Elsevier

Controlled Clinical Trials

Volume 20, Issue 6, December 1999, Pages 573-600
Controlled Clinical Trials

Design paper
The Age-Related Eye Disease Study (AREDS): Design Implications AREDS Report No. 1

https://doi.org/10.1016/S0197-2456(99)00031-8Get rights and content

Abstract

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

Section snippets

Age-related macular degeneration

Age-related macular degeneration (AMD) a collection of clinically recognizable ocular findings, is a leading cause of registered blindness in both England [1] and the United States 2, 3. Clinical findings associated with AMD include drusen, retinal pigment epithelial (RPE) abnormalities, geographic atrophy, RPE detachment, choroidal neovascularization and its consequences (e.g., serous sensory retinal detachment, often accompanied by hard exudates and subretinal hemorrhages), and disciform

Cataract

Cataract is the term used for opacities in the normally transparent lens. These opacities can interfere with the formation of a sharp image on the retina. Age-related cataract, by far the most common type, is often categorized as nuclear, cortical, or posterior subcapsular in location. Nuclear and posterior subcapsular cataracts, which commonly affect the central visual axis, are the types most frequently associated with a need for cataract surgery. Cataract is a major public health problem

Treatment of cataract and age-related macular degeneration

There is no known effective preventive treatment for cataract or AMD. Surgical treatment for cataract is highly effective, although it entails some risk and is costly. 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 choroidal neovascularization (CNV) 6, 7, 8, but recurrence of CNV is common and often results in further vision loss 9, 10. There is no proven treatment for persons

Age-related eye disease study

The Age-Related Eye Disease Study, a long-term multicenter, prospective study of 4757 persons age 55 to 80 years is designed to assess the clinical course, prognosis, and risk factors of both AMD and cataract. The National Eye Institute (NEI) of the National Institutes of Health (NIH) provides primary support for the study through contract intramural research funds, with additional support from Storz Ophthalmic Pharmaceuticals, currently owned by Bausch and Lomb Pharmaceuticals. Staff of the

Study of clinical course and prognosis

The study is designed to assess the clinical course of, and risk factors for, the development and progression of cataract and AMD by collecting data on possible risk factors, measuring changes in visual acuity, photographically documenting changes in macula or lens status, and assessing self-reported visual function. Studies prior to the initiation of AREDS suggest that smoking status, nutritional status, gender, race, medical factors, iris color, and genetic markers may be associated with both

Clinical trials

Before the start of AREDS, several epidemiologic studies published data suggesting a possible role for antioxidants in reducing the risk of cancer, cardiovascular disease, and eye disease 22, 23, 24. In addition, results from a small, randomized clinical trial suggested that pharmacologic doses of zinc might provide some protection against vision loss from AMD [25]. With limited treatment options for AMD and no preventive measures for either AMD or cataract, the findings from these studies, and

Study population

Eligible participants were age 55 to 80 years old at enrollment and had to be free of any illness or condition that would make long-term follow-up or compliance with study medications unlikely or difficult. On the basis of fundus photographs graded by a central reading center, best corrected visual acuity, and ophthalmologic evaluations, participants were enrolled in one of several AMD categories as shown in Table 1. Category 1 was established to provide a comparison group of approximately 1000

Study outcomes

The main study outcome variables are change in visual acuity and change in ocular status (AMD or lens opacities). Centrally graded fundus and lens photographs are used to assess the progression of retinal or lens disease. Five comparisons of the effect of treatment on primary outcomes will include:

  • 1.

    Progression to advanced AMD (see below) comparing antioxidants and no antioxidants groups.

  • 2.

    Progression to advanced AMD comparing zinc and no zinc groups.

  • 3.

    15-letter decrease in visual acuity score

Collaboration with Industry

Collaboration between NIH-sponsored research and industry can facilitate answering important health questions in a cost-effective manner. The use of a CRADA in AREDS provided a framework for successful collaboration. A successful relationship must balance the needs and requirements of industry with the importance of maintaining the autonomy of NIH and the investigators in study decision processes. The composition and role of data and safety monitoring committees have been the subject of recent

Acknowledgements

Data and Safety Monitoring Committee (DSMC)

Janet Wittes, PhD—Chair, Gladys Block, PhD, David DeMets, PhD, Stuart Fine, MD, Curt Furberg, MD, PhD, M Cristina Leske, MD, MPH, Professor Giovanni Maraini, Donald Patrick, PhD, MSPH, and Robert Veatch, PhD.

Data and Safety Monitoring Committee (DSMC) Ex-Officios

Anne Sowell, PhD, Wiley Chambers, MD, Ellen Strahlman, MD, Matthew D. Davis, MD, Fred Ederer, MA, FACE, Frederick L. Ferris, III, MD, Karen Gamble, Carl Kupfer, MD, Natalie Kurinij, PhD, Anne

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    See appendix. Supported by contracts from the National Eye Institute, National Institutes of Health, with additional support from Bausch and Lomb Pharmaceuticals.

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