Vedolizumab as Induction and Maintenance Therapy for Ulcerative Colitis

There are limitations to the 3 most common means of therapy for ulcerative colitis, a chronic inflammatory bowel disease. Aminosalicylates are only modestly effective; glucocorticoids can cause unacceptable adverse events and do not provide a benefit as maintenance therapy; and tumor necrosis factor (TNF) antagonists, although efficacious, predispose patients to serious infection. There is a need for new treatment strategies for ulcerative colitis, according to researchers.

Vedolizumab, a humanized monoclonal antibody, selectively blocks gut lymphocyte trafficking without interfering with trafficking to the central nervous system. In this report [N Engl J Med. 2013;369(8):699-710], the authors wished to evaluate the efficacy and safety of vedolizumab in patients with ulcerative colitis. The investigators did this by conducting 2 integrated randomized, double-blind, placebo-controlled trials of vedolizumab (induction and maintenance therapy) in patients with active disease. The investigation was conducted at 211 medical centers (including 15 at which enrollment was discontinued) in 34 countries from 2008 to 2012.

Eligible patients were aged 18 to 80 years and had active ulcerative colitis, defined as a Mayo Clinic score of 6 to 12 (range, 0-12, with higher scores indicating more active disease) with a sigmoidoscopy subscore of at least 2, and disease that extended ≥15 cm from the anal verge. An additional eligibility criterion was documentation of unsuccessful previous treatment. For induction therapy, patients were randomly assigned, in a 3:2 ratio, to receive intravenous vedolizumab (300 mg) or placebo at days 1 and 15 (cohort 1), with 2 stratification factors: (1) concomitant use or nonuse of glucocorticoids, and (2) concomitant use or nonuse of immunosuppressive agents or prior use or nonuse of TNF antagonists.

The primary outcome for induction therapy was a clinical response at week 6, defined as a reduction in the Mayo Clinic score of at least 3 points and a decrease of at least 30% from the baseline score, with a decrease of at least 1 point on the rectal bleeding subscale or an absolute rectal bleeding score of 0 or 1. Secondary outcomes at week 6 were clinical remission, defined as a Mayo Clinic score of ≤2 and no subscore >1, and mucosal healing, defined as an endoscopic subscore of 0 or 1. The primary outcome for maintenance therapy was clinical remission at week 52.

In the trial of induction therapy, 225 patients were randomly assigned to receive vedolizumab and 149 to receive placebo (cohort 1). An additional 521 patients (cohort 2) received open-label vedolizumab. Patients in either cohort who had a response to vedolizumab at week 6 were enrolled in the trial of maintenance therapy, with 122, 125, and 126 patients randomly assigned to receive vedolizumab every 8 weeks, vedolizumab every 4 weeks, and placebo, respectively.

In the trial of maintenance therapy, 106 of the 225 patients receiving vedolizumab (47.1%) and 38 of the 149 patients receiving placebo (25.5%) at week 6 had a clinical response (difference with adjustment for stratification factors, 21.7 percentage points; 95% confidence interval [CI], 11.6-31.7; P<.001). A total of 38 patients receiving vedolizumab (16.9%) and 8 receiving placebo (5.4%) had clinical remission (P=.001). Of the 521 patients in cohort 2 who received open-label vedolizumab, 231 had a clinical response (44.3%), 100 had clinical remission (19.2%), and 191 had mucosal healing (36.7%).

At week 52, patients who were randomly assigned to continue receiving vedolizumab were more likely to have clinical remission than were those randomly assigned to switch to placebo (51 of 122 patients receiving vedolizumab every 8 weeks [41.8%] and 56 of 125 receiving vedolizumab every 4 weeks [44.8%] vs 20 of 126 receiving placebo [15.9%]; adjusted difference for vedolizumab every 8 weeks vs placebo, 26.1 percentage points [95% CI, 14.9-37.2; P<.001]; adjusted difference for vedolizumab every 4 weeks vs placebo, 29.1 percentage points [95% CI, 17.9-40.4; P<.001]).