Clinical Trial Design in Ulcerative Colitis: Interpreting Evolving Endpoints Based on Post Hoc Analyses of the Vedolizumab Phase 3 Trials GEMINI 1 and VISIBLE 1

William J Sandborn; Bruce E Sands; Sharif Uddin; Rana M Qasim Khan; Richa Sagar Mukherjee

doi:10.1093/crocol/otad076

Clinical Trial Design in Ulcerative Colitis: Interpreting Evolving Endpoints Based on Post Hoc Analyses of the Vedolizumab Phase 3 Trials GEMINI 1 and VISIBLE 1

Crohns Colitis 360. 2023 Dec 18;6(1):otad076. doi: 10.1093/crocol/otad076. eCollection 2024 Jan.

Authors

William J Sandborn¹, Bruce E Sands², Sharif Uddin³, Rana M Qasim Khan³, Richa Sagar Mukherjee³

Affiliations

¹ Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA.
² Dr. Henry D. Janowitz Division of Gastroenterology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³ Takeda Pharmaceuticals U.S.A., Inc., Lexington, MA, USA.

Abstract

Background: The 12-point total Mayo score including a Physician's Global Assessment (PGA) of disease activity has been used to assess outcomes in clinical trials for ulcerative colitis (UC). In 2016, the US Food and Drug Administration (FDA) issued guidance advising the removal of the PGA in future trials. We examined how endpoints in UC trials have evolved and conducted a post hoc analysis of the GEMINI 1 and VISIBLE 1 trials to understand how the use of a 9-point modified Mayo score, excluding PGA, compares with the total Mayo score.

Methods: Endpoint definitions of clinical remission in phase 3 trials were extracted from published literature and ClinicalTrials.gov. The difference (%Δ) between the proportions of patients in GEMINI 1 and VISIBLE 1 achieving clinical remission with vedolizumab versus placebo at week 52 was measured according to 4 endpoint definitions.

Results: Trials completed up to the end of 2019 used the total Mayo score to assess clinical remission. Most trials that were completed or estimated to be completed by June 2020 or later used modified Mayo scores. Post hoc analysis revealed decreasing endpoint stringency was associated with increasing %Δ values. The modified Mayo score definition most like the definition recommended by the FDA produced %Δ values like those reported using the total Mayo score in GEMINI 1 and VISIBLE 1.

Conclusions: Endpoint definitions for UC clinical trials have evolved following FDA guidance. The efficacy of vedolizumab, measured using modified Mayo scoring, was comparable to values reported using the total Mayo score.

Keywords: Mayo score; clinical trial; regulatory guidance; ulcerative colitis; vedolizumab.