AREDS 2001.

Methods	Parallel group RCT 2 x 2 factorial design. 67% participants took additional supplements to RDA levels (Centrum). In 1996 current smokers offered option of discontinuing supplementation; 2% of participants and 18% of smokers did so. A further 2.3% reassigned to no beta‐carotene group. Intention‐to‐treat analysis maintained. Method of allocation: coded bottles Masking: participant ‐ yes; provider ‐ yes; outcome ‐ yes Losses to follow‐up: 2.4% balanced across study groups
Participants	Country: USA Number of people randomised: 3640 (eyes unknown) Number (%) of people followed up: 2.4% lost to follow up Average age (range): 69 years (55 to 80) Percentage women: 56% Ethnic group: 96% white Baseline visual acuity: unknown Comorbidities affecting the eye: unknown Percentage current smokers: 8% Inclusion criteria: 20/32 or better in at least 1 eye ocular media clear and therefore able to obtain adequate stereoscopic fundus photographs at least 1 eye free from eye disease that could complicate assessment of AMD Exclusion criteria: illness or disorders that would make long‐term follow‐up or compliance with study protocol unlikely or difficult
Interventions	Intervention: antioxidants vitamin C 500 mg, vitamin E 400 IU, beta‐carotene 15 mg (daily) zinc 80 mg as zinc oxide, copper 2 mg as cupric oxide (daily) 2737 people randomised (eyes unknown) (945 antioxidants only, 904 zinc only, 888 antioxidants plus zinc) 2.4% lost to follow‐up but numbers by group not reported. Quote: "Participants without photographic or visual acuity follow‐up were evenly distributed across treatment groups." Comparator: placebo 903 people randomised (eyes unknown) 2.4% lost to follow‐up but numbers by group not reported. Quote: "Participants without photographic or visual acuity follow‐up were evenly distributed across treatment groups." Duration: average follow‐up 6.3 years Similarity between intervention and comparator: Quote: "Study medication tablets for the 4 treatment groups were identical in external appearance and similar in internal appearance and taste."
Outcomes	Primary: progression to advanced AMD (assessed using stereoscopic fundus colour photograph) 15 letter or more decrease in visual acuity score (EDTRS logMAR chart) Secondary: safety outcomes included: reported adverse events; serum levels of haemoglobin; hospitalisations and mortality. Follow‐up: annual follow‐up for at least 5 years Eyes: outcome was "in at least one eye" i.e. reported by person
Notes	Source of funding: Quote: "Supported by contracts from the National Eye Institute, National Institutes of Health, with additional support from Bausch and Lomb Pharmaceuticals." Declaration of interest: Quote: "The AREDS investigators have no commercial or proprietary interest in the supplements used in this study." Date study conducted: 1992 to 2001 Trial registration number: unknown
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "Simple randomization, stratified by clinical center and AMD category, was used to assign treatment. Participants in Categories 2, 3, and 4 were assigned with probability one quarter to each treatment group" Quote: "Multiple unique bottle codes were randomly assigned to each of the 4 treatments for Categories 2, 3, and 4, and also to each of the 2 treatments for participants in Category 1. A bottle code corresponding to the assigned treatment was randomly selected for each participant".
Allocation concealment (selection bias)	Low risk	Quote: "Multiple unique bottle codes were randomly assigned to each of the 4 treatments for Categories 2, 3, and 4, and also to each of the 2 treatments for participants in Category 1. A bottle code corresponding to the assigned treatment was randomly selected for each participant".
Blinding of participants and personnel (performance bias) Visual acuity	Low risk	Quote: "The 4 treatment interventions were double‐masked..." "Study medication tablets for the 4 treatment groups were identical in external appearance and similar in internal appearance and taste. The coordinating center was custodian of the treatment code" Quote: "Four participants (0.1%) were reported to have been unmasked during the trial"
Blinding of participants and personnel (performance bias) Progression AMD	Low risk	Quote: "The 4 treatment interventions were double‐masked..." Quote: "Study medication tablets for the 4 treatment groups were identical in external appearance and similar in internal appearance and taste. The coordinating center was custodian of the treatment code" Quote: "Four participants (0.1%) were reported to have been unmasked during the trial"
Blinding of outcome assessment (detection bias) Visual acuity	Low risk	Quote: "Visual acuity was assessed by certified examiners using the ETDRS logMAR chart and a standardized refraction and visual acuity protocol (AREDS Manual of Operations; The EMMES Corporation, Rockville, Md)"
Blinding of outcome assessment (detection bias) Progression AMD	Low risk	Quote: "Stereoscopic fundus photographs of the macula were taken at baseline and annually, beginning 2 years after randomization, and graded centrally using standardized grading procedures."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote: "Participants without photographic or visual acuity follow‐up were evenly distributed across treatment groups." Quote: "Only 2.4% of AREDS participants were lost to follow‐up (missed at least their last 2 consecutive visits). Losses to follow‐up were balanced across treatment groups" Quote: "Of almost 50,000 possible follow‐up visits, 10% were missed. The frequency of missed visits and mean follow‐up time (6.3 years) did not differ by treatment group. Most participants (90%) had at least 5 years of follow‐up."
Selective reporting (reporting bias)	Low risk	Quote: "At the start of the study, 2 primary outcomes were defined for study eyes in the AMD trial: (1) progression to advanced AMD and (2) at least a 15‐letter decrease in visual acuity score."