A composite disease activity index for early drug development in ulcerative colitis: development and validation of the UC-100 score

Background Combining clinical, endoscopic, and histological data associated with ulcerative colitis disease activity in a composite index could be a more sensitive way to detect efficacy in small numbers of patients during early drug development. Our aim was to derive and externally validate a novel index for this purpose. Methods Index development was done with data from a phase 2 placebo-controlled trial of ozanimod in patients with moderate-to-severe ulcerative colitis (n=179). Multivariable logistic regression modelling determined associations between candidate index items and absence of rectal bleeding (Mayo Clinic rectal bleeding subscore of 0), with items with a p value of less than 0.10 being taken forward into the final model. Model fit was internally validated and then externally validated in an independent phase 2 clinical trial data set (MLN02, n=146) by measuring the area under the curve of the receiver operating characteristic (AUROC). Findings In the derivation cohort, multivariable analysis indicated that the Mayo Clinic stool frequency subscore (odds ratio [OR] 0.43, 95% CI 0.30-0.61; p<0.0001) and the Robarts histopathology index (0.97,0.93-1.01; p=0.09) were associated with absence of rectal bleeding. Although the Mayo Clinic endoscopic subscore was not significantly associated with rectal bleeding in multivariable analysis (0.74,0.43-1.27; p=0.27), it was entered into the final model on the basis of the established diagnostic and prognostic significance of endoscopic findings. With these parameters, we established the composite UC-100 score (1+16x Mayo Clinic stool frequency subscore [0 to 3] + 6 x Mayo Clinic endoscopic subscore [0 to 3] + 1x Robarts histopathology index score [0 to 33]), which ranges from 1 (no disease activity) to 100 (severe disease activity). The UC-100 score strongly discriminated absence of rectal bleeding in both the development (AUROC 0.82, 95% CI 0.75-0.88) and validation cohorts (0.86, 0.80-0.92). A UC-100 score of 25 or less corresponds to a 95% probability of absence of rectal bleeding. Interpretation We have developed and validated a novel composite disease activity index (the UC-100 score) with good discriminative performance that could used in early phase trials of ulcerative colitis. Copyright (C) 2018 Elsevier Ltd. All rights reserved.