Clinical trial NCT00345176: Age-Related Eye Disease Study 2 (AREDS2)
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Age-related Macular Degeneration
Cataract
Keywords: age-related macular degeneration
AMD
lutein
zeaxanthin
docosahexaenoic acid
eicosapentaenoic acid
Lead sponsor: National Eye Institute (NEI)
Sponsor class: NIH
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: Office of Dietary Supplements (ODS)
name: National Center for Complementary and Integrative Health (NCCIH)
First posted: 2006-06-27
Enrollment: 4203
Sex: ALL
Minimum age (years): 50
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: 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

Primary outcomes:
measure: Development of Advanced AMD in People at Moderate to High Risk for Progression.
timeFrame: 5 years of follow-up
Secondary outcomes:
measure: Progression to Moderate Vision Loss
timeFrame: 5 years of follow-up
measure: Adverse Events
timeFrame: 5 years of follow-up
measure: Progression to Cataract Surgery
timeFrame: 5 years of follow-up
Other outcomes:
measure: Incident Cardiovascular Disease
timeFrame: 5 years of follow-up
measure: Cognition as Measured by a Telephone Battery
timeFrame: 5 years of follow-up
measure: Prevalence of Peripheral Changes as Measured Using OPTOS Imaging
timeFrame: 5 years of follow-up
measure: Genetics for the Association of AMD and Cataract
timeFrame: 5 years of follow-up
measure: Genetics for the Progression of AMD and Cataract
timeFrame: 5 years of follow-up
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham
state: Alabama
city: Little Rock
country: United States
facility: Jones Eye Institute - UAMS
state: Arkansas
city: Beverly Hills
country: United States
facility: Retina-Vitreous Associates Medical Group
state: California
city: La Jolla
country: United States
facility: Shiley Eye Center - UCSD
state: California
city: Loma Linda
country: United States
facility: Loma Linda University
state: California
city: Los Angeles
country: United States
facility: Doheny Eye Institute
state: California
city: Los Angeles
country: United States
facility: Jules Stein Eye Institute
state: California
city: Martinez
country: United States
facility: VA Northern California Health Care System
state: California
city: Palm Springs
country: United States
facility: Southern California Desert Retina Consultants, MC
state: California
city: Sacramento
country: United States
facility: University of California, Davis
state: California
city: San Francisco
country: United States
facility: West Coast Retina Medical Group, Inc
state: California
city: San Francisco
country: United States
facility: Pacific Eye Associates
state: California
city: Denver
country: United States
facility: Colorado Retina Associates
state: Colorado
city: Louisville
country: United States
facility: Eldorado Retina Associates, PC
state: Colorado
city: New Haven
country: United States
facility: Yale University Eye Center
state: Connecticut
city: Ft. Lauderdale
country: United States
facility: Retina Group of Florida
state: Florida
city: Jacksonville
country: United States
facility: University of Florida
state: Florida
city: Miami
country: United States
facility: Bascom Palmer Eye Institute
state: Florida
city: Sarasota
country: United States
facility: Sarasota Retina Institute
state: Florida
city: Winter Haven
country: United States
facility: Center for Retina and Macular Disease
state: Florida
city: Atlanta
country: United States
facility: Emory University Eye Center
state: Georgia
city: Decatur
country: United States
facility: Georgia Retina, PC
state: Georgia
city: Chicago
country: United States
facility: Northwestern University
state: Illinois
city: Chicago
country: United States
facility: The University of Illinois
state: Illinois
city: Glenview
country: United States
facility: NorthShore University HealthSystems
state: Illinois
city: Harvey
country: United States
facility: Ingalls Memorial Hospital
state: Illinois
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
city: Lexington
country: United States
facility: Retina Associates of Kentucky
state: Kentucky
city: Paducah
country: United States
facility: Paducah Retinal Center
state: Kentucky
city: Baltimore
country: United States
facility: Elman Retina Group
state: Maryland
city: Baltimore
country: United States
facility: Wilmer Eye Institute, Johns Hopkins Hospital
state: Maryland
city: Bethesda
country: United States
facility: National Eye Institute
state: Maryland
city: Chevy Chase
country: United States
facility: The Retina Group of Washington
state: Maryland
city: Boston
country: United States
facility: Massachusetts Eye and Ear Infirmary
state: Massachusetts
city: Boston
country: United States
facility: Ophthalmic Consultants of Boston
state: Massachusetts
city: Detroit
country: United States
facility: Kresge Eye Institute
state: Michigan
city: Detroit
country: United States
facility: Henry Ford Health System - Eye Care Services
state: Michigan
city: Grand Rapids
country: United States
facility: Vision Research Foundation
state: Michigan
city: Royal Oak
country: United States
facility: Vision Research Foundation
state: Michigan
city: Traverse City
country: United States
facility: Vision Research Foundation
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Columbia
country: United States
facility: University Health Care - Mason Eye Institute
state: Missouri
city: Kansas City
country: United States
facility: Eye Foundation of Kansas City
state: Missouri
city: Kansas City
country: United States
facility: Mid-America Retina Consultants, PA
state: Missouri
city: St Louis
country: United States
facility: The Retina Institute
state: Missouri
city: St. Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Lawrenceville
country: United States
facility: Delaware Valley Retina Associates
state: New Jersey
city: Newark
country: United States
facility: UMDNJ
state: New Jersey
city: Lynbrook
country: United States
facility: Ophthalmic Consultants of Long Island
state: New York
city: New York
country: United States
facility: New York Eye and Ear Infirmary
state: New York
city: New York
country: United States
facility: Manhattan Eye, Ear and Throat Hospital
state: New York
city: Rochester
country: United States
facility: University of Rochester Eye Institute
state: New York
city: Slingerlands
country: United States
facility: Retina Consultants, PLLC
state: New York
city: Stony Brook
country: United States
facility: The Research Foundation of SUNY/Stony Brook
state: New York
city: Asheville
country: United States
facility: Western Carolina Retinal Associates
state: North Carolina
city: Chapel Hill
country: United States
facility: UNC Department of Ophthalmology
state: North Carolina
city: Charlotte
country: United States
facility: Charlotte Eye Ear Nose and Throat Associates
state: North Carolina
city: Durham
country: United States
facility: Duke University
state: North Carolina
city: Winston-Salem
country: United States
facility: Wake Forest University Eye Center
state: North Carolina
city: Cleveland
country: United States
facility: Case Western Reserve University
state: Ohio
city: Cleveland
country: United States
facility: Retina Associates of Cleveland
state: Ohio
city: Columbus
country: United States
facility: Ohio State University
state: Ohio
city: Middleburg Heights
country: United States
facility: Retina Associates of Cleveland
state: Ohio
city: Youngstown
country: United States
facility: Retina Associates of Cleveland
state: Ohio
city: Oklahoma City
country: United States
facility: Dean McGee Eye Institute
state: Oklahoma
city: Portland
country: United States
facility: Devers Eye Institute
state: Oregon
city: Portland
country: United States
facility: Retina Northwest, PC
state: Oregon
city: Camp Hill
country: United States
facility: Pennsylvania Retina Specialists, PC
state: Pennsylvania
city: Hershey
country: United States
facility: Penn State M.S. Hershey Medical Center
state: Pennsylvania
city: Philadelphia
country: United States
facility: Scheie Eye Institute
state: Pennsylvania
city: Philadelphia
country: United States
facility: Wills Eye Hospital/Mid Atlantic Retina
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Retina Vitreous Consultants
state: Pennsylvania
city: Pittsburgh
country: United States
facility: University of Pittsburgh Medical Center
state: Pennsylvania
city: Columbia
country: United States
facility: Palmetto Retina Center
state: South Carolina
city: Columbia
country: United States
facility: Carolina Retina Center
state: South Carolina
city: Knoxville
country: United States
facility: Southeastern Retina Associates, PC
state: Tennessee
city: Memphis
country: United States
facility: University of Tennessee
state: Tennessee
city: Nashville
country: United States
facility: Vanderbilt Eye Institute
state: Tennessee
city: Arlington
country: United States
facility: Texas Retina Associates
state: Texas
city: Dallas
country: United States
facility: Texas Retina Associates
state: Texas
city: Dallas
country: United States
facility: UT Southwestern Medical Center
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Houston
country: United States
facility: Retina Consultants of Houston
state: Texas
city: Lubbock
country: United States
facility: Texas Retina Associates
state: Texas
city: Temple
country: United States
facility: Scott and White Memorial Hospital
state: Texas
city: Salt Lake City
country: United States
facility: John Moran Eye Center
state: Utah
city: Burlington
country: United States
facility: Fletcher Allen Health Care
state: Vermont
city: Fairfax
country: United States
facility: The Retina Group of Washington
state: Virginia
city: Silverdale
country: United States
facility: Retina Center Northwest
state: Washington
city: Madison
country: United States
facility: University of Wisconsin
state: Wisconsin
city: Milwaukee
country: United States
facility: The Medical College of Wisconsin
state: Wisconsin
Study officials:
affiliation: National Eye Institute, National Institutes of Health
name: Emily Y Chew, MD
role: STUDY_CHAIR
affiliation: National Eye Institute, National Institutes of Health
name: John Paul SanGiovanni, Sc.D.
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.