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

• ClinicalTrials.gov Identifier: NCT00345176
• Recruitment Status: Completed
• First Posted: June 27, 2006
• Results First Posted: December 24, 2013
• Last Update Posted: May 5, 2015
• Sponsor: National Eye Institute (NEI)
• Collaborators: National Heart, Lung, and Blood Institute (NHLBI); Office of Dietary Supplements (ODS); National Center for Complementary and Integrative Health (NCCIH)
• Information provided by (Responsible Party): National Eye Institute (NEI)

Tracking Information

• First Submitted Date: June 14, 2006
• First Posted Date: June 27, 2006
• Results First Submitted Date: November 1, 2013
• Results First Posted Date: December 24, 2013
• Last Update Posted Date: May 5, 2015
• Study Start Date: September 2006
• Actual Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 1, 2013)

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.

• Original Primary Outcome Measures (submitted: June 23, 2006): Progression to advanced AMD and/or moderate vision loss in people at moderate to high risk for progression.

Current Secondary Outcome Measures (submitted: November 1, 2013)

• 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
• Adverse Events [ Time Frame: 5 years of follow-up ]
  Safety outcomes included serious adverse events and mortality.
• 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.

• Original Secondary Outcome Measures: Not Provided

Current Other Pre-specified Outcome Measures (submitted: April 13, 2015)

• Incident Cardiovascular Disease [ Time Frame: 5 years of follow-up ]
  Effects of oral supplementation of omega-3 fatty acids, lutein/zeaxanthin on cardiovascular disease
• 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
• 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
• Genetics for the Association of AMD and Cataract [ Time Frame: 5 years of follow-up ]
• Genetics for the Progression of AMD and Cataract [ Time Frame: 5 years of follow-up ]

• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment

Condition

• Age-related Macular Degeneration
• Cataract

Intervention

• Dietary Supplement: Lutein/zeaxanthin
  10 mg lutein and 2 mg zeaxanthin (1 tablet) Placebo-DHA/EPA (2 soft-gel capsules)
• Dietary Supplement: DHA/EPA
  Placebo-lutein/zeaxanthin (1 tablet) 350 mg DHA and 650 mg EPA (2 soft-gel capsules)
  Other Name: docosahexaenoic acid; eicosapentaenoic acid
• 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)

Study Arms

• Active Comparator: Lutein/Zeaxanthin
  lutein (10mg)/zeaxanthin (2 mg)
  Intervention: Dietary Supplement: Lutein/zeaxanthin
• Active Comparator: DHA/EPA
  DHA (350 mg)/EPA (650 mg)
  Intervention: Dietary Supplement: DHA/EPA
• Active Comparator: Lutein/Zeaxanthin + DHA/EPA
  lutein (10 mg)/zeaxanthin (2 mg) + DHA (350 mg)/EPA (650 mg)
  Intervention: Drug: Lutein/zeaxanthin and DHA/EPA
• Placebo Comparator: Placebo/Control
  Considered control because all participants received the AREDS formulation

Publications *

• Chew EY, Clemons TE, Agrón 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.
• 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 ω-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.
• 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, Agrón 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.
• 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.
• 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.
• 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.
• 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. Erratum in: JAMA. 2013 Jul 10;310(2):208.
• 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.
• 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.
• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: April 30, 2013): 4203
• Original Enrollment (submitted: June 23, 2006): 4000
• Actual Study Completion Date: October 2012
• Actual Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 50 Years to 85 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00345176
• 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 )
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: National Eye Institute (NEI)
• Study Sponsor: National Eye Institute (NEI)

Collaborators

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

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

• PRS Account: National Eye Institute (NEI)
• Verification Date: April 2015