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A composite disease activity index for early drug development in ulcerative colitis: development and validation of
Vipul Jairath1, Jenny Jeyarajah2, Guangyong Zou3
1Robarts Clinical Trials Inc, London, ON, Canada; Department of Medicine, University of Western Ontario, London, ON, Canada; Department of Epidemiology and Biostatistics, University of Western Ontario, London, ON, Canada.
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 dataset (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 + 16 × Mayo Clinic stool frequency subscore [0 to 3] + 6 × Mayo Clinic endoscopic subscore [0 to 3] + 1 × 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.
Funding:
None.
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