Age-Related Eye Disease Study 2 (AREDS2) (AREDS2)

April 13, 2015 updated by: National Eye Institute (NEI)

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

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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.

Study Type

Interventional

Enrollment (Actual)

4203

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Alabama
      • Birmingham, Alabama, United States, 35294
        • University of Alabama at Birmingham
    • Arkansas
      • Little Rock, Arkansas, United States, 72205
        • Jones Eye Institute - UAMS
    • California
      • Beverly Hills, California, United States, 90211
        • Retina-Vitreous Associates Medical Group
      • La Jolla, California, United States, 92093
        • Shiley Eye Center - UCSD
      • Loma Linda, California, United States, 92354
        • Loma Linda University
      • Los Angeles, California, United States, 90033
        • Doheny Eye Institute
      • Los Angeles, California, United States, 90095
        • Jules Stein Eye Institute
      • Martinez, California, United States, 94553
        • VA Northern California Health Care System
      • Palm Springs, California, United States, 92262
        • Southern California Desert Retina Consultants, MC
      • Sacramento, California, United States, 95817
        • University of California, Davis
      • San Francisco, California, United States, 94115
        • Pacific Eye Associates
      • San Francisco, California, United States, 94107
        • West Coast Retina Medical Group, Inc
    • Colorado
      • Denver, Colorado, United States, 80218
        • Colorado Retina Associates
      • Louisville, Colorado, United States, 80027
        • Eldorado Retina Associates, PC
    • Connecticut
      • New Haven, Connecticut, United States, 06510
        • Yale University Eye Center
    • Florida
      • Ft. Lauderdale, Florida, United States, 33334
        • Retina Group of Florida
      • Jacksonville, Florida, United States, 32209
        • University of Florida
      • Miami, Florida, United States, 33136
        • Bascom Palmer Eye Institute
      • Sarasota, Florida, United States, 34239
        • Sarasota Retina Institute
      • Winter Haven, Florida, United States, 33880
        • Center for Retina and Macular Disease
    • Georgia
      • Atlanta, Georgia, United States, 30322
        • Emory University Eye Center
      • Decatur, Georgia, United States, 30030
        • Georgia Retina, PC
    • Illinois
      • Chicago, Illinois, United States, 60611
        • Northwestern University
      • Chicago, Illinois, United States, 60612
        • The University of Illinois
      • Glenview, Illinois, United States, 60026
        • NorthShore University HealthSystems
      • Harvey, Illinois, United States, 60426
        • Ingalls Memorial Hospital
    • Iowa
      • Iowa City, Iowa, United States, 52242
        • University of Iowa
    • Kentucky
      • Lexington, Kentucky, United States, 40509
        • Retina Associates of Kentucky
      • Paducah, Kentucky, United States, 42001
        • Paducah Retinal Center
    • Maryland
      • Baltimore, Maryland, United States, 21237
        • Elman Retina Group
      • Baltimore, Maryland, United States, 21287
        • Wilmer Eye Institute, Johns Hopkins Hospital
      • Bethesda, Maryland, United States, 20892
        • National Eye Institute
      • Chevy Chase, Maryland, United States, 20815
        • The Retina Group of Washington
    • Massachusetts
      • Boston, Massachusetts, United States, 02114
        • Massachusetts Eye and Ear Infirmary
      • Boston, Massachusetts, United States, 02114
        • Ophthalmic Consultants of Boston
    • Michigan
      • Detroit, Michigan, United States, 48201
        • Kresge Eye Institute
      • Detroit, Michigan, United States, 48202
        • Henry Ford Health System - Eye Care Services
      • Grand Rapids, Michigan, United States, 49546
        • Vision Research Foundation
      • Royal Oak, Michigan, United States, 48073
        • Vision Research Foundation
      • Traverse City, Michigan, United States, 49686
        • Vision Research Foundation
    • Minnesota
      • Rochester, Minnesota, United States, 55905
        • Mayo Clinic
    • Missouri
      • Columbia, Missouri, United States, 65212
        • University Health Care - Mason Eye Institute
      • Kansas City, Missouri, United States, 64108
        • Eye Foundation of Kansas City
      • Kansas City, Missouri, United States, 64111
        • Mid-America Retina Consultants, PA
      • St Louis, Missouri, United States, 63110
        • The Retina Institute
      • St. Louis, Missouri, United States, 63110
        • Washington University School of Medicine
    • New Jersey
      • Lawrenceville, New Jersey, United States, 08648
        • Delaware Valley Retina Associates
      • Newark, New Jersey, United States, 07103
        • UMDNJ
    • New York
      • Lynbrook, New York, United States, 11563
        • Ophthalmic Consultants of Long Island
      • New York, New York, United States, 10003
        • New York Eye and Ear Infirmary
      • New York, New York, United States, 10021
        • Manhattan Eye, Ear and Throat Hospital
      • Rochester, New York, United States, 14642
        • University of Rochester Eye Institute
      • Slingerlands, New York, United States, 12159
        • Retina Consultants, PLLC
      • Stony Brook, New York, United States, 11794
        • The Research Foundation of SUNY/Stony Brook
    • North Carolina
      • Asheville, North Carolina, United States, 28803
        • Western Carolina Retinal Associates
      • Chapel Hill, North Carolina, United States, 27599
        • UNC Department of Ophthalmology
      • Charlotte, North Carolina, United States, 28210
        • Charlotte Eye Ear Nose and Throat Associates
      • Durham, North Carolina, United States, 27710
        • Duke University
      • Winston-Salem, North Carolina, United States, 27157
        • Wake Forest University Eye Center
    • Ohio
      • Cleveland, Ohio, United States, 44106
        • Case Western Reserve University
      • Cleveland, Ohio, United States, 44122
        • Retina Associates of Cleveland
      • Columbus, Ohio, United States, 43210
        • Ohio State University
      • Middleburg Heights, Ohio, United States, 44130
        • Retina Associates of Cleveland
      • Youngstown, Ohio, United States, 44505
        • Retina Associates of Cleveland
    • Oklahoma
      • Oklahoma City, Oklahoma, United States, 73104
        • Dean McGee Eye Institute
    • Oregon
      • Portland, Oregon, United States, 97210
        • Devers Eye Institute
      • Portland, Oregon, United States, 97210
        • Retina Northwest, PC
    • Pennsylvania
      • Camp Hill, Pennsylvania, United States, 17011
        • Pennsylvania Retina Specialists, PC
      • Hershey, Pennsylvania, United States, 17033
        • Penn State M.S. Hershey Medical Center
      • Philadelphia, Pennsylvania, United States, 19104
        • Scheie Eye Institute
      • Philadelphia, Pennsylvania, United States, 19107
        • Wills Eye Hospital/Mid Atlantic Retina
      • Pittsburgh, Pennsylvania, United States, 15213
        • University of Pittsburgh Medical Center
      • Pittsburgh, Pennsylvania, United States, 15213
        • Retina Vitreous Consultants
    • South Carolina
      • Columbia, South Carolina, United States, 29223
        • Carolina Retina Center
      • Columbia, South Carolina, United States, 29204
        • Palmetto Retina Center
    • Tennessee
      • Knoxville, Tennessee, United States, 37909
        • Southeastern Retina Associates, PC
      • Memphis, Tennessee, United States, 38163
        • University of Tennessee
      • Nashville, Tennessee, United States, 37232
        • Vanderbilt Eye Institute
    • Texas
      • Arlington, Texas, United States, 76012
        • Texas Retina Associates
      • Dallas, Texas, United States, 75390
        • UT Southwestern Medical Center
      • Dallas, Texas, United States, 75231
        • Texas Retina Associates
      • Houston, Texas, United States, 77030
        • Baylor College of Medicine
      • Houston, Texas, United States, 77030
        • Retina Consultants of Houston
      • Lubbock, Texas, United States, 79424
        • Texas Retina Associates
      • Temple, Texas, United States, 76508
        • Scott and White Memorial Hospital
    • Utah
      • Salt Lake City, Utah, United States, 84132
        • John Moran Eye Center
    • Vermont
      • Burlington, Vermont, United States, 05401
        • Fletcher Allen Health Care
    • Virginia
      • Fairfax, Virginia, United States, 22031
        • The Retina Group of Washington
    • Washington
      • Silverdale, Washington, United States, 98383
        • Retina Center Northwest
    • Wisconsin
      • Madison, Wisconsin, United States, 53705
        • University of Wisconsin
      • Milwaukee, Wisconsin, United States, 53226
        • The Medical College of Wisconsin

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

48 years to 83 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
5 years of follow-up

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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
5 years of follow-up
Adverse Events
Time Frame: 5 years of follow-up
Safety outcomes included serious adverse events and mortality.
5 years of follow-up
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.
5 years of follow-up

Other Outcome Measures

Outcome Measure
Measure Description
Time Frame
Incident Cardiovascular Disease
Time Frame: 5 years of follow-up
Effects of oral supplementation of omega-3 fatty acids, lutein/zeaxanthin on cardiovascular disease
5 years of follow-up
Cognition as Measured by a Telephone Battery
Time Frame: 5 years of follow-up
Effects of oral supplementation of omega-3 fatty acids, lutein/zeaxanthin, zinc, and beta-carotene on cognitive function
5 years of follow-up
Prevalence of Peripheral Changes as Measured Using OPTOS Imaging
Time Frame: 5 years of follow-up
Effects of oral supplementation of omega-3 fatty acids, lutein/zeaxanthin on the peripheral retina
5 years of follow-up
Genetics for the Association of AMD and Cataract
Time Frame: 5 years of follow-up
5 years of follow-up
Genetics for the Progression of AMD and Cataract
Time Frame: 5 years of follow-up
5 years of follow-up

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Eye Institute (NEI)

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)
National Center for Complementary and Integrative Health (NCCIH)
Office of Dietary Supplements (ODS)

Investigators

  • Study Chair: Emily Y Chew, MD, National Eye Institute, National Institutes of Health
  • Study Director: John Paul SanGiovanni, Sc.D., National Eye Institute, National Institutes of Health

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

September 1, 2006

Primary Completion (Actual)

October 1, 2012

Study Completion (Actual)

October 1, 2012

Study Registration Dates

First Submitted

June 14, 2006

First Submitted That Met QC Criteria

June 23, 2006

First Posted (Estimate)

June 27, 2006

Study Record Updates

Last Update Posted (Estimate)

May 5, 2015

Last Update Submitted That Met QC Criteria

April 13, 2015

Last Verified

April 1, 2015

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NEI-120
  • N01-EY-5-0007 (Other Grant/Funding Number: NIH)
  • HHS-N-260-2005-00007-C (Other Grant/Funding Number: HHS)
  • CC-070025 (Other Identifier: NIH Clinical Center)
  • 07-EI-0025 (Other Identifier: National Eye Institute)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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