Vedolizumab Induction Therapy for Patients With Crohn’s Disease and Prior Anti-TNF Antagonist Failure: A Randomized, Placebo-controlled, Double-blind, Multicenter Trial (2012)

Vedolizumab (VDZ) is an investigational gut-selective monoclonal antibody targeting the α4β7 integrin. We assessed the efficacy and safety of VDZ as induction therapy in patients with Crohn’s disease (CD), with the primary analysis in patients with prior TNFα antagonist failure. In a 10-wk, phase 3 study, adult patients with moderately to severely active CD (CD Activity Index [CDAI] of 220-400) and with either a CRP >2.87 mg/L, or colonoscopy photo of active CD within 4 months prior to randomization, or a fecal calprotectin >250 μg/g stool at screening plus imaging or endoscopic evidence of CD within 4 months prior to screening, despite treatment with purine antimetabolites, TNFα antagonists, and/or, for patients outside the US, corticosteroids, were randomized 1:1 to receive VDZ 300 mg IV or placebo (PBO) at wks 0, 2, and 6. The primary endpoint was clinical remission (CDAI ≤150) at wk 6 in patients who had prior TNFα antagonist failure. Secondary endpoints were clinical remission at wk 6 in the overall population (TNFα antagonist naïve and TNFα antagonist failure), clinical remission at wk 10 in the TNFα antagonist failure and overall populations, sustained clinical remission (CDAI ≤150 at wk 6 and wk 10) in the TNFα antagonist failure and overall populations, and CDAI 100 response (≥100-point decrease from baseline in CDAI) in the TNFα antagonist failure population. All endpoints were tested sequentially; Hochberg method was used to control alpha for endpoints in the 2 populations. Of 416 patients randomized, 315 (76%) had prior TNFα antagonist failure. Patient demographics were similar between treatment groups, except the baseline CDAI was slightly higher in the VDZ than the PBO group (313.9 vs 301.3; P = 0.015). In the TNFα antagonist failure subpopulation, the difference in the proportion of patients in the VDZ and PBO groups with clinical remission at wk 6 was not statistically significant (Table). Because the primary endpoint was not met, analyses of key secondary endpoints are considered exploratory. In the anti-TNFα failure subpopulation, greater proportions of VDZ-treated patients had achieved CDAI 100 response by wk 6 and were in clinical remission by wk 10 compared to PBO. In the overall population, more patients in the VDZ group than the PBO group were in clinical remission at wk 6 and wk 10, and at both time points (ie, sustained clinical remission). Treatment-emergent AEs were reported in 56% of the VDZ patients vs 60% of PBO patients; serious AEs were reported in 6% vs 8%, respectively. No deaths occurred. Although VDZ therapy was not more effective than PBO for inducing clinical remission at wk 6 in the anti-TNFα failure population, clinical remission rates at wk 10 were higher with VDZ than PBO, indicating that patients with previous anti-TNFα failure may require an additional dose for induction. Notably, VDZ therapy resulted in higher rates, compared with PBO, of achieving CDAI 100 response at wk 6, in both anti-TNFα failure and overall populations, and in clinical remission at wk 6 and at wk 10 in the overall population.