PHS 2008Low.

Methods	Physicians Health Study II (PHS II). Randomised, double‐blind, placebo‐controlled trial using two‐by‐two‐by‐two‐by‐two factorial design.
Participants	Country: United States of America. Number of participants randomised: 14 641 US male physicians, aged 50 years or older, mean age 64.3 years. Inclusion criteria: US male physicians willing to take part in this trial, and willing to forgo during the course of PHS II any current use of multivitamins or individual supplements containing more than 100% of the recommended daily allowance of vitamin E, vitamin C, beta carotene, or vitamin A. Exclusion criteria: a history of cirrhosis, active liver disease, were taking anticoagulants, or reported a serious illness that might preclude participation.
Interventions	Physicians were randomly assigned to receive: group 1: active vitamin E (synthetic alpha tocopherol) 400 IU every other day, ; group 2: placebo vitamin E 400 IU every other day; group 3: active vitamin C 500 mg (synthetic ascorbic acid) daily ; group 4: placebo vitamin C 500 mg daily ; group 5: active beta‐carotene 50 mg every other day; group 6: active beta‐carotene 50 mg every other day; group 7: multivitamin daily (Centrum silver); group 8: placebo multivitamin daily for a mean period of 8 years, median 7.6 years.
Outcomes	The primary outcome measures were cardiovascular diseases, cancer, and mortality. Secondary outcome measure was adverse events.
Notes	Participants were sent monthly calendar packs, containing vitamin E or placebo (taken every other day), and vitamin C or placebo (taken daily), every 6 months for the first year and annually thereafter. Participants also were sent annual questionnaires asking about adherence, potential adverse events, the occurrence of new end points, and updated risk factors. Treatment and follow‐ up continued in a blinded fashion through August 31, 2007, the scheduled end of the vitamin E and C components of PHS II. Beta‐carotene component (50 mg Lurotin or placebo on alternate days; BASF Corporation), was terminated on schedule in March 2003.The multivitamin component is still ongoing. Morbidity and mortality follow‐up were extremely high at 95.3% and 97.7%, respectively. Adherence was defined from participant self‐reports as taking at least two thirds of the study agents. For active vitamin E and its placebo, adherence among participants at 4 years was 78% and 77%, respectively (P = 0.12), and at the end of follow‐up (mean of 8 years), 72% and 70% (P = 0.004). For active vitamin C and its placebo, adherence among participants at 4 years was 78% and 78%, respectively (P = 0.99), and at the end of follow‐up, 71% and 71% (P = 0.54). The trial was supported by grant from BASF Corporation (Florham Park, New Jersey). Study agents and packaging were provided by BASF Corporation, Wyeth Pharmaceuticals (Madison, New Jersey), and DSM Nutritional Products Inc (formerly Roche Vitamins) (Parsippany, New Jersey).
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Sequence generation was achieved using computer random number generation.
Allocation concealment (selection bias)	Low risk	Allocation was controlled by a central and independent randomisation unit so that intervention allocations could not have been foreseen in advance of, or during, enrolment.
Blinding (performance bias and detection bias) All outcomes	Low risk	The trial was described as blinded, the parties that were blinded, and the method of blinding was described, so that knowledge of allocation was adequately prevented during the trial.
Incomplete outcome data (attrition bias) All outcomes	Low risk	The numbers and reasons for dropouts and withdrawals in all intervention groups were described.
Selective reporting (reporting bias)	Low risk	Pre‐defined, or clinically relevant and reasonably expected outcomes are reported on.
Other bias	Low risk	The trial appears to be free of other components that could put it at risk of bias.