National Eye Institute (NEI) Age-Related Eye Disease Study 2 (AREDS2)

The Age-Related Eye Disease Study 2 (AREDS2) was a multi-center, randomized Phase III clinical trial designed to assess the effects of oral supplementation of high doses of lutein, zeaxanthin, and omega-3 fatty acids (docosahexaenoic acid [DHA] and eicosapentaenoic acid [EPA]) in reducing the risk of progression to late age-related macular degeneration (AMD), progression to cataract surgery, and/or progression to moderate vision loss in high-risk participants. The effect of the study supplements on cardiovascular outcomes and cognitive function were also examined. Other study goals included evaluation of eliminating beta-carotene and/or reducing zinc in the original AREDS formulation on the progression and development of late AMD. AREDS2 sought to validate the AREDS AMD scale developed from the photographic data obtained from AREDS, (Study Accession: phs000001).

Eighty-two clinical sites across the United States enrolled 4,203 participants aged 50 to 85 (mean age 74 years) between October 2006 and September 2008. Enrollment was restricted to people at high risk of progression to late AMD with either bilateral large drusen or large drusen in 1 eye and late AMD in the fellow eye. Follow-up assessments in the clinic occurred on an annual basis for an average of 5 years, with telephone calls every six months during each year.

Blood or saliva samples were also collected from 2,000+ AREDS2 participants for genetic research. Of these, samples from 1,800+ AREDS2 participants were included in the International Age-Related Macular Degeneration Genomics Consortium - Exome Chip Experiment, and have exome chip data available in the dbGaP (Study Accession: phs001039). In addition, samples from 1300+ AREDS2 participants were included in the  International Age-Related Macular Degeneration Genomics Consortium - Whole Genome Sequencing Study in the dbGaP (Study Accession: TBD).

• Study Design:
  • Case Set
• Study Type:
  • Case Set
  • Clinical Trial
• dbGaP estimated ancestry using GRAF-pop
• Total number of consented subjects: 4203
• Subject Sample Telemetry Report (SSTR)

• Clinical Trials
  • NCT00345176

Inclusion Criteria

Children are not included because AMD is, by definition, an adult disease.

1. Men and women aged 50 to 85 years at the Qualification Visit.
2. Bilateral large drusen (≥ 125 microns) or large drusen in one eye and advanced AMD in the fellow eye. A study eye (eye without advanced AMD) may have definite geographic atrophy not involving the center of the macula without evidence of drusen.
3. Study eye(s) with fundus photographs assessed by the Reading Center to be of adequate photo quality.
4. Pupillary dilation ≥ 5 mm in each eye for all participants, except that dilation < 5 mm in an aphakic or pseudophakic eye will not exclude a participant with adequate quality fundus photographs.
5. Randomization within three months following the Qualification Visit.
6. Willingness to stop taking any supplements containing lutein, zeaxanthin, omega-3 LCPUFAs (specifically DHA and EPA), vitamin C, vitamin E, beta-carotene, zinc or copper, other than those supplied by AREDS2. Willingness to stop taking other supplements is demonstrated by refraining from use of vitamin or mineral supplements that are part of the randomized trial during the entire run-in period. Continued use of nutritional supplements that are not part of the randomized trial (e.g., calcium) does not exclude a participant, provided that these supplements are taken one to two hours before or after the study supplements. If the participant wants to continue taking a multivitamin and/or multimineral supplement during the study he/she will be provided Centrum Silver®.
7. Demonstration that at least 75 percent of run-in medication was consumed, as determined by an estimated count of the remaining run-in tablets/capsules (exceptions may be made by appeal to the AREDS2 Coordinating Center) and willingness to take the randomized trial supplements for the next five years.
8. Likelihood, willingness, and ability to undergo examinations at yearly intervals for at least five years.
9. People who currently smoke are eligible to enroll in this study. However if the smoker elects to participate in the AREDS-type supplement (ATS) formulation randomization, they will be randomized to one of the two arms of the AREDS formulation without beta-carotene.
10. Ability and willingness to consent to both the Qualification and the Randomization/Follow up phases of the study. Participants will be provided a Participant Information Booklet that will explain the overall study. For clinical sites using two consent forms, the First Informed Consent describes the responsibilities of the participant and the study during the run-in period. The Second Informed Consent describes responsibilities following randomization. For clinical sites using the AREDS2 Central IRB or whose local IRB requests it, the information in the First and Second Informed Consent has been combined into one document that must be signed at the Qualification Visit. For sites using two consent forms, an AREDS2 Second Informed Consent must be signed, even if a First Informed Consent was signed previously.
11. Participants with advanced AMD in one eye may have received treatment for advanced AMD in the eye identified as having advanced AMD. These treatments include: intravitreal injections of pharmacological agents (i.e. Avastin®, Lucentis™, Macugen®, Kenalog, and others), laser, photodynamic therapy and others. However, a participant is not eligible if the fellow (study) eye has ever received any of these treatments for advanced AMD.

Exclusion Criteria

1. Ocular disease in either eye, other than AMD, which may confound assessment of the retina, including:
   1. Diabetic retinopathy unless retinopathy is limited to fewer than 10 microaneurysms and/or small retinal hemorrhages,
   2. Angioid streaks,
   3. Central serous choroidopathy,
   4. Surface wrinkling retinopathy (epiretinal membrane) that is more severe than the mild surface wrinkling retinopathy,
   5. Optic atrophy,
   6. Pigmentary abnormalities considered by the Clinical Center ophthalmologist to be less typical of AMD than of some other condition, such as pattern dystrophy or chronic central serous retinopathy,
   7. Myopic crescent of the optic disc the width of which is ≥ 50% of the longest diameter of the disc, or pigmentary abnormalities in the posterior pole considered by the clinic ophthalmologist more likely to be due to myopia than to AMD,
   8. Macular hole or pseudohole,
   9. Retinal vein occlusion, active uveitis, presumed ocular histoplasmosis syndrome, other sight-threatening retinopathies, and other retinal degenerations, significant explained or unexplained visual field loss, or any other type of retinopathy or retinal degeneration,
   10. A choroidal nevus within 2 DD of the center of the macula associated with depigmentation or overlying atypical drusen.
   11. Epiretinal membrane of significant size located in the macular area that potentially can cause vision loss.
   12. Other ocular diseases or conditions, the presence of which may now or in the future complicate evaluation of AMD.
   13. Amblyopia (in study eye only)
2. Previous retinal or other ocular surgical procedures, the effects of which may now or in the future complicate assessment of the progression of AMD. Examples are argon laser trabeculoplasty, radial keratotomy, trabeculectomy, cryosurgery (except to repair a peripheral retinal hole), lamellar keratoplasty, pterygium surgery that affects or threatens the visual axis, radiation for ocular tumor, or repair of corneal or sclera laceration. Cataract surgery more than three months prior to randomization is not an exclusion criterion, unless complicated by a condition that is causing, or is likely to cause, a decrease in visual acuity. Laser photocoagulation for drusen and non-choroidal neovascularization in the non-study eye will not be exclusion factors.
3. Chronic requirement for any systemic or ocular medication administered for other diseases such as glaucoma and known to be toxic to the retina or optic nerve, such as:
   1. Deferoxamine
   2. Chloroquine/Hydroxychloroquine (Plaquinil)
   3. Tamoxifen
   4. Chlorpromazine
   5. Phenothiazines
   6. Chronic systemic steroid use of at least 10 mg per day or more
   7. Ethambutol
4. Unwillingness or inability to stop taking supplements containing lutein, zeaxanthin, omega-3 LCPUFAs, vitamin C, vitamin E, betacarotene, zinc or copper during the run-in period and for the next five years, or failure to take at least 75 percent of run-in medication as determined by a estimated count of placebo tablets and capsules (exceptions may be made by appeal to the AREDS2 Coordinating Center).
5. Participants supplementing with 2 mg or more of lutein and/or 500mg or more of omega-3 long-chain polyunsaturated fatty acids (DHA and EPA) for a period of 1 year or more prior to the date of randomization. A participant is eligible for the study if he/she agrees to refrain from taking these supplements during the Qualification period.
6. Intraocular pressure 26 mm Hg or higher, or if there is some reason to believe that the participant may have glaucoma (e.g., history of the diagnosis of glaucoma, past or present use of medications to control intraocular pressure, or disc/nerve fiber layer defects suggestive of glaucoma), then the absence of a glaucomatous visual field defect must be documented by a normal Goldmann, Humphrey, or Octopus perimetry test within 6 months prior to qualification. (In the judgment of the investigator, the participant may be ineligible due to glaucoma based upon IOP measurements, disc/nerve fiber layer defects suggestive of glaucoma, and visual field abnormalities).
7. Cataract surgery within three months or capsulotomy within six weeks prior to the Qualification Visit.
8. History of lung cancer.
9. Any systemic disease with a poor five-year survival prognosis (e.g. cancer, cardiovascular disease). If a vascular condition appears stable and the initial event occurred more than 12 months ago, the participant is eligible for the study.
10. Hemochromatosis, Wilson's Disease, or recent diagnosis of oxalate kidney stones.
11. Participant that has any condition that would make adherence or follow-up to the examination schedule of annual intervals for at least five years difficult or unlikely (e.g., personality disorder, use of major tranquilizers such as Haldol or Phenothiazine, chronic alcoholism or drug abuse).
12. Current participation in other studies that is likely to affect adherence with the AREDS2 follow-up schedule.
13. Participant is taking a systemic anti-angiogenic (such as squalamine lactate, avastin, etc.) for treatment of choroidal neovascularization or cancer. The use of intravitreal anti-VEGF such as Avastin®, Lucentis™, or Macugen®, in the eye that had advanced AMD at baseline is allowed. However, a participant is not eligible if the fellow (study) eye has ever received any of these treatments for advanced AMD.

Eye disorders presenting in late adulthood contribute a substantial burden to society as the primary cause of blinding conditions and low vision. Human and animal studies provided a reasonable basis for speculating that certain nutrients accreted to and concentrated in the eye have the capacity to modulate factors and processes implicated in the pathogenesis of AMD and cataract. Results from the Age-Related Eye Disease Study (AREDS), phs000001, on the relationship of lutein/zeaxanthin and omega-3, long-chain polyunsaturated fatty acid (LCPUFA) intake with advanced AMD were informative, yet the non-experimental sampling (observational) design limited the strength of inference. AREDS2 was a multi-center Phase III randomized clinical trial designed to assess the effects of oral supplementation of high doses of macular xanthophylls (lutein and zeaxanthin) and/or omega-3 LCPUFAs as a treatment for AMD, cataract and moderate vision loss.

• Primary Phenotype: Macular Degeneration
• Cataract

• Study Sponsor - National Eye Institute
  • Emily Chew, MD, Study Chair. National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
  • Frederick Ferris III, MD, NEI Clinical Director. National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
  • John Paul SanGiovanni, ScD, Project Officer. National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
• Coordinating Center - The Emmes Company
  • Traci Clemons, PhD, Principal Investigator. The Emmes Company, Rockville, MD, USA.
  • Anne Lindblad, PhD, Co-Investigator. The Emmes Company, Rockville, MD, USA.
  • Robert Lindblad, MD, Chief Medical Officer. The Emmes Company, Rockville, MD, USA.
  • Wendy McBee, MS, Project Director. The Emmes Company, Rockville, MD, USA.
  • Gary Gensler, MS, Statistician. The Emmes Company, Rockville, MD, USA.
  • Molly Harrington, MS, ForeseeHome Project Director. The Emmes Company, Rockville, MD, USA.
  • Alice Henning, MS, Director of Genetics Ancillary Study. The Emmes Company, Rockville, MD, USA.
• Fundus Photograph Reading Center - University of Wisconsin
  • Amitha Domalpally, MD, PhD, Co-Director. University of Wisconsin, Madison, WI, USA.
  • Ronald Danis, MD, Principal Investigator. University of Wisconsin, Madison, WI, USA.
  • Barbara Blodi, MD, Co-Principal Investigator. University of Wisconsin, Madison, WI, USA.
  • Ronald Klein, MD, Co-Principal Investigator. University of Wisconsin, Madison, WI, USA.
• Central Laboratory - Centers for Disease Control and Prevention
  • Rosemary Schleicher, PhD, Lead Investigator. Centers for Disease Control and Prevention, Atlanta GA, USA.
• Funding Source
  • N01-EY-5-0007. National Institutes of Health, Bethesda, MD, USA.