Gastroenterology

Gastroenterology

Volume 132, Issue 2, February 2007, Pages 763-786
Gastroenterology

Special reports and reviews
A Review of Activity Indices and Efficacy End Points for Clinical Trials of Medical Therapy in Adults With Ulcerative Colitis

https://doi.org/10.1053/j.gastro.2006.12.038Get rights and content

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The Consensus Process

The need for a systematic evaluation of the outcomes used for clinical trials in UC came about from perceived inconsistencies in regulatory decision making. This issue was identified by a few individuals who are regularly involved in the design and implementation of randomized controlled trials of therapy for this disorder. The clinical trials task force of the International Organization of Inflammatory Bowel Disease (IOIBD) initiated this process of developing a systematic review in 2003.

Definitions

The scores described below are based on signs and symptoms for which no standard definitions have been developed. A “bowel movement” for instance could be any trip to the bathroom with passage of fecal material through the anus, but some patients with severe disease may be incontinent making the definition unsuitable.3 The upper limit of normal for stool frequency is quite variable and may be up to 3 or 4 stools per day. Thus, defining an increased stool frequency may require a comparison to a

Classification and Treatment Indications According to Disease Extent

Colonoscopy can be used to classify patients with UC according to the macroscopic extent of disease. Population-based studies from Scandinavia have demonstrated that, at diagnosis, 40% of patients with UC have disease limited to the rectum (ulcerative proctitis), 30%–40% to the rectosigmoid colon (ulcerative proctosigmoiditis) or the left-colon (left-sided UC), and 20%–30% have disease extending proximal to the splenic flexure or involving the entire colon (extensive UC or substantial UC and

Response to Treatment and Induction of Clinical Remission for Mildly to Moderately Active UC

The clinical and composite end points based on the clinical instruments and the composite clinical and endoscopic end points discussed above that have been used for clinical trials in patients with mildly to moderately active UC (and outpatients with moderately to severely active UC) are summarized in Table 1. Clinical trials with topical agents for left-sided and distal colitis generally used the same scores to assess disease activity/treatment success as trials for more extensive colitis.

Noninferiority Study Designs

Because mesalamine is safe and effective for the induction and maintenance of response and remission in patients with UC, true placebo-controlled trials in which no concomitant therapies for UC are permitted may not always be possible. Thus, to evaluate new therapies as potential first-line treatments (as an alternative to mesalamine), noninferiority (equivalence) study designs may be required.99, 100 Few noninferiority studies have been performed in patients with inflammatory bowel disease.69,

Placebo Response

When designing placebo-controlled trials in patients with UC, careful consideration must be given to the expected placebo response for the specific treatment indication and patient population and taking into account the primary end point of the study and the instrument used to measure disease activity. Three metaanalyses have been performed that quantify the placebo response in patients with UC.105, 106, 107 These metaanalyses as well as the placebo response and remission rates outlined in

Conclusions

During the last 50 years, there has been considerable heterogeneity and confusion regarding the optimal instruments (activity indices) and end points for assessing the efficacy of medical therapies for UC. This review has allowed the development of a consensus opinion regarding the optimal end points for the indications of treatment and induction of remission, maintenance of remission, and endoscopic remission in UC patients. There is preliminary experience with clinical trials targeting the

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  • Cited by (0)

    The authors are affiliated with the following organizations: The Clinical Trials Task Force of the International Organization of Inflammatory Bowel Disease (IOIBD; Geert D’Haens, MD; William J. Sandborn, MD; Karel Geboes, MD; Stephen B. Hanauer, MD; E. Jan Irvine, MD; Marc Lémann, MD; Philippe Marteau, MD; Paul Rutgeerts, MD; Jurgen Schölmerich, MD; Lloyd R. Sutherland, MD), the European Crohn’s and Colitis Organization (ECCO; Geert D’Haens, MD; Marc Lémann, MD), The Clinical Alliance of the Crohn’s and Colitis Foundation of America (CCFA; William J. Sandborn, MD; Stephen B. Hanauer, MD), the Clinical Network of the Crohn’s and Colitis Foundation of Canada (CCFC; Brian G. Feagan, MD; E. Jan Irvine, MD; Lloyd R. Sutherland, MD), and the Groupe d’Etude Thérapeutique des Affections Inflammatoires Digestives (GETAID; Marc Lémann, MD; Philippe Marteau, MD).

    Except for the first 2 authors, the authors are listed in alphabetical order.

    G.D’H. and W.J.S. contributed equally to this manuscript.

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