CARET 2004Low.

Methods	The Beta‐Carotene and Retinol Efficacy Trial (CARET). Randomised, double‐blind, placebo‐controlled trial with two‐by‐two factorial design in a pilot phase and then one‐by‐one.
Participants	Country: United States of America. Number of participants randomised: 18314; 12025 males and 6289 females. Inclusion criteria: smokers, former smokers, and workers exposed to asbestos at high risk of developing lung cancer. A total of 4060 male workers, mean age 57 years, exposed to asbestos and 14254 heavy smokers (44% of whom were women), mean age 58 years, were randomised. The participants agreed to limit their supplemental intake of vitamin A to less than 5500 IU per day and to take no supplemental beta‐carotene.
Interventions	CARET builds on the experience of two pilot studies performed in Seattle (1985‐1988). The first pilot study initiated a phase III trial of the safety and efficacy of the study vitamins in 816 asbestos‐exposed participants randomised to a daily combination of 15 mg 13‐carotene and 25,000 IU retinol or a placebo medication. Participants were eligible up to age 74 and were not required to have a history of cigarette smoking; otherwise, the eligibility criteria were the same as for the asbestos‐exposed population in CARET. The second pilot study was a phase II trial of the comparative safety of the study vitamins in heavy smokers. The eligibility criteria were identical to those for heavy smokers in CARET. Overall 539 men and 490 women were randomised to one of four intervention groups: group 1: a daily combination of 30 mg beta‐carotene and 25,000 IU retinol; group 2: 30 mg beta‐carotene only; group 3: 25,000 IU retinol only; group 4: placebo medication. All 1845 participants in the two pilot studies continue to be followed for outcomes in CARET, together with approximately 16,000 additional participants. Participants of CARET trial were randomly assigned to receive: group 1: combination of 30 mg beta‐carotene and 25,000 IU vitamin A (n = 9420); group 2: placebo, (n = 8894). Both formulations were given as capsules. Beta‐carotene beadlets were combined with retinyl palmitate in a single capsule and dispensed in bottles, which were weighed and their content checked. The design projected active intervention until late 1997. The CARET active intervention was stopped 21 months earlier because of clear evidence of no benefit and substantial evidence of possible harm. The average duration of follow‐up was 10.0 years
Outcomes	The primary outcome measure was: the incidence of lung cancer. Other outcomes reported are: mortality rates, and incidence of other cancers.
Notes	Compliance was assessed by weighing the returned bottles to estimate the number of capsules remaining (in 85% of the assessments), or by relying on the participants own estimates (in 15% of the assessments). Compliance with treatment was excellent. Among the active participants, the mean rate of capsule consumption was 93% through five years of follow‐up, with no significant differences between the treatment groups. Participants who stopped receiving study vitamins for any reason other than death were defined as inactive participants and were still followed for outcomes and counted in the analysis. As of December 15, 1995 ascertainment of vital status for more than 98% was complete. The losses to follow‐up were less than 2% at the end of treatment. Active agents and placebos were purchased from Hoffmann‐La Roche and formulated by Tischon Corporation. Data were extracted from the primary publication, but additional information was received through personal communication with the authors.
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.