AREDS2 2014.

Methods	Age‐Related Eye Disease Study 2 (AREDS2) RCT, parallel, 2 × 2 factorial (n‐3 EPA + DHA vs nil) also randomised to lutein and zeaxanthin vs nil), 5 years Summary risk of bias: low
Participants	People aged 50‐85 years at high risk of progression to advanced age‐related macular degeneration (AMD) N: 2147 intervention (1068 DHA/EPA, 1079 DHA/EPA + lutein/zeaxanthin), 2056 control (1012 placebo, 1044 lutein/zeaxanthin) Level of risk for CVD: low (however ˜20% had previous CV event) Men: intervention 42.1%, control 44.4% Age in years: intervention median 74.6 (IQR 11.1), control median 74 (IQR 11.1) Age range: 68‐79 years Smokers: intervention 6.3%, control 7.2% Hypertension: unclear Medications taken by at least 50% of those in the control group: multivitamins Medications taken by 20%‐49% of those in the control group: cholesterol lowering drugs, aspirin Medications taken by some, but less than 20% of the control group: NSAID, paracetamol Location: USA Ethnicty: white 96.5% intervention, 96.6% control; Hispanic: 2.6 intervention, 1.3 control
Interventions	Type: supplement (capsule) Comparison: EPA + DHA vs nil Intervention 350 mg/d DHA plus 650 mg/d EPA added to the standard AREDS supplement of Vitamin C (500 mg/d), Vitamin E (440 IU/d), beta‐carotene (15 mg/d), zinc oxide (80 mg/d) and cupric oxide (2 mg/d). Dose: +1 g/d EPA + DHA Control: standard AREDS supplement of Vitamin C (500 mg/d), Vitamin E (400IU/d), beta‐carotene (15 mg/d), zinc oxide (80 mg/d) and cupric oxide (2 mg/d). Compliance: assessed by pill count – 84% of participants in each group took at least 75% of study medications Length of intervention: 60 months
Outcomes	Main study outcome: development of advanced AMD Dropouts: intervention 200 died, 165 discontinued, 80 were lost to follow‐up; control 168 died, 140 discontinued, 61 were lost to follow‐up Available outcomes: deaths, cardiovascular death, MI, stroke, angina, heart failure, revascularisation, cognition, eye health, (authors provided data on diabetes diagnosis, depression diagnosis, breast cancer) Response to contact: yes (data provided)
Notes	Study funding: National Eye Institute/National Institutes of Health, Department of Health and Human Services
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote: "random block design was implemented using the AREDS2 Advantage Electronic Data Capture system by the AREDS2 Coordinating Center"
Allocation concealment (selection bias)	Low risk	Each treatment was assigned 5 bottle numbers. Bottle numbers were issued via an electronic randomisation system for each participant once study eligibility was verified. The assigned bottle number was used to distribute the study treatment(s). AREDS2 Coordinating centre personnel involved in creating the randomisation system had access to the bottle number/treatment assignments.
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"Participants, investigators, study coordinators, and all other study personnel are masked to treatment assignment". However, no information was given regarding the taste, smell, or appearance of the active or placebo capsules.
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The coordinating centre randomly assigned the event to a study adjudicator, who made the final determination of these study endpoints through review of the medical records and applying the endpoint criterion defined a priori. All adjudicators were masked to study assignment.
Incomplete outcome data (attrition bias) All outcomes	Low risk	< 20% attrition over 5 years, balanced reasons for dropouts
Selective reporting (reporting bias)	Low risk	Outcomes in trials registry entry appear to all be reported (NCT00345176). Entry received June 2006, recruitment September 2006 – October 2012
Attention	Low risk	Participants, investigators, study coordinators, and all other study personnel are masked to treatment assignment, so attention bias not feasible
Compliance	Unclear risk	Assessed by pill count – 84% of participants in each group took at least 75% of study medications
Other bias	Low risk	None noted