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Randomised clinical trial: individualised vs. weight‐based dosing of azathioprine in Crohn's disease
Author(s) -
Dassopoulos T.,
Dubinsky M. C.,
Bentsen J. L.,
Martin C. F.,
Galanko J. A.,
Seidman E. G.,
Sandler R. S.,
Hanauer S. B.
Publication year - 2014
Publication title -
alimentary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.308
H-Index - 177
eISSN - 1365-2036
pISSN - 0269-2813
DOI - 10.1111/apt.12555
Subject(s) - medicine , dosing , thiopurine methyltransferase , azathioprine , gastroenterology , weight loss , clinical trial , crohn's disease , surgery , disease , obesity
Summary Background Azathioprine ( AZA ), a pro‐drug metabolised to the active metabolites 6‐tioguanine nucleotides (6 TGN ), is a steroid‐sparing therapy for Crohn's disease ( CD ). Aim To investigate whether AZA therapy is optimised by individualised dosing based on thiopurine methyltransferase ( TPMT ) activity and 6 TGN concentrations. Methods This 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 16 weeks. In the weight‐based arm, subjects received 2.5 mg/kg/day. In the individualised dosing arm, the initial AZA dose was 1.0 mg/kg/day (if intermediate TPMT ) or 2.5 mg/kg/day (if normal TPMT ). Starting at week 5, the dose was adjusted to target 6 TGN concentrations of 250–400 pmol/8 × 10 8 red blood cells ( RBC ), or to a maximal dose of 4 mg/kg/day. Results After 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 6 TGN concentrations in PP remitters and nonremitters were 216 and 149 pmol/8 × 10 8 RBC respectively ( P = 0.07). Conclusions Despite 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 6 TGN concentrations in the individualised arm. [ Clinicaltrials.Gov Identifier Nct00113503].