Efficacy and safety of biosimilar CT-P13 compared with originator infliximab in patients with active Crohn's disease: an international, randomised, double-blind, phase 3 non-inferiority study.

BACKGROUND: The infliximab biosimilar CT-P13 was approved for use in Crohn's disease after clinical comparison with originator infliximab in ankylosing spondylitis and rheumatoid arthritis; however, concerns about such indication extrapolation have been expressed. This study investigated whether CT-P13 is non-inferior to infliximab in patients with Crohn's disease who were naive to biological therapy. METHODS: In this randomised, multicentre, double-blind, phase 3 non-inferiority study, we enrolled patients with active Crohn's disease who had not responded to, or were intolerant to, non-biological treatments. Patients were randomly assigned (1:1:1:1) to receive CT-P13 then CT-P13, CT-P13 then infliximab, infliximab then infliximab, or infliximab then CT-P13, with switching occurring at week 30. Patients received 5 mg/kg CT-P13 or infliximab at weeks 0, 2, 6, and then every 8 weeks up to week 54. The primary endpoint was the proportion of patients with a decrease of 70 points or more in Crohn's Disease Activity Index (CDAI) from baseline to week 6. A non-inferiority margin of -20% was set (CT-P13 was non-inferior to infliximab if the lower limit of the two-sided 95% CI for the treatment difference was greater than -20). This trial is registered with ClinicalTrials.gov, number NCT02096861, and is completed. FINDINGS: Between Aug 20, 2014, and Feb 15, 2017, 308 patients were assessed for eligibility, and 220 patients were enrolled: 111 were randomly assigned to initiate CT-P13 (56 to the CT-P13-CT-P13 group and 55 to the CT-P13-infliximab group) and 109 to initiate infliximab (54 to the infliximab-infliximab group and 55 to the infliximab-CT-P13 group). CDAI-70 response rates at week 6 were similar for CT-P13 (77 [69·4%, 95% CI 59·9 to 77·8] of 111) and infliximab (81 [74·3%, 95% CI 65·1 to 82·2] of 109; difference -4·9% [95% CI -16·9 to 7·3]), thereby establishing non-inferiority. Over the total study period, 147 (67%) patients experienced at least one treatment-emergent adverse event (36 [64%] in the CT-P13-CT-P13 group, 34 [62%] in the CT-P13-infliximab group, 37 [69%] in the infliximab-infliximab group, and 40 [73%] in the infliximab-CT-P13 group). INTERPRETATION: This study showed non-inferiority of CT-P13 to infliximab in patients with active Crohn's disease. Biosimilar CT-P13 could be a new option for the treatment of active Crohn's disease. FUNDING: Celltrion, Pfizer.

Budesonide Suppositories Are Effective and Safe for Treating Acute Ulcerative Proctitis.

BACKGROUND & AIMS: Although proctitis is the most limited form of ulcerative colitis, it causes unpleasant symptoms. Topical mesalamine, the standard treatment, is not always effective. We conducted a randomized phase 2 trial to determine the efficacy and safety of 2 doses of a budesonide suppository vs mesalamine suppositories vs combined budesonide and mesalamine suppositories for proctitis. METHODS: We performed a prospective, double-blind, double-dummy, multicenter trial in 337 patients with active proctitis to compare the efficacies of 4 different suppository treatments. Patients were randomly assigned to groups given 2 mg budesonide suppositories (2 mg BUS; n = 89 patients), 4 mg BUS (n = 79), 1 g mesalamine suppositories (1 g MES; n = 81), or the combination of 2 mg BUS and 1 g MES (n = 88). The study was performed from November 2013 through July 2015 at 36 study sites in Europe and Russia. The primary end point was the time to resolution of clinical symptoms, defined as the first of 3 consecutive days with a score of 0 for rectal bleeding and stool frequency. RESULTS: The mean time to resolution of symptoms in the 4 mg BUS (29.8 days) and combination of 2 mg BUS and 1 g MES (29.3 days) groups resembled that of the standard 1 g MES treatment (29.2 days), but was significantly longer in the 2 mg BUS group (35.5 days). Furthermore, proportions of patients with deep, clinical, and endoscopic remission, as well as mucosal healing, were similar among the 1 g MES, 4 mg BUS, and combination therapy groups, but significantly lower in the group that received 2 mg BUS. No safety signals were observed, and the patients' treatment acceptance was high (67%-85% of patients). CONCLUSIONS: In a multicenter randomized trial, we found that the efficacy and safety of 4 mg BUS in treatment of active proctitis did not differ significantly from those of 1 g MES. Budesonide suppositories offer an alternative therapy to mesalamine for topical treatment of proctitis. Clinicaltrialsregister.eu no: 2012-003362-41.

Randomized, Ascending Dose, Phase 2 Study of KHK4083, an Anti-OX40 Monoclonal Antibody, in Moderately Active Ulcerative Colitis.

Background: OX40 (CD134) plays a role in the maintenance of late T-cell proliferation and survival. KHK4083 is a monoclonal antibody directed against OX40. We aimed to assess the safety and preliminary efficacy of KHK4083 in patients with moderately active ulcerative colitis (UC). Methods: In this multicenter, double-blind, parallel-group, phase 2 study, patients with moderately active UC patients were randomized to ascending doses of intravenous KHK4083 (1, 3, or 10 mg/kg) or placebo every 2 weeks for 12 weeks. The primary endpoint was safety. The primary efficacy end point was the change from baseline in mean modified Mayo endoscopy subscore at week 12. Treatment with KHK4083 or placebo was continued every 4 weeks for up to 52 weeks in responders. Results: Long-term treatment with KHK4083 was well tolerated, with treatment-related adverse events being predominantly transient mild-to-moderate infusion-related reactions. Exploratory analysis of biopsy samples showed the virtually complete elimination of OX40+ cells in colon mucosa after 12 weeks of KHK4083 treatment. There were no significant differences between any of the randomized KHK4083 dose groups and placebo for the mean change in Mayo endoscopy subscore from baseline to week 12. Conclusions: KHK4083 can be safely administered intravenously at doses up to 10 mg/kg every 2 or 4 weeks for up to 52 weeks. Proof of pharmacodynamic action was confirmed by depletion of the elevated levels of the OX40+ cells associated with UC at all tested doses. Clinical response and mucosal healing (endoscopic improvement) in this population was not correlated with ablation of OX40+ T cells.

Corrigendum to: Randomized, Ascending Dose, Phase 2 Study of KHK4083, an Anti-OX40 Monoclonal Antibody, in Moderately Active Ulcerative Colitis.

[This corrects the article DOI: 10.1093/crocol/otaa049.].