Folic acid for the prevention of colorectal adenomas: a randomized clinical trial.

Randomized, double-blind, placebo-controlled multicenter trial in adults with a prior history of colorectal adenomas after a qualifying colonoscopy and safety screening. The active folic acid arm included 516 participants; the placebo arm included 505 participants, with randomization stratified by study center, sex, and age.

Oral folic acid 1 mg/day versus matching placebo, taken daily for a planned 3-year treatment period. Some participants continued in extended follow-up after treatment discontinuation.

Folic acid did not reduce colorectal adenoma recurrence and overall showed no clear benefit, with some outcomes suggesting possible harm. In the first 3-year follow-up interval, any adenoma occurred in 44.1% of the folic acid group versus 42.4% of placebo (RR 1.04, 95% CI 0.90-1.20; P=.58), and advanced lesions occurred in 11.4% versus 8.6% (RR 1.32, 0.90-1.92; P=.15). In the later interval, advanced lesions were more frequent with folic acid (11.6% vs 6.9%; RR 1.67, 1.00-2.80; P=.05), and multiple adenomas were also higher (9.9% vs 4.3%; RR 2.32, 1.23-4.35; P=.02). Overall adenoma rate was 71.3% with folic acid versus 65.5% with placebo (RR 1.09, 0.98-1.21; P=.12).

Interpretation is limited by relatively few advanced lesion events and subgroup analyses, which reduce precision for detecting benefit or harm. Treatment was given during an era of folic acid food fortification, which may have altered baseline folate exposure and diluted any effect. Some participants remained under observation after treatment stopped, adding complexity to long-term inference and attribution.