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P196. Are the results of multicenter trials hampered by country variability? Comparison between two endpoints used in a study with interferon-β-1a in ulcerative colitis

P. Mannon1, W. Reinisch2, P. Miner3, Y. Xi4, A. McAllister4, F. Cataldi4

1UAB, Birmingham, AL, United States; 2Vienna University, Vienna, Austria; 3OFFDR, Oklahoma-City, OK, United States; 4BiogenIdec, Cambridge, MA, United States

Aim: Based on the encouraging results of a small NIH open label pilot of interferon-β-1a (IFN) in ulcerative colitis (UC), we conducted a phase IIa multicenter, placebo-controlled trial in North America (USA and Canada) and Eastern Europe (Russia, Czech Republic, Hungary, Poland and Slovakia). We measured outcomes with two endpoints, the Mayo score and the Simple Clinical Colitis Activity Index (SCCAI) (used in the NIH study) in order to benchmark results to current standards of UC trials and to the results of the NIH study. In fact, the latest UC trials employ the Mayo score that measures daily stool frequency (SF) using an unusual quantification of SF by counting numbers of stools as “more than normal” and not as the actual absolute number of daily stools as is done by the SCCAI. The Mayo score also includes measures of rectal bleeding (RB), physician-global-assessment and mucosal healing. The SCCAI includes SF for day and night; urgency; RB; general-well-being and extracolonic-manifestations. We conducted a post-hoc analysis comparing the SF outcome of the two scores overall and by each country participating in the study to assess site-specific effects in outcome reporting.

Methods: Patients (age 18–65) with moderate-severe UC (modified Mayo score 6–13) were randomized to receive IFN 30 μg IM or placebo (P) twice at WK, for 12 weeks. The primary endpoint was clinical response at Week 8, defined as a decrease from baseline in the Total Mayo Score of ≥3 points and ≥30%. The secondary endpoint was the clinical response at Weeks 8 defined as a decrease in the SCCAI score of ≥3 points.

Results: A post-hoc analysis of the change in the 4 sub-domains of the Mayo score from baseline to week 8 showed that the only negative result (improved response in placebo over IFN) was seen in the SF subscore, 41% IFN vs. 48% P (p = 0.47). However the opposite was observed when SF was measured by the SCCAI, 77% IFN vs. 46% P (p < 0.001). Furthermore, remarkable result differences were observed among participating countries (Table).

Conclusions: In this study, overall efficacy assessments were influenced by the SF sub-domain outcome when measured by the Mayo score but not by the SCCAI. Because SF is a critically important but very subjective endpoint, better definitions of such bowel function are needed in order to measure these outcomes. Also a true definition of “normal” stool frequency does not exist and patients may have more difficulties in quantifying their bowel habits in this manner. Lastly, in global clinical trials a country bias needs to be accounted for differences in health care, culture, language and symptoms perception. Further work is needed to improve precision and accuracy in measurement of clinical scores in UC.

Improvement in stool frequencya
 Mayo ScoreSCCAI (Day & night)
 IFN % (n/n)P % (n/n)IFN % (n/n)P % (n/n)
Russia35 (6/17)40 (8/20)94 (16/17)33 (6/18)
Czech. Rep.50 (5/10)55 (5/9)72 (8/11)45 (5/11)
Hungary30 (3/10)37 (3/8)60 (6/10)50 (4/8)
Poland54 (7/13)53 (8/15)77 (10/13)47 (7/15)
Slovakia0 (0/1)100 (1/1)– (0/0)100 (1/1)
USA50 (2/4)100 (2/2)67 (2/3)100 (2/2)
Canada33 (1/3)0 (0/1)67 (2/3)100 (1/1)
aNumber of the subject with 1 point reduction at Week 8.
Subjects with baseline subscore less than 1 have been removed from the analyses.
Numbers in parentheses are patients with reduction/patients dosed.
The numbers of patients enrolled in Slovakia, USA and Canada were small and the comparison of the two methods was difficult to interpret.
The number of responders in the patients enrolled in Russia, Czech Republic, Hungary and Poland was significantly higher using the SCCAI compared to the Mayo score.