) and its consequences (e.g., serous sensory retinal detachment, often accompanied by hard exudates and subretinal hemorrhages) and disciform scar. The prevalence of ophthalmoscopically or photographically identifiable drusen increases with age, especially after the sixth decade. Eyes without drusen are generally not considered to have AMD. Larger and more extensive drusen seem to be associated with an increased risk of central visual acuity loss. This loss can come from the development of CNV, the neovascular form of the disease that causes most of the severe vision loss from AMD, or from the other non-neovascular lesions of AMD listed above, of which the most important is geographic atrophy.

There is no known effective prophylaxis for AMD, and there is no effective treatment for most cases of AMD. Laser photocoagulation has been documented to be beneficial in a small proportion of patients with well-defined CNV (Macular Photocoagulation Study Group 1991, 1990b, 1993), but recurrence of CNV is common and often results in further vision loss (Macular Photocoagulation Study Group 1986, 1990a). There is no proven treatment for persons with the non-neovascular form of the disease. Zinc supplementation was assessed in a small clinical trial because the RPE, the tissue under the retina that nourishes the rods and cones, normally has a particularly high zinc content. It was hypothesized that poor zinc intake in elderly persons might result in zinc deficiency and the loss of zinc-dependent coenzymes in the RPE, resulting in development or worsening of AMD. Results from this randomized clinical trial suggested that pharmacological doses of zinc might provide some protection against vision loss from this non-neovascular form of the disease. (Newsome et al. 1988) In addition, before the start of AREDS, several epidemiological studies published data suggesting a possible role of antioxidants in reducing the risk of cancer, cardiovascular disease and eye disease. (both AMD and cataract) (Buring and Hennekens 1995, Sperduto et al. 1990, Stampfer et al. 1993) With limited treatment options and no prophylaxis available for AMD, the findings from these studies led to the widespread use of vitamin and mineral formulations containing antioxidants and zinc. This increased use occurred despite an admonition by the authors of the zinc trial that, “it is definitely premature to recommend widespread use of zinc” (Newsome et al. 1988). Extensive marketing of high dose commercially available preparations of antioxidant vitamins and zinc increased the visibility and availability of these products and contributed to their widespread use. An objective assessment of the efficacy and safety of nutritional intervention for preventing the development and progression of these conditions was judged to be needed. Because both AMD and cataract progress slowly, it appeared that a large and prolonged trial would be necessary to test the effect of nutritional supplementation. Details of the rationale for the eventual study sample size have been published elsewhere.³

Age-Related Eye Disease Study

The AREDS, which is sponsored by the National Eye Institute (NEI) of the National Institutes of Health, is a multicenter prospective study of 4757 persons aged 55–80 y that was designed to assess the clinical course, prognosis and risk factors of both AMD and cataract. The first participant was enrolled in November 1992, and recruitment of non–African Americans was essentially complete in 3 y, with the final non–African American participant enrolled in July 1996 and the final African American participant enrolled in January 1998. Participants are now being followed at 6-mo intervals. The clinical trial is planned for completion in April 2001 with followup of participants currently planned until at least 2006.

When the planning for AREDS began, pharmaceutical companies were marketing several formulations of the vitamins and minerals of interest. The formulation chosen for the AREDS clinical trials was based on recommendations from expert nutritionists, ophthalmologists and biochemists who reviewed basic science, clinical trial and epidemiological data at a series of meetings sponsored by the NEI. Two carotenoids, lutein and zeaxanthin, which are known to be present in the central retina, were strong candidates for inclusion in the AREDS formulation, but they were not commercially available when AREDS started. Beta-carotene, a carotenoid with systemic antioxidant properties, was chosen because the manufacturers of ophthalmic nutritional supplements were promoting its effectiveness, clinical trials of heart disease and cancer were studying it and it was commercially available. In addition, it was decided to include pharmacological doses of the antioxidant vitamins C and E. This vitamin/antioxidant formulation was expected to possibly affect the progression of both cataract and AMD.

Zinc had been reported to be beneficial for AMD, but there was no evidence of an effect on lens opacities. It was decided to assess whether zinc, alone or in combination with the vitamin/antioxidant formulation, could slow the progression of AMD. Formulations that included zinc also had copper added to offset potential zinc-induced copper deficiency anemia. Study participants who were thought to be at risk of vision loss from AMD on the basis of the presence of drusen or RPE changes were part of a factorial design that evaluated both the zinc formulation and the vitamin/antioxidant formulation. Study participants without these AMD lesions were not assigned to receive zinc because of possible toxicity and no evidence of potential ocular benefit. They were assigned to receive either the vitamin/antioxidant formulation or placebo. The 3640 participants at risk of AMD progression were randomly assigned in a factorial design to receive zinc alone, antioxidants alone, zinc and antioxidants, or placebo (Fig. 1). The exact doses of the ingredients in these formulations are currently proprietary. The daily dosage of zinc oxide in the formulation is ≈5 times the current recommended daily allowance (RDA). The clinical trials are double masked in that neither the AREDS participant nor the study investigators know the participant’s treatment assignment.

FIGURE 1.

Factorial design of the Age-Related Eye Disease Study.

Study population

Eligible participants were 55–80 y old at enrollment and had to be free of any illness or condition that would make long-term followup or compliance with study medications unlikely or difficult. On the basis of fundus photographs graded at a central reading center, best-corrected visual acuity measured with a standard protocol and ophthalmological evaluations, participants were enrolled in one of several AMD categories. Details of the retinal classification of participants in the study are provided elsewhere.³

An important design feature of AREDS is the inclusion of participants who, at the time of screening, were current users of dietary supplements containing nutrients that are also contained in the study medication. Fifty-five percent of enrolled AREDS participants were supplementing their diet with at least one AREDS ingredient at the time of screening, and half of these participants were taking RDA dosages rather than the pharmacological dosages of the study medication. To accommodate such persons and to standardize the use of nonstudy supplements, a daily dose of a widely available multivitamin tablet (Centrum) is provided to each participant who wishes to take or continue taking a multivitamin. Approximately 60% of AREDS participants chose to take Centrum. Persons in the “placebo” group who take Centrum will have a dietary intake of vitamins C and E, beta-carotene and zinc plus an additional RDA amount that is contained in Centrum. Similarly, persons in the “active” treatment groups will be increasing their intake by an RDA amount of the study vitamins and minerals if they take Centrum. The statistical power of the study to test its primary hypothesis regarding pharmacological doses of these nutrients may be reduced to the extent that prior use or the continued use of RDA dosages of these nutrients affects the outcomes of interest. However, by including such persons in the study population, the AREDS population more closely resembles the supplementation habits of the general population in this age group.

Study outcomes

The main study outcome variables for the zinc trial are change in visual acuity and change in AMD. An eye is considered as having progressed to advanced AMD when vision-threatening lesions have developed. These lesions include signs of geographic atrophy involving the center of the macula or signs of CNV (defined as the presence beneath the RPE or sensory retina of fluid, blood or fibrovascular or fibrous tissue). Centrally graded fundus photographs are used to assess the progression of retinal disease. Four comparisons of the effect of treatment on primary outcomes will include the following: (1) progression to advanced AMD in a comparison of the antioxidant and no-antioxidant groups, (2) progression to advanced AMD in a comparison of the zinc and no-zinc groups, (3) a 15-letter decrease in visual acuity score in a comparison of the antioxidant and no-antioxidant groups and (4) a 15-letter decrease in visual acuity score in a comparison of the zinc and no-zinc groups.

If there is evidence of a statistically significant interaction between zinc and antioxidants, then analyses will be restricted to outcomes within each of the four treatment cells.

Data collection

Baseline data and data on potential risk factors for the development and progression of AMD were obtained by examination and interview at the time of randomization. These data, which were collected for all participants, included comorbidity (e.g., history of malignancy, cardiovascular disease), current and past medication and hormone use and an assessment of nutrient intake using a modified Block Food Frequency Questionnaire, which assessed dietary intake during the year before randomization. Then 24-h dietary recall interviews were conducted by telephone by workers at the nutrition center on a sample of 197 participants from the three clinical centers at which serum samples are collected (see later). An interview designed to calculate mean annual effective ocular sunlight exposure (Carson et al. 1996, Rosenthal et al. 1991) was implemented in 1996. Starting in 1998, study participants were asked to donate blood samples for DNA isolation and the creation of immortalized cell lines to be used in current and future studies of genetic markers for AMD and cataract.

The 25-item NEI Visual Function Questionnaire with an appendix of 11 additional questions (NEI VFQ-25, 1996) was incorporated in 1997 to measure the effect of vision on daily living activities. The questionnaire is administered to all participants at the 5-y followup visit and on two occasions at a 3-y interval. Best-corrected visual acuity is measured at randomization and at yearly intervals using a standard protocol adapted from the Early Treatment of Diabetic Retinopathy Study (Ferris et al. 1982). The AREDS researchers made minor modifications to the Early Treatment of Diabetic Retinopathy Study protocol, including the use of a rear-lighted instead of a front-lighted box (Ferris and Sperduto 1982). Standard lens and fundus photographs are taken at baseline and at yearly follow-up visits, beginning 2 y after enrollment.

Possible adverse experiences are monitored in all participants through interview data (e.g., fatigue, gastric complications, skin color change) every 6 mo. Hematocrit levels are measured annually for all participants to assess possible copper deficiency anemia, which may be associated with the administration of zinc. At 3 of the 11 AREDS clinical centers, additional serum samples were collected before randomization, and they are collected at each annual visit after a 12-h limited fast and a 4-h complete fast. Tests on these samples include measurement of serum levels of zinc, copper, cholesterol, vitamins E and C and carotenoids, including lutein/zeaxanthin and alpha-carotene. Lutein/zeaxanthin and alpha-carotene are measured because pharmacological doses of beta-carotene may affect the serum levels of other carotenoids. HDL, total cholesterol and triglycerides are also measured because of reports that zinc use may affect serum lipid levels (Black et al. 1988, Freeland-Graves et al. 1982, Goodwin et al. 1985, Hooper et al. 1980). Hospitalization data, including discharge summaries, are obtained. Staff at the Coordinating Center use International Classification of Disease–Ninth Revision coding to assign the causes of hospitalization. Self-reported adverse experiences are recorded if the participant or the participant’s health care provider reports a possible relationship with the study medication. Deaths are reported to the Coordinating Center within 24 h after the clinical center is notified. Death certificates are obtained and causes of death are assigned by Coordinating Center staff according to International Classification of Disease–Ninth Revision codes.

Discussion

The AREDS will provide information on two important diseases that affect an aging population. The study is collecting data on the factors that influence the development and progression of lens opacities and AMD in persons supplementing and not supplementing with pharmacological doses of antioxidants and zinc. Flexibility in multivitamin use while controlling for the type and or dosage of vitamin, by providing Centrum to those who wish to supplement, may increase adherence to the assigned intervention. In addition, standardization of supplement intake increases our ability to estimate and describe the vitamin and mineral intake in the AREDS population. This large cohort of elderly persons, randomly assigned in a factorial design to receive zinc and antioxidants, will be followed on treatment until 2001, for an average of 8 y. After the trial is complete, follow-up of the cohort will continue until at least 2006. These data will provide the opportunity for rigorous comparisons of the effects of long-term supplementation with pharmacological doses of zinc on macular degeneration, serum zinc levels, hematocrit and HDL, total cholesterol and triglyceride levels. Because both the physician and the patient are masked as to whether the assigned intervention contains zinc or placebo, the incidence of physician- and patient-reported adverse events (e.g., gastrointestinal disorders, fatigue/weakness) can also be compared between the two groups. These clinical trial data can provide additional information on the risks and benefits of both zinc and antioxidants. Persons interested in ancillary studies using this cohort are encouraged to contact the AREDS Coordinating Center regarding procedures for application.