Colon to Rectum
Lancet Gastroenterol Hepatol. 2022;7(2):118–27
Etrolizumab versus infliximab for the treatment of moderately to severely active ulcerative colitis (GARDENIA): A randomized, double-blind, double-dummy, phase 3 study
Background: Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In a previous phase 2 induction study, etrolizumab significantly improved clinical remission versus placebo in patients with moderately to severely active ulcerative colitis. The authors aimed to compare the safety and efficacy of etrolizumab with infliximab in patients with moderately to severely active ulcerative colitis.
Methods: They conducted a randomized, double-blind, double-dummy, parallel-group, phase 3 study (GARDENIA) across 114 treatment centers worldwide, and included adults (age 18–80 years) with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6–12 with an endoscopic subscore of ≥ 2, a rectal bleeding subscore of ≥ 1, and a stool frequency subscore of ≥ 1) who were naive to tumor necrosis factor inhibitors. Patients were required to have had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. Participants were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks or intravenous infliximab 5 mg/kg at 0, 2, and 6 weeks and every 8 weeks thereafter for 52 weeks. Randomization was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants, and baseline disease activity. All participants and study site personnel were masked to treatment assignment. The primary end point was the proportion of patients who had both clinical response at week 10 (MCS ≥ 3-point decrease and ≥ 30% reduction from baseline, plus ≥ 1-point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) and clinical remission at week 54 (MCS ≤ 2, with individual subscores ≤ 1); efficacy was analyzed using a modified intention-to-treat population (all randomized patients who received at least 1 dose of study drug). GARDENIA was designed to show superiority of etrolizumab over infliximab for the primary end point.
Findings: Between December 24, 2014, and June 23, 2020, 730 patients were screened for eligibility and 397 were enrolled and randomly assigned to etrolizumab (n = 199) or infliximab (n = 198). 95 patients (48%) in the etrolizumab group and 103 (52%) in the infliximab group completed the study through week 54. At week 54, 37 of 199 patients (18.6%) in the etrolizumab group and 39 of 198 (19.7%) in the infliximab group met the primary end point (adjusted treatment difference -0.9%; 95% confidence interval: -8.7–6.8; p = 0.81). The number of patients reporting ≥ 1 adverse events was similar between treatment groups (154 of 199 [77%] in the etrolizumab group and 151 of 198 [76%] in the infliximab group); the most common adverse event in both groups was ulcerative colitis (55 patients [28%] in the etrolizumab group and 43 [22%] in the infliximab group). More patients in the etrolizumab group reported serious adverse events (including serious infections) than did those in the infliximab group (32 [16%] vs. 20 [10%]); the most common serious adverse event was ulcerative colitis (12 [6%] and 11 [6%]). There was 1 death during follow-up, in the infliximab group due to a pulmonary embolism, which was not considered to be related to study treatment.
Interpretation: To the authors’ knowledge, this trial is the first phase 3 maintenance study in moderately to severely active ulcerative colitis to use infliximab as an active comparator. Although the study did not show statistical superiority for the primary end point, etrolizumab performed similarly to infliximab from a clinical viewpoint.