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MERIT-UC Interim Reports – 2011

Report November 2011

Executive Summary for CCFA: Status Merit-UC November 2011

Hans Herfarth

Study in ClinicalTrials.gov

There are fewer therapeutic options for patients with active ulcerative colitis (UC) compared to patients with active Crohn’s disease (CD) and we are facing a persistent unmet need for additional effective and affordable therapies for patients with UC. Methotrexate (MTX) 25 mg once weekly administered subcutaneously (sq) or intramuscularly (im) is an efficient therapy to induce and maintain steroid free remission in patients with CD. Only one small prospective placebo controlled trial investigating the oral administration of 12.5 mg MTX once weekly compared to placebo has been conducted. The results did not demonstrate superiority of MTX compared to placebo. We conducted a systematic literature research to identify published clinical efficacy data of MTX in patients with UC and found several retrospective and prospective case series demonstrating clinical efficacy of MTX, when the drug was administered in a comparable dose and similar route (im or sq) as in CD. The conflicting data of the only placebo controlled trial and the published clinical experience may be explained by the fact, that MTX has a known dose response curve as shown in patients with CD or rheumatoid arthritis and also has a significant lower bioavailability if applied orally especially in higher doses such as the one used in CD. We therefore hypothesize that MTX presents an effective therapy for patients with UC if administered in a similar fashion as in CD patients.

We propose a prospective placebo controlled study to investigate the safety and efficacy of 25 mg MTX 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 from 10/2010 -6/2011 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 Investigational New Drug Application (IND) with the FDA (108,560) 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 NIDDK awarded an U0-1 grant to our consortium in August 2011. Since then we finalized trial contracts with more than 70% of the sites. We are currently in the process to get IRB approval for the last protocol version 1.7 by all participating sites and are establishing a more refined data capturing system which would also allow us online monitoring of all the site. The initial investigator/coordinator meetings for the study will take place on 12/7/2011 and 12/15/ 2011. We originally planned to include the first study patient in December 2011, but currently methotrexate 2 ml 25mg/ml vials are not available in the USA (like many other generics). We contacted the FDA about the possibility to refill methotrexate from larger size bottles in the 2 ml vials by our investigational pharmacy and are currently waiting for a reply.