Gastroenterology

Gastroenterology

Volume 146, Issue 3, March 2014, Pages 681-688.e1
Gastroenterology

Original Research
Full Report: Clinical—Alimentary Tract
Methotrexate in Combination With Infliximab Is No More Effective Than Infliximab Alone in Patients With Crohn's Disease

https://doi.org/10.1053/j.gastro.2013.11.024Get rights and content

Background & Aims

Methotrexate and infliximab are effective therapies for Crohn's disease (CD). In the combination of maintenance methotrexate-infliximab trial, we evaluated the potential superiority of combination therapy over infliximab alone.

Methods

In a 50-week, double-blind, placebo-controlled trial, we compared methotrexate and infliximab with infliximab alone in 126 patients with CD who had initiated prednisone induction therapy (15–40 mg/day) within the preceding 6 weeks. Patients were assigned randomly to groups given methotrexate at an initial weekly dose of 10 mg, escalating to 25 mg/week (n = 63), or placebo (n = 63). Both groups received infliximab (5 mg/kg of body weight) at weeks 1, 3, 7, and 14, and every 8 weeks thereafter. Prednisone was tapered, beginning at week 1, and discontinued no later than week 14. The primary outcome was time to treatment failure, defined as a lack of prednisone-free remission (CD Activity Index, <150) at week 14 or failure to maintain remission through week 50.

Results

Patients' baseline characteristics were similar between groups. By week 50, the actuarial rate of treatment failure was 30.6% in the combination therapy group compared with 29.8% in the infliximab monotherapy group (P = .63; hazard ratio, 1.16; 95% confidence interval, 0.62–2.17). Prespecified subgroup analyses failed to show a benefit in patients with short disease duration or an increased level of C-reactive protein. No clinically meaningful differences were observed in secondary outcomes. Combination therapy was well tolerated.

Conclusions

The combination of infliximab and methotrexate, although safe, was no more effective than infliximab alone in patients with CD receiving treatment with prednisone. ClincialTrials.gov number, NCT00132899.

Section snippets

Materials and Methods

This trial was performed at 15 centers in Canada between December 2005 and February 2008. The investigational review board at each center approved the protocol and all patients provided written informed consent.

Patient Disposition and Characteristics

Supplementary Figure 1 shows the disposition of the study patients. Of the 132 patients who were screened, 126 patients were randomized, with 63 assigned to each treatment group. Six patients withdrew from the study for reasons not related to treatment failure; 2 of these patients were assigned to methotrexate (both patients withdrew because of adverse events) and 4 patients were assigned to placebo (2 patients withdrew consent, 1 patient withdrew because of an adverse event, and 1 patient was

Discussion

We found the combination of methotrexate and infliximab to be no more effective than infliximab alone for inducing and maintaining remission in patients with active CD who were receiving treatment with prednisone. Seventy-six percent of patients assigned to combination therapy achieved prednisone-free remission at the end of 14 weeks of treatment compared with 78% of those who were assigned to infliximab and placebo. Corresponding values for overall treatment success at week 50 were 56% and

Acknowledgments

The authors wish to thank Mrs Beverley Jasevicius for expert secretarial support.

References (29)

Cited by (291)

  • Combination Therapy With Immunomodulators Improves the Pharmacokinetics of Infliximab But Not Vedolizumab or Ustekinumab

    2023, Clinical Gastroenterology and Hepatology
    Citation Excerpt :

    Conversely, we did not see any significant difference in drug levels when comparing monotherapy vs combination therapy with an immunomodulator in patients receiving ustekinumab or vedolizumab. The IBD literature has mainly supported the use of thiopurines or parenteral methotrexate to augment the pharmacokinetics of infliximab.7 Our findings offer evidence that oral methotrexate can be an alternative to the combination treatment regimen and could be tailored to patients based on demographics and risk factors for adverse events to each drug.

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Author names in bold designate shared co-first authorship.

Conflicts of interest These authors disclose the following: Brian Feagan has received grant/research support from Millennium Pharmaceuticals, Merck, Tillotts Pharma AG, Abbott Labs, Novartis Pharmaceuticals, Centocor, Inc, Elan/Biogen, UCB Pharma, Bristol-Myers Squibb, Genentech, ActoGenix, and Wyeth Pharmaceuticals, Inc; consulting fees from Millennium Pharmaceuticals, Merck, Centocor, Inc, Elan/Biogen, Janssen-Ortho, Teva Pharmaceuticals, Bristol-Myers Squibb, Celgene, UCB Pharma, Abbott Labs, Astra Zeneca, Serono, Genentech, Tillotts Pharma AG, Unity Pharmaceuticals, Albireo Pharma, Given Imaging, Inc, Salix Pharmaceuticals, Novonordisk, GlaxoSmithKline, Actogenix, Prometheus Therapeutics and Diagnostics, Athersys, Axcan, Gilead, Pfizer, Shire, Wyeth, Zealand Pharma, Zyngenia, GiCare Pharma, Inc, Sigmoid Pharma; and has served as a member of the speakers bureau for UCB, Abbott, and J&J/Janssen; John McDonald, Allan Donner, Cindy Wong, Guangyong Zou, Margaret Vandervoort, and Marybeth Hopkins are employees of Robarts Clinical Trials, which was the research organization that conducted this study; Remo Panaccione has received consultant and/or lecture fees from Abbott Laboratories, Amgen, AstraZeneca, Axcan Pharma (now Aptalis), Biogen Idec, Bristol-Myers Squibb, Centocor, ChemoCentryx, Eisai Medical Research, Inc, Elan Pharmaceuticals, Ferring, Genentech, GlaxoSmithKline, Janssen, Merck Sharp and Dohme Corp, Millennium Pharmaceuticals, Inc (now Takeda), Ocera Therapeutics, Inc, Otsuka America Pharmaceutical, Pfizer, Shire Pharmaceuticals, Prometheus Laboratories, Schering-Plough, Synta Pharmaceuticals Corp, Teva, UCB Pharma, and Warner Chilcott; Robert Enns has received research/grant support from Abbvie Canada, Aptalis Pharma, AstraZeneca, Boston Scientific, Bristol Myers Squibb, Cook Canada, Ferring, Janssen Canada Olympus, Pentax, Shire Pharmaceuticals, Takeda, UCB Pharma, Vertex, and Warner-Chilcott; Charles Bernstein has received consultant fees from Abbott Canada, Abbvie Canada, Janssen Canada, Bristol Myers Squibb, and Vertex Pharmaceuticals; and has received research grants from Abbott Canada and Abbvie Canada, and an unrestricted educational grant from Aptalis; Raymond Bourdages has received consultant and/or lecture fees from Abbott Laboratories, Aptalis, Janssen, Shire, Takeda, and Warner-Chilcott; Donald MacIntosh has received consultant and/or lecture feels from Abbott Laboratories, Centocor, and Janssen; Chrystian Dallaire has received consultant and/or lecture fees from Abbott Laboratories, Aptalis, Janssen, Shire, Merck, and Roche; Albert Cohen has received consultant and/or lecture fees from Abbvie, Janssen, and Shire, and educational grants from Abbvie and Janssen; Richard Fedorak has received consultant fees from Abbvie, Centocor, Ferring, Janssen, Shire, and VSL Pharmaceuticals; unrestricted clinical/basic research grants from Abbvie, Alba, Bristol Myers Squibb, Centocor, GlaxoSmithKline, Genentech, Janssen, Merck, Millennium, Novartis, Pfizer, Proctor & Gamble, Roche, and VSL Pharmaceuticals; and is an owner and shareholder in Metablolomic Technologies, Inc; Pierre Paré has received consultant or lecture fees from Abbott Laboratories, Forest Laboratories, Janssen, Novartis, Shire, and Warner-Chilcott; research grants from Abbott Laboratories, Glaxo, Santarus, and Shire; and advisory fees from Abbott Laboratories and Janssen; Alain Bitton has received consultant and/or lecture fees from Abbott Laboratories, Aptalis, Janssen, Shire, Takeda, and Warner-Chilcott; Fred Saibil has received consultancy and/or educational grant support from Abbott Laboratories, Aptalis, Ferring, Inc, Janssen, Shire, and Warner-Chilcott; and Gordon Greenberg has received grant/research support from UCB Pharma, Centocor, Inc, and Millennium Pharmaceuticals; and lecture/consultant fees from Janssen Canada, Merck, Prometheus Laboratories, and Abbott Laboratories.

Funding Supported by the Crohn's and Colitis Foundation of America, Merck/Schering-Plough Canada, and Prometheus Laboratories, Inc.

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