Original ResearchFull Report: Clinical—Alimentary TractMethotrexate Is Not Superior to Placebo in Maintaining Steroid-Free Response or Remission in Ulcerative Colitis
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Trial Design and Oversight
The trial was conducted at 37 sites (see Supplementary Material for site list) across the United States. Patients were recruited between February 2012 and May 2016. The study was designed by investigators of the Crohn’s and Colitis Foundation’s Clinical Research Alliance, and the majority of centers were affiliated with the Clinical Research Alliance.20 The institutional review board at each participating institution approved the protocol, and all the patients provided written informed consent
Results
Between February 2012 and May 2016, 256 patients were screened at 37 sites across the United States. Of these, 77 patients were excluded, mostly because of insufficient disease activity, and 179 patients were included in the induction period (Table 1 and Supplementary Figure 1). At week 16, 91 of 179 (51%) of the patients achieved a steroid-free clinical response, and of these, 52 of 179 (29%) were in steroid-free clinical remission. Patients with previous therapeutic failure of thiopurines
Discussion
To our knowledge, MERIT-UC is the first randomized, placebo-controlled study investigating the efficacy of subcutaneously applied MTX at a dose of 25 mg/wk in patients who had previously responded to open label MTX. Despite a relatively large proportion of patients achieving steroid-free response and remission during the open label induction phase, which in its magnitude was similar to the METEOR trial, MTX was not superior to placebo in maintaining these therapeutic effects.18 The METEOR trial
Acknowledgments
Author contributions: Hans Herfarth: study concept and design; acquisition of data; analysis and interpretation of data; drafting and critical revision of the manuscript; statistical analysis. Edward L. Barnes: analysis and interpretation of data; drafting and critical revision of the manuscript; statistical analysis. John F. Valentine: acquisition of data; drafting and critical revision of the manuscript. John Hanson: acquisition of data; drafting and critical revision of the manuscript. Peter
References (40)
- et al.
Clinical practice guidelines for the medical management of nonhospitalized ulcerative colitis: the Toronto consensus
Gastroenterology
(2015) - et al.
Methotrexate in chronic active ulcerative colitis: a double-blind, randomized, Israeli multicenter trial
Gastroenterology
(1996) - et al.
The METEOR Trial: the burial of methotrexate in ulcerative colitis?
Gastroenterology
(2016) - et al.
A review of activity indices and efficacy end points for clinical trials of medical therapy in adults with ulcerative colitis
Gastroenterology
(2007) - et al.
Combination therapy with infliximab and azathioprine is superior to monotherapy with either agent in ulcerative colitis
Gastroenterology
(2014) - et al.
Combination therapy with methotrexate in inflammatory bowel disease: time to COMMIT?
Gastroenterology
(2014) - et al.
Correlation between concentrations of fecal calprotectin and outcomes of patients with ulcerative colitis in a phase 2 trial
Gastroenterology
(2016) - et al.
The role of centralized reading of endoscopy in a randomized controlled trial of mesalamine for ulcerative colitis
Gastroenterology
(2013) - et al.
Experts opinion on the practical use of azathioprine and 6-mercaptopurine in inflammatory bowel disease
Inflamm Bowel Dis
(2016) - et al.
Third European Evidence-Based Consensus on Diagnosis and Management of Ulcerative Colitis. Part 2: current management
J Crohns Colitis
(2017)
Association between use of thiopurines or tumor necrosis factor antagonists alone or in combination and risk of lymphoma in patients with inflammatory bowel disease
JAMA
Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis
Rheumatology (Oxford)
Mechanism of action of methotrexate in rheumatoid arthritis, and the search for biomarkers
Nat Rev Rheumatol
Still trying to understand methotrexate
J Rheumatol
Methotrexate for the treatment of Crohn's disease. The North American Crohn’s Study Group Investigators
N Engl J Med
A comparison of methotrexate with placebo for the maintenance of remission in Crohn's disease. North American Crohn’s Study Group Investigators
N Engl J Med
Methotrexate for induction of remission in refractory Crohn’s disease
Cochrane Database Syst Rev
Methotrexate for maintenance of remission in Crohn's disease
Cochrane Database Syst Rev
Methotrexate treatment in pediatric Crohn disease patients intolerant or resistant to purine analogues
J Pediatr Gastroenterol Nutr
Efficacy of methotrexate in pediatric Crohn’s disease: a French multicenter study
Inflamm Bowel Dis
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Conflicts of interest These authors disclose the following: Bincy Abraham has received consulting fees from AbbVie, Daiichi Sankyo, Diasoren, Janssen, Pfizer, Salix, Takeda, and UCB, and she has received research funding from AbbVie, Celgene, Genentech, Janssen, UCB. Edward Barnes has received consulting fees from Janssen and research support from TARGET PharmaSolutions. Raymond K. Cross has received consulting fees from AbbVie, Janssen, Pfizer, and Takeda. He has received research funding from AbbVie. Gerald Dryden has received consulting fees from AbbVie, Takeda, Janssen, Allergan, Gilead, Takeda, and he has received research funding from AbbVie, Takeda, Janssen, Gilead, Eli Lilly, TiGenix, MedImmune. Monika Fischer has received consulting fees from AbbVie and Finch Therapeutics. John Hanson has received consulting fees from AbbVie and Target PharmaSolutions. Hans Herfarth has received consulting fees from Merck, Pfizer, Celltrion, Lycera, Boehringer-Ingelheim, and Seres. Peter Higgins has received consulting fees from AbbVie, Allergan, Amgen, Eli Lilly, GI Health Foundation, Janssen, Lycera, PRIME Medical Education, Takeda, and UCB, and he has received research funding from AbbVie, Amgen, Arean, Ascentage, BCBS of Michigan, Buhlmann, Eli Lilly, Genentech, Janssen, Lycera, MedImmune, Nestle, Pfizer, Seres, Shire, Takeda, and UCB. Kim Isaacs received consulting fees from Allergan and Johnson & Johnson. James Lewis has received consulting fees from Merck, Pfizer, Janssen, AbbVie, Immune Pharmaceuticals, AstraZeneca, Amgen, MedImmune, Nestle Health Science, Lilly, Samsung Bioepis, Johnson & Johnson Consumer Products, Takeda, Gilead, Celgene, and Bridge Biotherapeutics; he has received research funding from Takeda, Shire, and Nestle Health Science; and he has received nongrant research support from AbbVie. Millie Long has received consulting fees from Pfizer, AbbVie, Takeda, Theravance, UCB, and Target PharmaSolutions, and she has received research funding from Takeda. Robert McCabe received consulting fees from Janssen. Mark Osterman has received consulting fees from AbbVie, Janssen, Lycera, Merck, Pfizer, Takeda, and UCB, and he has received research funding from UCB. Steven Polyak has received research funding from AbbVie, Celgene, Gilead, and Takeda. Bruce Sands has received consulting fees and research grants from AbbVie, Pfizer, Amgen, Bristol-Myers Squibb, Celgene, Janssen, and Takeda, and he has received consulting fees from Boehringer Ingelheim, Akros Pharma, Arena Pharmaceuticals, Forward Pharma, Immune Pharmaceuticals, Lilly, Synergy Pharmaceuticals, Theravance, Receptos, TiGenix, TopiVert Pharma, MedImmune, Vedanta Biosciences, Allergan, UCB Pharma, EnGene, Target PharmaSolutions, Lycera, Lyndra, Vivelix Pharmaceuticals, Oppilan Pharma, and Gilead. Sumona Saha received consulting fees from UCB. John Valentine received research funding from Pfizer, AbbVie, Celegene, Janssen, Roche/Genentech, Takada, and UCB. Emmanuelle Williams received consulting fees from AbbVie. Vijay Yajnik is currently a fulltime employee of Takeda Pharmaceuticals; at the time of the study he worked at Massachusetts General Hospital and received consulting fees from Jansen, Takeda, Pfizer, and NPS Pharmaceuticals. The remaining authors disclose no conflicts.
Funding The study was funded by the National Institute of Diabetes and Digestive Kidney Diseases (U01DK092239). The Clinical Research Alliance is supported by the Crohn's and Colitis Foundation. The Data Management Center of the Center for Gastrointestinal Biology and Disease is supported by the Crohn’s and Colitis Foundation and the National Institutes of Health (P30 DK034987).