S875 The Evolution of Clinical Trial Design in Ulcerative Colitis: Interpreting Future Endpoints Based on Post-Hoc Analyses of the Vedolizumab Phase 3 Trials GEMINI 1 and VISIBLE 1 (2021)

Introduction: Ulcerative colitis (UC) is a chronic, relapsing disease characterized by inflammation of the colon. In UC clinical trials, the Mayo score is used to assess outcomes. The 12-point total Mayo (t-Mayo) score incorporates measures of stool frequency, rectal bleeding, endoscopic findings, and a Physician Global Assessment (PGA) of disease activity. However, because the PGA may not fully capture improvements across all signs and symptoms associated with UC, in 2016 the US Food and Drug Administration (FDA) issued guidance advising removal of the PGA in favor of a broader patient- or observer-reported outcome instrument for future trials.1 We examined how endpoints in UC trials have evolved in response to FDA guidance and conducted a post hoc analysis of two vedolizumab trials, GEMINI 1 and VISIBLE 1, to understand how use of a 9-point modified Mayo (m-Mayo) score, excluding PGA, compares with the t-Mayo score. Methods: Endpoint definitions of clinical remission in phase 3 trials of biologic maintenance treatment were extracted from published literature and ClinicalTrials.gov. For post hoc analysis of data from GEMINI 1 and VISIBLE 1, we measured the difference (%Δ) between the proportions of patients achieving clinical remission with vedolizumab versus placebo at week 52 according to a range of four selected endpoint definitions of differing stringency (Figure 1). Results: Phase 3 UC trials completed up to the end of 2019 used the t-Mayo score to assess the endpoint of clinical remission. Trials that began in 2015 or later and were completed or estimated to be completed in 2020 or later used m-Mayo scores that excluded the PGA (Table 1). Post hoc analysis of GEMINI 1 and VISIBLE 1 data revealed a trend of increasing %Δ values as the stringency of endpoint definition decreased. The second-least stringent definition produced %Δ values most like those reported for GEMINI 1 and VISIBLE 1 using the t-Mayo score (Figure 1). Conclusion: Endpoint definitions for UC clinical trials have evolved following FDA guidance to remove the subjective PGA. Our post hoc analysis of GEMINI 1 and VISIBLE 1 reveals that the effectiveness of vedolizumab, measured using endpoint definitions like those used in recent UC trials (Figure 1, definitions C and D), was comparable to that previously reported using the t-Mayo score.Figure 1.: Difference between the proportion of patients achieving clinical remission with vedolizumab versus placebo at week 52 in the GEMINI 1 and VISIBLE 1 trials according to each of four endpoint definitions of differing stringency and the primary analysis definition. *Patients received intravenous vedolizumab once every 8 weeks. † Patients received subcutaneous vedolizumab once every 2 weeks. ǂNew definitions are based on most (A) to least (D) stringent criteria. (A) RBS = 0, ES = 0, and ≥ 1-point decrease in SFS from baseline to achieve a subscore of 0 or 1 (B) RBS = 0, ES = 0, SFS ≤ 1 (0 or 1) (C) RBS = 0, ES ≤ 1 (0 or 1), and ≥ 1-point decrease in SFS from baseline to achieve a subscore of 0 or 1 (D) RBS = 0, ES ≤ 1 (0 or 1), SFS ≤ 1 (0 or 1) (E) Total Mayo score at week 52 ≤ 2 with no individual subscore > 1 CI, confidence interval; ES, endoscopic subscore; RBS, rectal bleeding subscore; SFS, stool frequency subscore. 1. Feagan BG et al. New Engl J Med 2013;369:699–710. 2. Sandborn WJ et al. Gastroenterology 2020;158:562–72Table 1.: Endpoint definitions for clinical remission during maintenance treatment in phase 3 UC trials. *For the ACT1 infliximab trial, the primary endpoint was clinical response and clinical remission was a secondary endpoint. †Excludes Physician Global Assessment. ǂIncludes Physician Global Assessment. EBS, endoscopy/bleeding/stool frequency; ES, endoscopic subscore; RBS, rectal bleeding subscore; SFS, stool frequency subscore; UC, ulcerative colitis.