Age-Related Eye Disease Study 2 (AREDS2)

Overview

Oral supplementation with the Age-Related Eye Disease Study (AREDS) formulation (antioxidant vitamins C and E, beta carotene, and zinc) has been shown to reduce the risk of progression to advanced age-related macular degeneration (AMD). Observational data suggest that increased dietary intake of lutein + zeaxanthin (carotenoids), omega-3 long-chain polyunsaturated fatty acids (docosahexaenoic acid [DHA] + eicosapentaenoic acid [EPA]), or both might further reduce this risk. AREDS2 was designed to test whether adding lutein + zeaxanthin, DHA + EPA, or lutein + zeaxanthin and DHA + EPA to the AREDS formulation might further reduce the risk of progression to advanced AMD. A secondary goal was to test the effects of eliminating beta carotene and reducing zinc dose in the AREDS formulation.

Full Title of Study: “Age-Related Eye Disease Study 2 (AREDS2): A Multi-center, Randomized Trial of Lutein, Zeaxanthin and Omega-3 Long-Chain Polyunsaturated Fatty Acids (Docosahexaenoic Acid [DHA] and Eicosapentaenoic Acid [EPA]) in Age-Related Macular Degeneration”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Treatment
    • Masking: Double (Participant, Investigator)
  • Study Primary Completion Date: October 2012

Detailed Description

AREDS2 was a randomized, double-masked, placebo-controlled, 2×2 factorial trial evaluating the risks and benefits of adding lutein (10 mg) + zeaxanthin (2 mg), DHA (350 mg) + EPA (650 mg), or both to the AREDS formulation, which consisted of vitamins C (500 mg), vitamin E (400 international units), beta carotene (15 mg), zinc (80 mg as zinc oxide), and copper (2 mg as cupric oxide) for the treatment of progression to advanced AMD. The study enrolled 4,203 participants aged 50 to 85 years, with sufficiently clear ocular media to allow accurate assessment of AMD from fundus photographs. Subjects were enrolled on the basis of the AREDS Simplified Severity Scale for defining risk categories for development of advanced age-related macular degeneration. All participants were 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 amount of zinc (25 mg); and (3) no beta-carotene and lower amount of zinc (25 mg). Eligible participants were followed for a minimum of five years. Multiple ancillary studies were conducted using the parent study (AREDS2) data to explore: 1. Effects of oral supplementation of omega-3 fatty acids, lutein/zeaxanthin, zinc, and beta-carotene on cognitive function 1. Outcome is measured with a battery of tests administered over the telephone at baseline, and at years 2 and 4 of the study. 2. Primary outcome is the change in the composite score for the results of the cognitive function testing from baseline over time. 2. Effects of oral supplementation of omega-3 fatty acids, lutein/zeaxanthin on cardiovascular disease a. Primary measure of cardiovascular morbidity and mortality 3. Effects of oral supplementation of omega-3 fatty acids, lutein/zeaxanthin on the peripheral retina a. Primary outcome is the development of peripheral drusen, geographic atrophy, reticular pigmentary changes, and pseudoreticular drusen. 4. Association of genotype polymorphisms with age-related macular degeneration and cataract a. Whole genome sequencing will be completed. Evaluation of association genetic associations with disease will be conducted using AREDS controls. 5. Association of genotype polymorphisms with progression of age-related macular degeneration a. Whole genome sequencing is conducted. Progression from early to late and severe stages of AMD will be examined with the genotype data to evaluate the risks of progression associated with the genotype polymorphisms. 6. Association of genotype polymorphisms with dietary intake a. Whole genome sequencing is conducted. Progression from early to late and severe stages of AMD will be examined regarding potential interaction of the dietary intake with the genotype data to evaluate the risks of progression. 7. Association of genotype polymorphisms with AREDS2 supplements a. Interaction of genetic polymorphisms with AREDS2 supplements for progression to late AMD will be evaluated using the data from the whole genome sequencing project.

Interventions

  • Dietary Supplement: Lutein/zeaxanthin
    • 10 mg lutein and 2 mg zeaxanthin (1 tablet) Placebo-DHA/EPA (2 soft-gel capsules)
  • Dietary Supplement: DHA/EPA
    • Placebo-lutein/zeaxanthin (1 tablet) 350 mg DHA and 650 mg EPA (2 soft-gel capsules)
  • Drug: Lutein/zeaxanthin and DHA/EPA
    • 10 mg lutein and 2 mg zeaxanthin (1 tablet) 350 mg DHA and 650 mg EPA (2 soft-gel capsules)

Arms, Groups and Cohorts

  • Active Comparator: Lutein/Zeaxanthin
    • lutein (10mg)/zeaxanthin (2 mg)
  • Active Comparator: DHA/EPA
    • DHA (350 mg)/EPA (650 mg)
  • Active Comparator: Lutein/Zeaxanthin + DHA/EPA
    • lutein (10 mg)/zeaxanthin (2 mg) + DHA (350 mg)/EPA (650 mg)
  • Placebo Comparator: Placebo/Control
    • Considered control because all participants received the AREDS formulation

Clinical Trial Outcome Measures

Primary Measures

  • Development of Advanced AMD in People at Moderate to High Risk for Progression.
    • Time Frame: 5 years of follow-up
    • Defined as central geographic atrophy or retinal features of choroidal neovascularization detected on central grading of the stereoscopic fundus photographs or a history of treatment for advanced AMD after study enrollment.

Secondary Measures

  • Progression to Moderate Vision Loss
    • Time Frame: 5 years of follow-up
    • Loss defined as >/= 3 lines of letters from baseline or treatment for choroidal neovascularization
  • Adverse Events
    • Time Frame: 5 years of follow-up
    • Safety outcomes included serious adverse events and mortality.
  • Progression to Cataract Surgery
    • Time Frame: 5 years of follow-up
    • The study examined the effects of lutein/zeaxanthin on progression to cataract surgery with data collected during regular telephone contacts and the annual study visits.

Participating in This Clinical Trial

Inclusion Criteria

  • Men and women between the ages of 50 and 85 years – 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 Exclusion Criteria:

  • Ocular media not clear enough to allow good fundus photography

Gender Eligibility: All

Minimum Age: 50 Years

Maximum Age: 85 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • National Eye Institute (NEI)
  • Collaborator
    • National Heart, Lung, and Blood Institute (NHLBI)
  • Provider of Information About this Clinical Study
    • Sponsor
  • Overall Official(s)
    • Emily Y Chew, MD, Study Chair, National Eye Institute, National Institutes of Health
    • John Paul SanGiovanni, Sc.D., Study Director, National Eye Institute, National Institutes of Health

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