Age-Related Eye Disease Study 2 (AREDS2)

National Institutes of Health (NIH)

Status and phase: Completed; Phase 3

Conditions: Cataract; Age-related Macular Degeneration

Treatments: Drug: Lutein/zeaxanthin and DHA/EPA; Dietary Supplement: Lutein/zeaxanthin; Dietary Supplement: DHA/EPA

Study type: Interventional

Funder types: NIH

Identifiers

NCT00345176

HHS-N-260-2005-00007-C (Other Grant/Funding Number)

NEI-120

N01-EY-5-0007 (Other Grant/Funding Number)

07-EI-0025 (Other Identifier)

CC-070025 (Other Identifier)

Details and patient eligibility

About

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 description

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:

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.

Enrollment: 4,203 patients

Sex: All

Ages: 50 to 85 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Double Blind

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4,203 participants in 4 patient groups, including a placebo group

Lutein/Zeaxanthin

Active Comparator group

Description:

lutein (10mg)/zeaxanthin (2 mg)

Treatment:

Dietary Supplement: Lutein/zeaxanthin

DHA/EPA

Active Comparator group

Description:

DHA (350 mg)/EPA (650 mg)

Treatment:

Dietary Supplement: DHA/EPA

Lutein/Zeaxanthin + DHA/EPA

Active Comparator group

Description:

lutein (10 mg)/zeaxanthin (2 mg) + DHA (350 mg)/EPA (650 mg)

Treatment:

Drug: Lutein/zeaxanthin and DHA/EPA

Placebo/Control

Placebo Comparator group

Description:

Considered control because all participants received the AREDS formulation