P814 Clinical trial design in Crohn’s disease: interpreting future endpoints based on post hoc analyses of the vedolizumab phase 3 trials GEMINI 2 and VISIBLE 2

Khan, R.M.Q.(1);Schwartz, D.A.(2);Sands, B.E.(3);Hanauer, S.(4);Uddin, S.(1);Mukherjee, R.(1);Lichtenstein, G.(5)*;

(1)Takeda Pharmaceuticals U.S.A.- Inc., US Medical, Lexington- MA, United States;(2)Vanderbilt University Medical Center, Department of Gastroenterology, Nashville- TN, United States;(3)The Mount Sinai Hospital- Feinstein IBD Clinical Center- Icahn School of Medicine at Mount Sinai, The Henry D Janowitz Division of Gastroenterology, New York- NY, United States;(4)Northwestern University Feinberg School of Medicine, Division of Gastroenterology, Chicago- IL, United States;(5)University of Pennsylvania, School of Medicine, Philadelphia- PA, United States;


Crohn’s disease (CD) is a chronic, relapsing–remitting disease characterized by inflammation of the gastrointestinal tract. Historically, the Crohn’s Disease Activity Index (CDAI) has been used to assess outcomes in clinical trials involving patients with CD. However, in contrast to the alignment of regulatory standards for trials in ulcerative colitis, the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) differ regarding the most appropriate endpoint definitions for trials in CD. We examined how clinical remission endpoints in CD trials have evolved and conducted post hoc analyses of two vedolizumab trials, GEMINI 2 and VISIBLE 2, to understand how endpoint definitions influence clinical trial outcome measures of treatment efficacy.


Endpoint definitions of clinical remission in completed and ongoing phase 3 trials of advanced therapies in CD were extracted from published literature and Post hoc analyses of data from GEMINI 2 and VISIBLE 2 were conducted by measuring the difference (%Δ) between the proportions of patients achieving clinical remission with vedolizumab versus placebo at week 52 as assessed by six endpoint definitions (A: stool frequency score [SFS] ≤ 2.8 and not worse than baseline score; B: SFS ≤ 3 and not worse than baseline score; C: abdominal pain score (APS) ≤ 1 and not worse than baseline score; D: SFS ≤ 2.8 and APS ≤ 1; E: SFS ≤ 3 and APS ≤ 1; F: CDAI ≤ 150) (Figure 1).


Most phase 3 trials of advanced therapies in CD included a clinical remission endpoint that was defined by CDAI score: typically, CDAI < 150 or ≤ 150. However, several recent trials have also included a primary or secondary clinical remission endpoint defined using components of the CDAI score such as SFS and APS (Table 1). Post hoc analyses of GEMINI 2 and VISIBLE 2 revealed minimal change in %Δ for each of the new endpoint definitions tested compared with the primary analysis for each trial (Figure 1).


Objective measures, including patient-reported outcomes and components of the CDAI score such as SFS and APS, have been used to define clinical remission in recent CD trials. Despite differences in regulatory guidance for defining clinical remission, our post hoc analyses of GEMINI 2 and VISIBLE 2 reveal that the efficacy of vedolizumab, measured using a variety of endpoint definitions from recent CD trials, was similar to that previously reported using CDAI ≤ 150.