Randomised clinical trial: individualised vs. weight-based dosing of azathioprine in Crohn's disease

BackgroundAzathioprine (AZA), a pro-drug metabolised to the active metabolites 6-tioguanine nucleotides (6TGN), is a steroid-sparing therapy for Crohn's disease (CD). AimTo investigate whether AZA therapy is optimised by individualised dosing based on thiopurine methyltransferase (TPMT) activity and 6TGN concentrations. MethodsThis multicentre, double-blind, randomised controlled trial compared the efficacy and safety of weight-based vs. individualised AZA dosing in inducing and maintaining remission in adults and children with steroid-treated CD. The primary outcome was clinical remission (CR) at 16weeks. In the weight-based arm, subjects received 2.5mg/kg/day. In the individualised dosing arm, the initial AZA dose was 1.0mg/kg/day (if intermediate TPMT) or 2.5mg/kg/day (if normal TPMT). Starting at week 5, the dose was adjusted to target 6TGN concentrations of 250-400 pmol/8x10(8) red blood cells (RBC), or to a maximal dose of 4mg/kg/day. ResultsAfter randomising 50 subjects, the trial was stopped prematurely due to insufficient enrolment. In intention-to-treat analysis, CR rates at week 16 were 40% in the individualised arm vs. 16% in the weight-based arm (P=0.11). In per-protocol (PP) analysis, week 16 CR rates were 60% in the individualised arm and 25% in the weight-based arm (P=0.12). At week 16, median 6TGN concentrations in PP remitters and nonremitters were 216 and 149pmol/8x10(8) RBC respectively (P=0.07). ConclusionsDespite trends favouring individualised over weight-based AZA dosing, there were no statistically significant differences in efficacy, likely due to low statistical power and inability to achieve the target 6TGN concentrations in the individualised arm.