UvA-DARE ( Digital Academic Repository ) Adalimumab for induction of clinical remission in moderately to severely active ulcerative colitis : results of a randomised controlled trial

Objective The aim of this study was to assess the efficacy and safety of adalimumab (ADA), a recombinant human monoclonal antibody against tumour necrosis factor a (TNF), for the induction of clinical remission in anti-TNF naı̈ve patients with moderately to severely active ulcerative colitis. Methods This 8-week, multicentre, randomised, doubleblind, placebo-controlled study (NCT00385736), conducted at 94 centres in North America and Europe, enrolled ambulatory adult patients with Mayo score of $6 points and endoscopic subscore of $2 points despite treatment with corticosteroids and/or immunosuppressants. Under the original study protocol, 186 patients were randomised (1:1) to subcutaneous treatment with ADA160/80 (160 mg at week 0, 80 mg at week 2, 40 mg at weeks 4 and 6) or placebo. Subsequently, at the request of European regulatory authorities, the protocol was amended to include a second induction group (ADA80/40: 80 mg at week 0, 40 mg at weeks 2, 4 and 6). The primary efficacy endpoint was clinical remission (Mayo score #2 with no individual subscore >1) at week 8, assessed in 390 patients randomised (1:1:1) to ADA160/80, ADA80/40, or placebo. Safety was assessed in all enrolled patients. Patients, study site personnel, investigators, and the sponsor were blinded to treatment assignment. Results At week 8, 18.5% of patients in the ADA160/80 group (p1⁄40.031 vs placebo) and 10.0% in the ADA80/40 group (p1⁄40.833 vs placebo) were in remission, compared with 9.2% in the placebo group. Serious adverse events occurred in 7.6%, 3.8% and 4.0% of patients in the placebo, ADA80/40, and ADA160/80 groups, respectively. There were two malignancies in the placebo group, none in the ADA groups. There were no cases of tuberculosis and no deaths. Conclusions ADA160/80 was safe and effective for induction of clinical remission in patients with moderately to severely active ulcerative colitis failing treatment with corticosteroids and/or immunosuppressants. Clinical trial NCT00385736. INTRODUCTION Ulcerative colitis is an idiopathic, chronic inflammatory disease of the large intestine, usually involving the rectum, characterised by a continuous pattern of inflammation and ulceration of the intestinal mucosa and submucosa. Ulcerative colitis has a significant negative impact on patient quality of life and places a substantial financial burden on healthcare systems, with direct cost estimates exceeding $3.4 billion in the USA and €5.4 billion in Europe. The goal of therapy in ulcerative colitis is to induce and maintain remission. Conventional medical therapies include 5-aminosalicylic acid, corticosteroids and oral immunosuppressants (azathioprine, 6-mercaptopurine and cyclosporine). However, these agents inadequately control the disease in a substantial proportion of patients and can lead to adverse events (AEs). Thus, there is a need for new therapies beyond conventional treatment options for many patients with ulcerative colitis. See Commentary, p 741 < Additional materials are published online only. To view these files please visit the journal online (http://gut.bmj.com). Medical University Vienna, Vienna, Austria Mayo Clinic, Rochester, Minnesota, USA Leiden University Medical Center, Leiden, Netherlands Academic Medical Centre, Amsterdam, Netherlands University of Chicago Medical Center, Chicago, Illinois, USA Christian-Albrechts-University, University-Hospital Schleswig-Holstein, Medical Department I, Kiel, Germany University of Calgary, Calgary, AB, Canada University of Alberta, Edmonton, AB, Canada Abbott, Abbott Park, Illinois, USA Abbott, Maidenhead, UK Abbott, Ludwigshafen, Germany Correspondence to Dr Walter Reinisch, Universitätsklinik für Innere Medizin III, Abteilung Gastroenterologie and Hepatologie, Waehringer Guertel 18-20, A-1090 Vienna, Austria; walter.reinisch@ meduniwien.ac.at Revised 3 November 2010 Accepted 15 November 2010 Published Online First 5 January 2011 Significance of this study What is already known about this subject? < Conventional treatments for moderate to severely active ulcerative colitis have limited efficacy and are associated with adverse events. < One biological therapy, the anti-TNFa chimeric monoclonal antibody infliximab, has been proven to induce and maintain remission in ulcerative colitis patients. < Adalimumab (ADA), a fully human monoclonal antibody against TNFa, is effective in inducing and maintaining remission in moderately to severely active Crohn’s disease, but its efficacy in ulcerative colitis is unknown. What are the new findings? < This trial demonstrated that ADA is effective in inducing remission in moderately to severely active ulcerative colitis. < At week 8, 18.5% of patients in the ADA160/80 group (p1⁄40.031 vs placebo) and 10.0% in the ADA80/40 group (p1⁄40.833 vs placebo) were in remission, compared with 9.2% in the placebo group. < Adalimumab was well tolerated, with a safety profile comparable to those seen in clinical trials. How might it impact on clinical practice in the foreseeable future? < Follow-up of the patients in this trial is ongoing. 780 Gut 2011;60:780e787. doi:10.1136/gut.2010.221127 Inflammatory bowel disease group.bmj.com on April 9, 2013 Published by gut.bmj.com Downloaded from