Evaluation of an Interim Crohn’s Disease Outcome Measure (PRO−2) Based on 2 Patient-Reported Components (Stool Frequency, Abdominal Pain) of the Crohn’s Disease Activity Index (CDAI) in the Ustekinumab CERTIFI Study (2014)

Introduction: The CDAI has been the standard outcome measure in CD trials for ˜40 years, but its complexity, high placebo response, and inconsistency with FDA guidance on patient-reported outcome (PRO) measures are disadvantages. This has generated interest in exploring a PRO based on the stool frequency (SF) and abdominal pain (AP) components of the CDAI, known as PRO-2. A potential PRO-2 definition for remission (mean daily score of AP≤1 AND [also] SF≤1.5) was proposed based on data from 2 CD populations, one with mild-moderate disease and one with steroid-dependent disease. Whether this PRO-2 definition is optimal in patients with moderate-to-severe disease, and/or refractory to tumor necrosis factor (TNF)-α antagonists is unknown. Methods: Using the previously reported 8 week induction data from the ustekinumab (UST) Phase 2 CERTIFI study (in patients previously failing and/or intolerant to TNF-antagonists; mean baseline CDAI=324), the contributions of SF/AP to baseline CDAI and subsequent improvements post-treatment were assessed. Sensitivity(SENS)/specificity(SPEC) analyses that defined optimal cutoffs for detecting remission (CDAI<150) at week 8 were used to generate remission definitions based on unweighted mean daily scores for AP alone, SF alone, or both: Either requiring maximums for each (e.g. AP≤1 AND SF≤1.5) or, applying maximum thresholds to the sum of AP+SF, using standard CDAI weightings. The treatment effects of UST in CERTIFI were then evaluated and compared using the selected definitions. Results: The unweighted mean daily score cutoffs of AP ≤1/SF ≤3/combined AP≤1 AND SF≤3, respectively, provided better balance of SENS (87.1%; 84.7%; 72.9%) and SPEC (77.1%; 73.9%; 94.1%) compared with the previously proposed cutoff of combined AP≤1 AND SF≤1.5 (55.3% SENS;96.8% SPEC) in the detection of remission at week 8. A weighted total AP+SF score cutoff of <75 best optimized SENS ( 91.8%) and SPEC (85.3%) compared with the unweighted mean daily AP/SF cutoffs. Candidate remission definitions all demonstrated significant treatment effects (UST vs. PBO): total AP+SF <75 (29.4% vs.16.7%; p=0.004), combined AP≤1 AND SF≤3 (19.3% vs.9.1%; p=0.007), combined AP≤1 AND SF≤1.5 (13.7% vs.5.3%; p=0.009). Conclusion: Definitions of PRO-2 remission based on SF&AP CDAI components are sensitive and specific in an anti-TNF refractory/intolerant population with high CD activity. In this population, the PRO-2 definition of AP≤1 AND SF≤3 better reflects clinical remission than the previously proposed AP≤1 AND SF≤1.5 threshold, identified in the mild-to-moderate patient populations. A weighted total AP+SF score <75 may be a good PRO-2 definition of remission, because it provides the best overall balance of SENS/SPEC and facilitates comparisons with studies utilizing the full CDAI. Disclosure - C Gasink-employee Janssen R&D, LLC; J Friedman-employee Janssen R&D, LLC; LL Gaoemployee Janssen R&D, LLC; D Chan- employee Janssen R&D, LLC; W Sandborn-Grant/Research support Janssen R&D, LLC; B Feagan-Grant/Research support Janssen R&D, LLC