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Age-related Macular DegenerationPhase 3AREDS2NCT00345176

Age-Related Eye Disease Study 2 (AREDS2)

A Phase 3 study testing Lutein/zeaxanthin, DHA/EPA and Lutein/zeaxanthin and DHA/EPA in people with Age-related Macular Degeneration and Cataract, run by National Eye Institute (NEI) at 91 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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). Read more about this study

Who is it for?
Ages 50 to 85 years
Conditions the study is for
Age-related Macular Degeneration, Cataract
What is being tested?
Lutein/zeaxanthin, DHA/EPA and Lutein/zeaxanthin and DHA/EPA
Type of treatment
Pill or oral medicine
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
4,203 participants
Where
91 sitesUnited States
Study dates
Sep 2006to Oct 2012
Phase
Phase 3
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 50 to 85 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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

Who cannot join

  • Ocular media not clear enough to allow good fundus photography

Trial locations and contacts

91 sites in 1 country.

91 sites in 1 country

United States91 sites

  • Texas Retina Associates

    Arlington, Texas, 76012

  • Western Carolina Retinal Associates

    Asheville, North Carolina, 28803

  • Emory University Eye Center

    Atlanta, Georgia, 30322

  • Elman Retina Group

    Baltimore, Maryland, 21237

  • Wilmer Eye Institute, Johns Hopkins Hospital

    Baltimore, Maryland, 21287

  • National Eye Institute

    Bethesda, Maryland, 20892

  • Retina-Vitreous Associates Medical Group

    Beverly Hills, California, 90211

  • University of Alabama at Birmingham

    Birmingham, Alabama, 35294

  • Massachusetts Eye and Ear Infirmary

    Boston, Massachusetts, 02114

  • Ophthalmic Consultants of Boston

    Boston, Massachusetts, 02114

  • Fletcher Allen Health Care

    Burlington, Vermont, 05401

  • Pennsylvania Retina Specialists, PC

    Camp Hill, Pennsylvania, 17011

  • UNC Department of Ophthalmology

    Chapel Hill, North Carolina, 27599

  • Charlotte Eye Ear Nose and Throat Associates

    Charlotte, North Carolina, 28210

  • The Retina Group of Washington

    Chevy Chase, Maryland, 20815

  • Northwestern University

    Chicago, Illinois, 60611

  • The University of Illinois

    Chicago, Illinois, 60612

  • Case Western Reserve University

    Cleveland, Ohio, 44106

  • Retina Associates of Cleveland

    Cleveland, Ohio, 44122

  • University Health Care - Mason Eye Institute

    Columbia, Missouri, 65212

  • Palmetto Retina Center

    Columbia, South Carolina, 29204

  • Carolina Retina Center

    Columbia, South Carolina, 29223

  • Ohio State University

    Columbus, Ohio, 43210

  • Texas Retina Associates

    Dallas, Texas, 75231

  • UT Southwestern Medical Center

    Dallas, Texas, 75390

  • Georgia Retina, PC

    Decatur, Georgia, 30030

  • Colorado Retina Associates

    Denver, Colorado, 80218

  • Kresge Eye Institute

    Detroit, Michigan, 48201

  • Henry Ford Health System - Eye Care Services

    Detroit, Michigan, 48202

  • Duke University

    Durham, North Carolina, 27710

  • The Retina Group of Washington

    Fairfax, Virginia, 22031

  • Retina Group of Florida

    Fort Lauderdale, Florida, 33334

  • NorthShore University HealthSystems

    Glenview, Illinois, 60026

  • Vision Research Foundation

    Grand Rapids, Michigan, 49546

  • Ingalls Memorial Hospital

    Harvey, Illinois, 60426

  • Penn State M.S. Hershey Medical Center

    Hershey, Pennsylvania, 17033

  • Baylor College of Medicine

    Houston, Texas, 77030

  • Retina Consultants of Houston

    Houston, Texas, 77030

  • University of Iowa

    Iowa City, Iowa, 52242

  • University of Florida

    Jacksonville, Florida, 32209

  • Eye Foundation of Kansas City

    Kansas City, Missouri, 64108

  • Mid-America Retina Consultants, PA

    Kansas City, Missouri, 64111

  • Southeastern Retina Associates, PC

    Knoxville, Tennessee, 37909

  • Shiley Eye Center - UCSD

    La Jolla, California, 92093

  • Delaware Valley Retina Associates

    Lawrenceville, New Jersey, 08648

  • Retina Associates of Kentucky

    Lexington, Kentucky, 40509

  • Jones Eye Institute - UAMS

    Little Rock, Arkansas, 72205

  • Loma Linda University

    Loma Linda, California, 92354

  • Doheny Eye Institute

    Los Angeles, California, 90033

  • Jules Stein Eye Institute

    Los Angeles, California, 90095

  • Eldorado Retina Associates, PC

    Louisville, Colorado, 80027

  • Texas Retina Associates

    Lubbock, Texas, 79424

  • Ophthalmic Consultants of Long Island

    Lynbrook, New York, 11563

  • University of Wisconsin

    Madison, Wisconsin, 53705

  • VA Northern California Health Care System

    Martinez, California, 94553

  • University of Tennessee

    Memphis, Tennessee, 38163

  • Bascom Palmer Eye Institute

    Miami, Florida, 33136

  • Retina Associates of Cleveland

    Middleburg Heights, Ohio, 44130

  • The Medical College of Wisconsin

    Milwaukee, Wisconsin, 53226

  • Vanderbilt Eye Institute

    Nashville, Tennessee, 37232

  • Yale University Eye Center

    New Haven, Connecticut, 06510

  • New York Eye and Ear Infirmary

    New York, New York, 10003

  • Manhattan Eye, Ear and Throat Hospital

    New York, New York, 10021

  • UMDNJ

    Newark, New Jersey, 07103

  • Dean McGee Eye Institute

    Oklahoma City, Oklahoma, 73104

  • Paducah Retinal Center

    Paducah, Kentucky, 42001

  • Southern California Desert Retina Consultants, MC

    Palm Springs, California, 92262

  • Scheie Eye Institute

    Philadelphia, Pennsylvania, 19104

  • Wills Eye Hospital/Mid Atlantic Retina

    Philadelphia, Pennsylvania, 19107

  • Retina Vitreous Consultants

    Pittsburgh, Pennsylvania, 15213

  • University of Pittsburgh Medical Center

    Pittsburgh, Pennsylvania, 15213

  • Devers Eye Institute

    Portland, Oregon, 97210

  • Retina Northwest, PC

    Portland, Oregon, 97210

  • Mayo Clinic

    Rochester, Minnesota, 55905

  • University of Rochester Eye Institute

    Rochester, New York, 14642

  • Vision Research Foundation

    Royal Oak, Michigan, 48073

  • University of California, Davis

    Sacramento, California, 95817

  • John Moran Eye Center

    Salt Lake City, Utah, 84132

  • West Coast Retina Medical Group, Inc

    San Francisco, California, 94107

  • Pacific Eye Associates

    San Francisco, California, 94115

  • Sarasota Retina Institute

    Sarasota, Florida, 34239

  • Retina Center Northwest

    Silverdale, Washington, 98383

  • Retina Consultants, PLLC

    Slingerlands, New York, 12159

  • The Retina Institute

    St Louis, Missouri, 63110

  • Washington University School of Medicine

    St Louis, Missouri, 63110

  • The Research Foundation of SUNY/Stony Brook

    Stony Brook, New York, 11794

  • Scott and White Memorial Hospital

    Temple, Texas, 76508

  • Vision Research Foundation

    Traverse City, Michigan, 49686

  • Wake Forest University Eye Center

    Winston-Salem, North Carolina, 27157

  • Center for Retina and Macular Disease

    Winter Haven, Florida, 33880

  • Retina Associates of Cleveland

    Youngstown, Ohio, 44505

Other trials in United States

About this study

Official title: 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.

Read the 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
  2. Outcome is measured with a battery of tests administered over the telephone at baseline, and at years 2 and 4 of the study.
  3. Primary outcome is the change in the composite score for the results of the cognitive function testing from baseline over time.
  4. Effects of oral supplementation of omega-3 fatty acids, lutein/zeaxanthin on cardiovascular disease
  5. Primary measure of cardiovascular morbidity and mortality
  6. Effects of oral supplementation of omega-3 fatty acids, lutein/zeaxanthin on the peripheral retina
  7. Primary outcome is the development of peripheral drusen, geographic atrophy, reticular pigmentary changes, and pseudoreticular drusen.
  8. Association of genotype polymorphisms with age-related macular degeneration and cataract
  9. Whole genome sequencing will be completed. Evaluation of association genetic associations with disease will be conducted using AREDS controls.
  10. Association of genotype polymorphisms with progression of age-related macular degeneration
  11. 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.
  12. 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.
  13. 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.
Being tested
Lutein/zeaxanthin, DHA/EPA, Lutein/zeaxanthin and DHA/EPA
Keywords
age-related macular degeneration, AMD, lutein, zeaxanthin, docosahexaenoic acid, eicosapentaenoic acid
Medical subject headings
Macular Degeneration, Cataract

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Lutein/zeaxanthinDietary supplement

    10 mg lutein and 2 mg zeaxanthin (1 tablet) Placebo-DHA/EPA (2 soft-gel capsules)

  • DHA/EPADietary supplement

    Also called docosahexaenoic acid; eicosapentaenoic acid

    Placebo-lutein/zeaxanthin (1 tablet) 350 mg DHA and 650 mg EPA (2 soft-gel capsules)

  • Lutein/zeaxanthin and DHA/EPADrug

    10 mg lutein and 2 mg zeaxanthin (1 tablet) 350 mg DHA and 650 mg EPA (2 soft-gel capsules)

Study groups in NCT00345176
Study groupRoleWhat they receive
Lutein/ZeaxanthinActive comparatorlutein (10mg)/zeaxanthin (2 mg)
Receives: Dietary Supplement: Lutein/zeaxanthin
DHA/EPAActive comparatorDHA (350 mg)/EPA (650 mg)
Receives: Dietary Supplement: DHA/EPA
Lutein/Zeaxanthin + DHA/EPAActive comparatorlutein (10 mg)/zeaxanthin (2 mg) + DHA (350 mg)/EPA (650 mg)
Receives: Drug: Lutein/zeaxanthin and DHA/EPA
Placebo/ControlPlacebo comparatorConsidered control because all participants received the AREDS formulation

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 5 years of follow-up

Secondary outcomes (3)

  1. Progression to Moderate Vision Loss

    Loss defined as >/= 3 lines of letters from baseline or treatment for choroidal neovascularization

    Measured: 5 years of follow-up

  2. Adverse Events

    Safety outcomes included serious adverse events and mortality.

    Measured: 5 years of follow-up

  3. 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.

    Measured: 5 years of follow-up

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted27 Jun 2006 (estimated)
  2. Study startSep 2006
  3. Primary completionOct 2012
  4. Study completionOct 2012

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 3
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
4,203 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00345176
Sponsor's protocol ID
NEI-120
Other IDs
N01-EY-5-0007, HHS-N-260-2005-00007-C, CC-070025, 07-EI-0025
Acronym
AREDS2
Status last verified
Apr 2015
First submitted
14 Jun 2006
Last updated
5 May 2015
Data monitoring committee
Yes

Publications

  • Evans JR, Lawrenson JG. Antioxidant vitamin and mineral supplements for slowing the progression of age-related macular degeneration. Cochrane Database Syst Rev. 2023 Sep 13;9(9):CD000254. doi: 10.1002/14651858.CD000254.pub5.

    PubMed 37702300

  • Bhandari S, Vitale S, Agron E, Clemons TE, Chew EY; Age-Related Eye Disease Study 2 Research Group. Cataract Surgery and the Risk of Developing Late Age-Related Macular Degeneration: The Age-Related Eye Disease Study 2 Report Number 27. Ophthalmology. 2022 Apr;129(4):414-420. doi: 10.1016/j.ophtha.2021.11.014. Epub 2021 Nov 16.

    PubMed 34793832

  • Keenan TD, Agron E, Mares JA, Clemons TE, van Asten F, Swaroop A, Chew EY; AREDS and AREDS2 Research Groups. Adherence to a Mediterranean diet and cognitive function in the Age-Related Eye Disease Studies 1 & 2. Alzheimers Dement. 2020 Jun;16(6):831-842. doi: 10.1002/alz.12077. Epub 2020 Apr 13.

    PubMed 32285590

  • Chew EY, Clemons TE, Agron E, Launer LJ, Grodstein F, Bernstein PS; Age-Related Eye Disease Study 2 (AREDS2) Research Group. Effect of Omega-3 Fatty Acids, Lutein/Zeaxanthin, or Other Nutrient Supplementation on Cognitive Function: The AREDS2 Randomized Clinical Trial. JAMA. 2015 Aug 25;314(8):791-801. doi: 10.1001/jama.2015.9677.

    PubMed 26305649

  • Writing Group for the AREDS2 Research Group; Bonds DE, Harrington M, Worrall BB, Bertoni AG, Eaton CB, Hsia J, Robinson J, Clemons TE, Fine LJ, Chew EY. Effect of long-chain omega-3 fatty acids and lutein + zeaxanthin supplements on cardiovascular outcomes: results of the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA Intern Med. 2014 May;174(5):763-71. doi: 10.1001/jamainternmed.2014.328.

    PubMed 24638908

  • Age-Related Eye Disease Study 2 (AREDS2) Research Group; Chew EY, Clemons TE, Sangiovanni JP, Danis RP, Ferris FL 3rd, Elman MJ, Antoszyk AN, Ruby AJ, Orth D, Bressler SB, Fish GE, Hubbard GB, Klein ML, Chandra SR, Blodi BA, Domalpally A, Friberg T, Wong WT, Rosenfeld PJ, Agron E, Toth CA, Bernstein PS, Sperduto RD. Secondary analyses of the effects of lutein/zeaxanthin on age-related macular degeneration progression: AREDS2 report No. 3. JAMA Ophthalmol. 2014 Feb;132(2):142-9. doi: 10.1001/jamaophthalmol.2013.7376.

    PubMed 24310343

  • Domalpally A, Danis RP, Chew EY, Clemons TE, Reed S, Sangiovanni JP, Ferris FL 3rd; Age-Related Eye Disease Study 2 Research Group. Evaluation of optimized digital fundus reflex photographs for lens opacities in the age-related eye disease study 2: AREDS2 report 7. Invest Ophthalmol Vis Sci. 2013 Sep 5;54(9):5989-94. doi: 10.1167/iovs.13-12301.

    PubMed 23887802

  • Toy BC, Krishnadev N, Indaram M, Cunningham D, Cukras CA, Chew EY, Wong WT. Drusen regression is associated with local changes in fundus autofluorescence in intermediate age-related macular degeneration. Am J Ophthalmol. 2013 Sep;156(3):532-542.e1. doi: 10.1016/j.ajo.2013.04.031. Epub 2013 Jul 3.

    PubMed 23830564

  • Age-Related Eye Disease Study 2 (AREDS2) Research Group; Chew EY, SanGiovanni JP, Ferris FL, Wong WT, Agron E, Clemons TE, Sperduto R, Danis R, Chandra SR, Blodi BA, Domalpally A, Elman MJ, Antoszyk AN, Ruby AJ, Orth D, Bressler SB, Fish GE, Hubbard GB, Klein ML, Friberg TR, Rosenfeld PJ, Toth CA, Bernstein P. Lutein/zeaxanthin for the treatment of age-related cataract: AREDS2 randomized trial report no. 4. JAMA Ophthalmol. 2013 Jul;131(7):843-50. doi: 10.1001/jamaophthalmol.2013.4412.

    PubMed 23645227

  • Age-Related Eye Disease Study 2 Research Group. Lutein + zeaxanthin and omega-3 fatty acids for age-related macular degeneration: the Age-Related Eye Disease Study 2 (AREDS2) randomized clinical trial. JAMA. 2013 May 15;309(19):2005-15. doi: 10.1001/jama.2013.4997.

    PubMed 23644932

  • Danis RP, Domalpally A, Chew EY, Clemons TE, Armstrong J, SanGiovanni JP, Ferris FL 3rd; AREDS2 Study Group. Methods and reproducibility of grading optimized digital color fundus photographs in the Age-Related Eye Disease Study 2 (AREDS2 Report Number 2). Invest Ophthalmol Vis Sci. 2013 Jul 8;54(7):4548-54. doi: 10.1167/iovs.13-11804.

    PubMed 23620429

  • Bernstein PS, Ahmed F, Liu A, Allman S, Sheng X, Sharifzadeh M, Ermakov I, Gellermann W. Macular pigment imaging in AREDS2 participants: an ancillary study of AREDS2 subjects enrolled at the Moran Eye Center. Invest Ophthalmol Vis Sci. 2012 Sep 14;53(10):6178-86. doi: 10.1167/iovs.12-10275.

    PubMed 22879423

  • Hubbard LD, Danis RP, Neider MW, Thayer DW, Wabers HD, White JK, Pugliese AJ, Pugliese MF; Age-Related Eye Disease 2 Research Group. Brightness, contrast, and color balance of digital versus film retinal images in the age-related eye disease study 2. Invest Ophthalmol Vis Sci. 2008 Aug;49(8):3269-82. doi: 10.1167/iovs.07-1267. Epub 2008 Apr 17.

    PubMed 18421079

Questions about this trial

What is this clinical trial studying?

A Phase 3 study testing Lutein/zeaxanthin, DHA/EPA and Lutein/zeaxanthin and DHA/EPA in people with Age-related Macular Degeneration and Cataract, run by National Eye Institute (NEI) at 91 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 2 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 5 May 2015. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 91 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 3 studies compare the treatment with the current standard treatment or a placebo in a large group, to confirm how well it works and watch for side effects.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 24 Dec 2013). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Development of Advanced AMD in People at Moderate to High Risk for Progression. (time frame: 5 years of follow-up). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00345176, which also lists 13 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 5 May 2015.

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Age-Related Eye Disease Study 2 (AREDS2) (NCT00345176) | AzTrials