PHS II 2012.

Methods	Method of allocation: coded tablets Masking: participant: yes; provider: yes; outcome: yes 95% follow‐up 2 x 2 x 2 x 2 factorial design.
Participants	Country: USA Number randomised: 14,236 with no diagnosis of AMD at baseline according to vitamin C/E paper; 14,233 with no diagnosis of AMD at baseline according to multivitamin paper. Average age: 64 years Sex: male Inclusion criteria: US male physicians; 50 years and older; participants in PHS I and new physician participants; willing to forego use of supplements for new trial; for new participants, do not report personal history of cancer (except non‐melanoma skin cancer). CVD, current liver disease, current renal disease, peptic ulcer or gout. Compliance with pill‐taking regimen in run‐in period. Exclusion criteria:History of cirrhosis; active liver disease in past six months; participants reporting cataract or AMD at baseline.
Interventions	Intervention: vitamin E (400 IU/alternate days) N = 7112 vitamin C (500 mg/day) N = 7149 multivitamin (Centrum silver: zinc 15 mg, vitamin E 45 IU, vitamin C 60 mg, beta‐carotene 5000 IU, vitamin A ‐ 20% as beta carotene, folic acid 2.5 mg, vitamin B6 50 mg, vitamin B12 1 mg/ day) N = 7111 Comparator: separate placebos for each type of vitamin: vitamin E placebo N = 7124, vitamin C placebo N = 7087, multivitamin placebo N = 7122 Alternate day beta‐carotene (50 mg) component terminated in March 2003. Lutein (added to Centrum Silver during course of study (250 µg) and doses of other nutrients changed Follow‐up: the multivitamin component had a longer duration. "An average of 8 years of treatment and follow‐up" for vitamin E and vitamin C Median duration of treatment for multivitamin analyses 11.2 years, IQR 10.7 to 13.3
Outcomes	Age‐related macular degeneration: reported diagnosis followed up by contact with treating ophthalmologist/optometrist Quote "We considered individuals, rather than eyes, as the unit of analysis and we classified individuals according to the status of the worse eye as defined by disease severity. When the worse eye was excluded because of visual acuity loss attributed to other ocular abnormalities, the fellow eye was considered for classification."
Notes	Funding source: Grants from National Eye Institute, National Institute on Ageing and the National Institutes of Health. BASF and DSM provided study agents and packaging. Declarations of interest: "The authors have no proprietary or commercial interest in any of the materials discussed in this article." Date study conducted: July 1997 to June 2011 (from clinicaltrials.gov) Trial id: NCT00270647
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Quote "Randomisation to the other agents, using a computer generated list of random numbers, will be stratified according to age"
Allocation concealment (selection bias)	Low risk	Judgement comment: central randomisation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Quote "The Physicians’ Health Study (PHS II) was a randomised, double‐blind, placebo‐controlled, factorial trial evaluating a daily multivitamin (Centrum Silver), alternate day vitamin E (400 IU synthetic α‐tocopherol), and daily vitamin C (500 mg synthetic ascorbic acid) in the prevention of cancer and CVD among 14,641 male physicians aged 50 years and older."
Blinding of outcome assessment (detection bias) AMD	Low risk	Quote "Random misclassification was reduced by the use of medical records to confirm the participant reports. Non‐random misclassification was unlikely since medical records were reviewed by an investigator (WGC) masked to treatment assignment, and study participants and treating ophthalmologists and optometrists were similarly unaware of treatment assignment."
Incomplete outcome data (attrition bias) All outcomes	Low risk	Quote "Morbidity and mortality follow‐up were extremely high, at 95.3% and 97.9%, respectively."
Selective reporting (reporting bias)	Low risk	Judgement comment: reported AMD outcomes as expected