Age-Related Eye Disease Study 2 (AREDS2)
Condition: Age-related Macular Degeneration; Cataract
MeSH terms: Cataract; Macular Degeneration; Eye Diseases
Study type: Interventional
Phase: Phase 3

Summary: 
      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: 
      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.
    

Intervention name(s): Lutein/zeaxanthin; DHA/EPA; Lutein/zeaxanthin and DHA/EPA
Intervention type(s): Dietary Supplement; Dietary Supplement; Drug
Intervention description(s): 10 mg lutein and 2 mg zeaxanthin (1 tablet) Placebo-DHA/EPA (2 soft-gel capsules); Placebo-lutein/zeaxanthin (1 tablet) 350 mg DHA and 650 mg EPA (2 soft-gel capsules); 10 mg lutein and 2 mg zeaxanthin (1 tablet) 350 mg DHA and 650 mg EPA (2 soft-gel capsules)
Other intervention name(s): docosahexaenoic acid; eicosapentaenoic acid
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: age-related macular degeneration; AMD; lutein; zeaxanthin; docosahexaenoic acid; eicosapentaenoic acid