SAN DIEGO — Adding methotrexate to infliximab was not superior to infliximab alone in Crohn's disease, according to a presentation at Digestive Disease Week.
Both drugs are effective on their own, but it was not known whether a combination approach would be more effective, said Dr. Brian Feagan, professor of medicine and professor of epidemiology and biostatistics at the University of Western Ontario, London, and director of Robarts Research Institute.
Dr. Feagan and his colleagues at 15 Canadian centers conducted a 50-week, double-blind, placebo-controlled parallel-design trial. All patients had active Crohn's disease and were randomly assigned to receive methotrexate or placebo in addition to infliximab. There were 63 patients in each group.
Both groups received intravenous infliximab at 5 mg/kg at weeks 1, 3, and 7 as well as every 8 weeks thereafter. All patients received intravenous infusions of hydrocortisone (200 mg) before infliximab.
The methotrexate group received 10 mg in week 1, 10 mg in week 2, and then 20 mg for 2 weeks, followed by 25 mg each week for the duration of the trial. Every patient received prednisone induction therapy within 6 weeks of the trial's start. Tapering of prednisone began at the study's start in a manner that ensured that all patients had discontinued by week 14.
The primary outcome was time to treatment failure, strictly defined as failure to enter prednisone-free remission at week 14 and failure to maintain remission through week 50. The analysis consisted of a survival analysis based on a log rank test for the primary analysis.
About half of the 126 patients completed to week 50. Overall, the patients were somewhat older than those who normally participate in induction studies, said Dr. Feagan, noting that the average age was 40 years. Also, the proportion of smokers was large—about 40%. The average score on the Crohn's Disease Activity Index (CDAI) was 210, despite the fact that patients were taking an average of 30 mg prednisone daily. One-quarter had received antimetabolite therapy in the past.
Overall, there was no difference between the methotrexate group and the placebo group. The induction success rate was high in both groups—76% for the methotrexate arm, and 78% for the placebo arm. At week 50, 56% of methotrexate patients and 57% of placebo patients had steroid-free remission.
There was a very high response rate—87% in both groups—in patients who had Crohn's for less than 2 years. For long-established disease, the response rate was lower, at 40% for both groups, he said.
The quality of life at the end of the study was very high—almost normal—for both groups, and there were no differences between the two arms in CDAI scores. The combination therapy was well tolerated, with slightly fewer in the methotrexate group having infections (59%, or 37 patients), compared with the placebo group (62%, or 39 patients).
There were 22 patients who had a serious adverse event in the methotrexate arm, compared to 11 for the placebo group, with the primary difference being an exacerbation of Crohn's.
Dr. Feagan concluded that the study showed a high degree of success in induction and maintenance of remission over 1 year in both treatment groups. The results mean that “our best inductive regimen is highly effective,” he said.
The study gives “a very clear message,” and that is, “if you're going to achieve very high rates of steroid-free remission in the long term you need to use both of our best agents together and you need to treat early,” Dr. Feagan said.
Dr. Feagan reported that he is a consultant for Centocor Inc., which makes and sells infliximab.