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P214. Mucosal healing an essential efficacy measure in ulcerative colitis: Effect of country-enrollment site in a phase IIa study with interferon-β-1a

P. Mannon1, B. Feagan2, Y. Xi3, A. McAllister3, F. Cataldi4

1UAB, Birmingham, AL, United States; 2Robarts Research Institute, London, ON, Canada; 3BiogenIdec, Cambridge, MA, United States; 4Biogen Idec, Cambridge, MA, United States

Aim: Mucosal healing (MH) is emerging as an important outcome in ulcerative colitis (UC) trials. The excess IL-13 produced in inflamed UC mucosa is directly toxic to epithelial cells and tight junction. Since type I interferons can block IL-13 production by human T cells, we propose that clinical efficacy in UC would be accompanied by improved barrier function and mucosal restitution. In an NIH pilot in UC, MH was observed in over 35% of patients reporting response to Interferon-β-1a (IFN). Moreover we observed high rates of improvement in MH in a phase IIa multicenter, placebo-controlled trial conducted in North America (USA and Canada) and Eastern Europe (Russia, Czech Republic, Hungary, Poland and Slovakia) with IFN in active UC.

Methods: Adult patients with moderate to severe UC were randomized to IFN 30 μg IM or placebo (P) twice a WK for 12 weeks. The primary endpoint was response at Week 8, defined as a ≥3 point decrease from baseline in the modified Mayo Score. Secondary endpoints were the % of patients with a ≥3 point decrease in the SCCAI and the % of patients with MH at Week 8 (defined as absolute Mayo subscore for endoscopy of 0 or 1). In the study, the endoscopy subscore was expanded to a 5-point scale to increase sensitivity, 0 to 4 (4 = deep ulceration). Therefore this modified Mayo Score ranged from 0 to 13 points.

Results: The ITT-intent to treat population included 123 patients, 61 on P and 62 on IFN. At week 8 based on the Mayo score, 53% of subjects on IFN vs. 44% on P reported response (P = 0.35). For the SCCAI 64% of IFN vs. 46% on P reported response (P = 0.05). For both groups, the baseline endoscopy scores were mainly 2 and 3 but at week 8, 50% of IFN patients vs. 36% of P showed MH scores ≤1 (P = 0.12). However important inter-country differences were observed in the mucosal healing rates including an overall elevated placebo rate (Table).

Mucosal healing at week 8
 IFN % (n/n)P % (n/n)
USA40 (2/5)100 (2/2)
Canada0 (0/3)100 (1/1)
Russia59 (10/17)24 (5/21)
Czech Republic17 (2/12)25 (3/12)
Hungary55 (6/11)25 (2/8)
Poland77 (10/13)50 (8/16)
Slovakia100 (1/1)100(1/1)
Mucosal healing is defined as an absolute endoscopy subscore of 0 or 1
In parentheses number of patients with MH/patients dosed.

Conclusions: Our biologically-plausible hypothesis that inhibition of IL-13 production by IFN plays an important role in gut epithelial restitution is supported by the data of this study where improvement in the endoscopic subscore showed a notable trend favoring MH in the IFN group. However, while endoscopic measures of mucosal healing can be a quantifiable and more objective correlate of clinical response, major differences were observed in results reported among different countries, including differences in the placebo effect on MH. Considering the increasing relevance of MH in inflammatory bowel disease studies, a more standardized approach should be employed in future trials such as a central scoring of recorded endoscopies by a panel of expert readers.