Age-Related Eye Disease Study 2 (AREDS2)

Study Overview
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Brief Summary
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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.

Detailed Description
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AREDS2 was a randomized, double-masked, placebo-controlled, 2x2 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: Effects of oral supplementation of omega-3 fatty acids, lutein/zeaxanthin, zinc, and beta-carotene on cognitive function Outcome is measured with a battery of tests administered over the telephone at baseline, and at years 2 and 4 of the study. Primary outcome is the change in the composite score for the results of the cognitive function testing from baseline over time. Effects of oral supplementation of omega-3 fatty acids, lutein/zeaxanthin on cardiovascular disease a. Primary measure of cardiovascular morbidity and mortality 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. 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. 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. 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. 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.

Official Title
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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

Conditions
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Age-related Macular Degeneration, Cataract

Intervention / Treatment
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* Dietary Supplement: Lutein/zeaxanthin
* Dietary Supplement: DHA/EPA
* Drug: Lutein/zeaxanthin and DHA/EPA


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Lutein/Zeaxanthin<br>lutein (10mg)/zeaxanthin (2 mg) | Dietary Supplement: Lutein/zeaxanthin<br>* 10 mg lutein and 2 mg zeaxanthin (1 tablet) Placebo-DHA/EPA (2 soft-gel capsules)<br>|
| Active Comparator: DHA/EPA<br>DHA (350 mg)/EPA (650 mg) | Dietary Supplement: DHA/EPA<br>* Placebo-lutein/zeaxanthin (1 tablet) 350 mg DHA and 650 mg EPA (2 soft-gel capsules)<br>* Other names: docosahexaenoic acid; eicosapentaenoic acid;|
| Active Comparator: Lutein/Zeaxanthin + DHA/EPA<br>lutein (10 mg)/zeaxanthin (2 mg) + DHA (350 mg)/EPA (650 mg) | Drug: Lutein/zeaxanthin and DHA/EPA<br>* 10 mg lutein and 2 mg zeaxanthin (1 tablet) 350 mg DHA and 650 mg EPA (2 soft-gel capsules)<br>|
| Placebo Comparator: Placebo/Control<br>Considered control because all participants received the AREDS formulation | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Development of Advanced AMD in People at Moderate to High Risk for Progression. | 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. | 5 years of follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression to Moderate Vision Loss | Loss defined as >/= 3 lines of letters from baseline or treatment for choroidal neovascularization | 5 years of follow-up | 
| Adverse Events | Safety outcomes included serious adverse events and mortality. | 5 years of follow-up | 
| Progression to Cataract Surgery | 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. | 5 years of follow-up | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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age-related macular degeneration, AMD, lutein, zeaxanthin, docosahexaenoic acid, eicosapentaenoic acid