PHS 1996Low.

Methods	Physicians Health Study (PHS). Randomised, double‐blind, placebo‐controlled trial with two‐by‐two factorial design.
Participants	Country: United States of America. Number of participants randomised: 22071 US male physicians at age 40 to 84 years, mean age 53 years. Inclusion criteria: US male physicians willing to take part in this trial. Exclusion criteria: chronic liver disease or evidence of abnormal liver function, severe renal disease or evidence of impaired renal function, inflammatory muscle disease or evidence of muscle problems (creatine kinase > 750 IU/L); concurrent treatment with cyclosporin, fibrates, or high‐dose niacin; child‐bearing potential; severe heart failure; some life‐threatening condition other than vascular disease or diabetes (eg, severe chronic airways disease or any cancer other than non‐melanoma skin cancer); or conditions that might limit long‐term compliance (eg, severely disabling stroke, dementia, or psychiatric disorder).
Interventions	Physicians were randomly assigned to one of the four groups including: group 1: active aspirin 325 mg on alternate days plus beta‐carotene placebo; group 2: active beta‐carotene 50 mg on alternate days plus aspirin placebo; group 3: both active agents; or group 4: both placebos. The randomised aspirin component of the study was terminated early, on 25 January 1988. The beta‐ carotene component continued uninterrupted until its scheduled end in December 1995. A total of 11036 physicians were assigned at random to receive beta‐carotene and 11035 to receive beta‐carotene placebo. Time from randomisation to the end of study averaged 12 years, and time of follow‐up 12.9 years.
Outcomes	The primary outcome measures were: overall and within subgroups, incidence of malignant neoplasms (except non melanoma skin cancer), incidence of cardiovascular disease, and overall mortality.
Notes	Compliance with treatment was checked by random serum assessments obtained at unannounced visits to trial participants. Compliance with treatment excellent, the average per cent of pills taken was 97% in both the active and placebo groups. There was 85% compliance with beta‐carotene treatment after five years and 78% after 12 years. The use of vitamin A supplements was reported by only 6% of the placebo group even by the end of trial. By December 31, 1995, the scheduled end of the trial, less than 1% of the participants were lost to follow up. Active trial packs and matching placebos were provided by: aspirin (Bufferin) by Bristol Meyers; beta‐carotene (Lurotin), BASF corporation. Additional information received through personal communication with the authors. Data were extracted from the article: Cook et al. Effects of beta‐carotene supplementation on cancer incidence by baseline characteristics in the Physicians' Health Study (United States). Cancer Causes and Control 2000; 11: 617‐26, with extended follow‐up of 12.9 years.
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.