We propose a prospective placebo controlled study to investigate the safety and efficacy of 25 mg MIX applied subcutaneously once weekly in patients with active UC, who are either steroid dependent or are intolerant or not responding to azathioprine/6-mercaptopurine therapy or have no response/ lost response to infliximab prior to the study inclusion. In the setting of an implementation-planning (U34) grant we finalized the study protocol and associated formal requirements for this trial. We obtained a lead IRB approval and are currently obtaining IRB approvals of the participating sites. We registered an IND number (108,560) with the FDA and established the study infrastructure for this prospective placebo-controlled multi-center study using the center framework of the Crohn's and Colitis Foundation of America (CCFA) Clinical Research Alliance (CRA).
The Specific Aims of the trial are: 1) To evaluate the safety and tolerability of 25 mg MTX applied sq once weekly over a time period of 48 weeks. 2) To evaluate the relapse-free survival of MTX maintenance therapy compared to placebo over a time period of 32 weeks. 3) To evaluate the efficacy of MTX over a time period of 16 weeks to induce steroid free remission. 4) To establish a DNA, plasma and serum library to enable the evaluation of clinical and pharmacogenomic models to predict the response to MTX therapy in patients with UC.

Public Health Relevance

Despite MTX being on the market for decades, the therapeutic approach using parenteral administered MTX in patients failing established therapies such as 5-ASA, thiopurines or anti-TNF therapies is pioneering a potential novel therapy. The results of the trial will provide the necessary data for the therapeutic value of MTX in UC patients, which will likely influence the current global therapeutic practice in UC.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project--Cooperative Agreements (U01)
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Study Section
Special Emphasis Panel (ZDK1-GRB-6 (M1))
Program Officer
Serrano, Jose
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University of North Carolina Chapel Hill
Internal Medicine/Medicine
Schools of Medicine
Chapel Hill
United States
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Kochar, Bharati; Barnes, Edward L; Herfarth, Hans H et al. (2018) Asians have more perianal Crohn disease and ocular manifestations compared with white Americans. Inflamm Intest Dis 2:147-153
Herfarth, Hans; Barnes, Edward L; Valentine, John F et al. (2018) Methotrexate Is Not Superior to Placebo in Maintaining Steroid-Free Response or Remission in Ulcerative Colitis. Gastroenterology 155:1098-1108.e9
Herfarth, Hans H; Jackson, Susan; Schliebe, Barbara G et al. (2017) Investigator-Initiated IBD Trials in the United States: Facts, Obstacles, and Answers. Inflamm Bowel Dis 23:14-22
Vande Casteele, Niels; Herfarth, Hans; Katz, Jeffry et al. (2017) American Gastroenterological Association Institute Technical Review on the Role of Therapeutic Drug Monitoring in the Management of Inflammatory Bowel Diseases. Gastroenterology 153:835-857.e6
Barnes, Edward L; Herfarth, Hans H; Sandler, Robert S et al. (2017) Pouch-Related Symptoms and Quality of Life in Patients with Ileal Pouch-Anal Anastomosis. Inflamm Bowel Dis 23:1218-1224
Kochar, Bharati; Long, Millie D; Shelton, Edward et al. (2017) Safety and Efficacy of Teduglutide (Gattex) in Patients With Crohn's Disease and Need for Parenteral Support Due to Short Bowel Syndrome-associated Intestinal Failure. J Clin Gastroenterol 51:508-511
Herfarth, Hans H; Kappelman, Michael D; Long, Millie D et al. (2016) Use of Methotrexate in the Treatment of Inflammatory Bowel Diseases. Inflamm Bowel Dis 22:224-33
Nakase, Hiroshi; Herfarth, Hans (2016) Cytomegalovirus Colitis, Cytomegalovirus Hepatitis and Systemic Cytomegalovirus Infection: Common Features and Differences. Inflamm Intest Dis 1:15-23
Herfarth, Hans H (2016) Methotrexate for Inflammatory Bowel Diseases - New Developments. Dig Dis 34:140-6
Abdalla, Maisa I; Herfarth, Hans (2016) Budesonide for the treatment of ulcerative colitis. Expert Opin Pharmacother 17:1549-59

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