AREDS2 2013.

Methods	Parallel group RCT Method of allocation: coded tablets Masking: participant ‐ yes; provider ‐ yes; outcome ‐ yes Loss to follow‐up: Quote: "Of the 4203 randomised participants, 141 (3%) were lost to follow‐up and 368 (9%) died during the course of the study. Distributions were similar across the 4 treatment groups." Quote: "Participants lost to follow‐up or who died during the course of the study were censored at the time of last contact." See follow‐up data below ‐ 99% of participants were included in the analysis.
Participants	Country: USA Number of people randomised: 4203 (6916 eyes) Number (%) of people followed up: 4176 (99%) using LOCF (6891 eyes) Average age (range): 74 years (68 to 79) Percentage women: 56% Ethnic group: 97% white Baseline visual acuity: average 78 letters on EDTRS chart Comorbidities affecting the eye: 25% bilateral pseudophakic, 13% with diabetes Percentage current smokers: 7% Inclusion criteria: high risk of progression to advanced AMD with either bilateral large drusen or non‐foveal geographic atrophy (no advanced AMD) or large drusen or non‐foveal geographic atrophy in one eye and advanced AMD in the fellow eye (AREDS Simple Scale Score of 2, 3 or 4) age 50 to 85 years took at least 75% of study medication during the run‐in phase able and willing to consent to both the qualification and the randomisation/follow‐up phases of the study likely, willing, and able to undergo yearly examinations for at least five years agreed to stop current use of supplements containing lutein, zeaxanthin, omega‐3 LCPUFAs (specifically DHA+EPA), vitamin C, vitamin E, beta‐carotene, zinc or copper, other than those supplied by AREDS2 fundus photographs of adequate quality as assessed with a standardized protocol by the Reading Center (University of Wisconsin Fundus Photograph Reading Center) randomised within three months following the qualification visit Exclusion criteria: the presence of ocular disease in either eye that may have confounded evaluation of the retina previous retinal or other ocular surgical procedures (other than cataract extraction) that may have complicated assessment of the progression of AMD a chronic requirement for any systemic or ocular medication administered for other diseases and known to be toxic to the retina or optic nerve previous daily supplementation with 2 mg or more of lutein, or 500 mg or more of omega‐3 LCPUFAs, or both, for a period of 1 year or more prior to the date of randomization. (A participant was eligible for the study if he or she agreed to stop taking these supplements during the study run‐in period) intraocular pressure of 26 mm Hg or higher, or some reason to believe that the participant might have glaucoma cataract surgery within 3 months or capsulotomy within 6 weeks prior to the qualification visit history of lung cancer any systemic disease with a poor five‐year survival prognosis haemochromatosis Wilson’s disease recent diagnosis of oxalate kidney stones any condition that would make adherence or follow‐up difficult or unlikely current participation in other studies that might affect adherence to the AREDS2 follow‐up schedule use of systemic anti‐angiogenic therapy for treatment of choroidal neovascularization or cancer
Interventions	Intervention: lutein 10 mg and zeaxanthin 2 mg (1 tablet/day) 2123 people randomised (3468 eyes) 2107 (99%) people followed up (3451 eyes) Comparator: placebo (1 tablet/day) 2080 people randomised (3448 eyes) 2069 (99%) people followed up (3440 eyes) Almost all participants in both intervention and comparator groups took AREDS supplement and multivitamin with the study medication. Duration: 5 years (median) Similarity between intervention and comparator: The placebo was composed from free flowing corn starch‐coated matrix of beadlets formed into a tablet of identical shape, size, and coating/internal colour (using the same quantity of colorings agents) as that containing lutein + zeaxanthin. Other study arm: There was another study arm looking at docosahexaenoic acid (DHA) 350 mg and eicosapentaenoic acid (EPA) 650 mg (2 soft‐gel capsules/day); it was not included in this review
Outcomes	Primary: • progression to advanced AMD in people at moderate to high risk for progression Secondary: • progression to moderate vision loss • adverse events • progression of lens opacity or incidence of cataract surgery • effect of study supplements on cognitive function • effect of DHA/EPA on cardiovascular morbidity and mortality Follow‐up: annual follow‐up for 5 years Eyes: Quote: "The unit of analysis for ophthalmic outcomes was by eye. The primary efficacy outcome, time to progression to advanced AMD, was assessed using a Cox proportional hazards model incorporating the method of Wei et al for obtaining robust variance estimates that allows for dependence among multiple event times (1 or 2 study eyes)."
Notes	Source of funding: Quote: "This study is supported by the intramural program funds and contracts from the National Eye Institute/National Institutes of Health (NEI/NIH), Department of Health and Human Services, Bethesda, MD. Contract No. HHS‐N‐260‐2005‐00007‐C. ADB Contract No. N01‐EY‐5‐0007. Funds were generously contributed to these contracts by the following NIH institutes: Office of Dietary Supplements (ODS), National Center for Complementary and Alternative Medicine (NCCAM), National Institute on Aging (NIA), National Heart, Lung and Blood Institute (NHLBI), and National Institute of Neurological Disorders and Stroke (NINDS)" Declaration of interest: Quote: "A complete list of all AREDS2 investigator financial disclosures, which were collected for regulatory purposes, pursuant to US FDA regulations in 21 CFR Part 54, can be found at www.areds2.org. The member(s) of the writing committee have made the following disclosure(s): Frederick L. Ferris III; Bausch & Lomb (P) and the remainder had no conflicts of interest." Date study conducted: September 2006 to October 2012 (from clinicaltrials.gov entry) Trial registration number: NCT00345176
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "A random block design was implemented using the AREDS2 Advantage Electronic Data Capture system (AdvantageEDC SM ) by the AREDS2 Co‐ordinating Center (The EMMES Corporation, Rockville, Maryland) and stratified by clinical center and AMD status (large drusen both eyes or large drusen in one eye and advanced AMD in the fellow eye) to assure approximate balance across centers over time."
Allocation concealment (selection bias)	Low risk	Judgement comment: Central co‐ordinating centre organised the random allocation and placebo controlled study.
Blinding of participants and personnel (performance bias) Visual acuity	Low risk	Judgement comment: Placebo controlled trial. Personnel measuring visual acuity unaware of allocation. Quote: "All 4 formulations are balanced on excipients and packaged in capsules of identical size, shape and color."
Blinding of participants and personnel (performance bias) Progression AMD	Low risk	Judgement comment: Placebo controlled trial. Fundus images graded by masked graders. Quote: "All 4 formulations are balanced on excipients and packaged in capsules of identical size, shape and color."
Blinding of outcome assessment (detection bias) Visual acuity	Low risk	Judgement comment: Placebo controlled trial. Personnel measuring visual acuity unaware of allocation. Quote: "All 4 formulations are balanced on excipients and packaged in capsules of identical size, shape and color."
Blinding of outcome assessment (detection bias) Progression AMD	Low risk	Judgement comment: Placebo controlled trial. Fundus images graded by masked graders. Quote: "All 4 formulations are balanced on excipients and packaged in capsules of identical size, shape and color."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Of the 4203 randomised participants, 141 (3%) were lost to follow‐up and 368 (9%) died during the course of the study. Distributions were similar across the 4 treatment groups."
Selective reporting (reporting bias)	Low risk	Judgement comment: AMD outcomes pre‐specified in clinical trials registry and in published protocol paper were reported.