BACKGROUND & AIMS: Maintenance treatment with vedolizumab, a monoclonal antibody that inhibits the gut-selective α4β7 integrin, is administered intravenously. Some patients might prefer a subcutaneous formulation of vedolizumab for maintenance treatment. Subcutaneous vedolizumab was investigated as maintenance treatment in patients with moderately to severely active ulcerative colitis.
METHODS: We performed a phase 3, double-blind, double-dummy trial at 141 sites in 29 countries from December 18, 2015 through August 21, 2018. Patients with moderately to severely active ulcerative colitis received open-label treatment with intravenous vedolizumab 300 mg at weeks 0 and 2. At week 6, patients with clinical response were randomly assigned maintenance treatment with subcutaneous vedolizumab 108 mg every 2 weeks, intravenous vedolizumab 300 mg every 8 weeks, or placebo. The primary end point was clinical remission at week 52, which was defined as a total Mayo score of ≤2 and no subscore >1.
RESULTS: Among the randomized 216 patients, clinical remission at week 52 was achieved by 46.2%, 42.6%, and 14.3% of patients in the subcutaneous vedolizumab, intravenous vedolizumab, and placebo groups, respectively (subcutaneous vedolizumab vs placebo: Δ32.3%; 95% confidence interval, 19.7%-45.0%; P < .001). The subcutaneous vedolizumab group also had greater endoscopic improvement and durable clinical response at week 52 compared with placebo (both P < .001). The incidence of injection-site reactions was more frequent in patients given subcutaneous vedolizumab (10.4%) than intravenous vedolizumab (1.9%) or placebo (0%); these were not treatment limiting, most were mild, and none resulted in discontinuation. Subcutaneous and intravenous vedolizumab safety profiles were otherwise similar.
CONCLUSIONS: Subcutaneous vedolizumab is effective as maintenance therapy in patients with moderately to severely active ulcerative colitis who had a clinical response to intravenous vedolizumab induction therapy. It has a favorable safety and tolerability profile. ClinicalTrials.gov ID: NCT02611830; EudraCT 2015-000480-14.
BACKGROUND: Biologic therapies are widely used in patients with ulcerative colitis. Head-to-head trials of these therapies in patients with inflammatory bowel disease are lacking.
METHODS: In a phase 3b, double-blind, double-dummy, randomized trial conducted at 245 centers in 34 countries, we compared vedolizumab with adalimumab in adults with moderately to severely active ulcerative colitis to determine whether vedolizumab was superior. Previous exposure to a tumor necrosis factor inhibitor other than adalimumab was allowed in up to 25% of patients. The patients were assigned to receive infusions of 300 mg of vedolizumab on day 1 and at weeks 2, 6, 14, 22, 30, 38, and 46 (plus injections of placebo) or subcutaneous injections of 40 mg of adalimumab, with a total dose of 160 mg at week 1, 80 mg at week 2, and 40 mg every 2 weeks thereafter until week 50 (plus infusions of placebo). Dose escalation was not permitted in either group. The primary outcome was clinical remission at week 52 (defined as a total score of ≤2 on the Mayo scale [range, 0 to 12, with higher scores indicating more severe disease] and no subscore >1 [range, 0 to 3] on any of the four Mayo scale components). To control for type I error, efficacy outcomes were analyzed with a hierarchical testing procedure, with the variables in the following order: clinical remission, endoscopic improvement (subscore of 0 to 1 on the Mayo endoscopic component), and corticosteroid-free remission at week 52.
RESULTS: A total of 769 patients underwent randomization and received at least one dose of vedolizumab (383 patients) or adalimumab (386 patients). At week 52, clinical remission was observed in a higher percentage of patients in the vedolizumab group than in the adalimumab group (31.3% vs. 22.5%; difference, 8.8 percentage points; 95% confidence interval [CI], 2.5 to 15.0; P = 0.006), as was endoscopic improvement (39.7% vs. 27.7%; difference, 11.9 percentage points; 95% CI, 5.3 to 18.5; P<0.001). Corticosteroid-free clinical remission occurred in 12.6% of the patients in the vedolizumab group and in 21.8% in the adalimumab group (difference, -9.3 percentage points; 95% CI, -18.9 to 0.4). Exposure-adjusted incidence rates of infection were 23.4 and 34.6 events per 100 patient-years with vedolizumab and adalimumab, respectively, and the corresponding rates for serious infection were 1.6 and 2.2 events per 100 patient-years.
CONCLUSIONS: In this trial involving patients with moderately to severely active ulcerative colitis, vedolizumab was superior to adalimumab with respect to achievement of clinical remission and endoscopic improvement, but not corticosteroid-free clinical remission. (Funded by Takeda; VARSITY ClinicalTrials.gov number, NCT02497469; EudraCT number, 2015-000939-33.).
BACKGROUND: Vedolizumab safety and efficacy have been established in many populations all over the world, but have never been studied in Japan. We report results from a Phase 3, randomized, double-blind, placebo-controlled study of vedolizumab in Japanese patients with active ulcerative colitis (UC).
METHODS: Patients with moderate-to-severe UC were enrolled into Cohort 1 (double-blinded) or Cohort 2 (open-label) in the induction phase. Cohort 1 was randomized 2:1 to receive 300 mg vedolizumab or placebo, while Cohort 2 received vedolizumab 300 mg only, at Weeks 0, 2, and 6. Patients from Cohorts 1 and 2 showing a clinical response to vedolizumab at Week 10 were randomized 1:1 to receive vedolizumab or placebo (double-blinded) at Week 14 and then every 8 weeks up to Week 54 as the maintenance phase. The primary endpoint was clinical response at Week 10, for the induction phase, and clinical remission at Week 60, for the maintenance phase.
RESULTS: A total of 292 patients were enrolled into the induction phase (246 in Cohort 1, 46 in Cohort 2); 83 patients achieved response to vedolizumab and were subsequently enrolled into the maintenance phase. Clinical response rates at Week 10 were 39.6% (65/164) and 32.9% (27/82) in the vedolizumab and placebo groups in Cohort 1, respectively (adjusted odds ratio [AOR] = 1.37, 95% CI 0.779-2.399; p = 0.2722). In the maintenance phase, clinical remission rate at Week 60 was significantly higher in the vedolizumab group, at 56.1% (23/41), versus 31.0% (13/42) for placebo (AOR = 2.88, 95% CI 1.168-7.108; p = 0.0210). Most adverse events were mild to moderate in intensity, and no deaths occurred during the study period.
CONCLUSIONS: Vedolizumab showed numerically greater efficacy compared with placebo as induction therapy, but the difference was not statistically significant. Vedolizumab was significantly superior to placebo as maintenance therapy in Japanese patients with UC. Vedolizumab has favourable safety and tolerability in these patients.
TRIAL REGISTRATION: ClinicalTrials.gov: NCT02039505.
BACKGROUND: The efficacy of ustekinumab, an antagonist of the p40 subunit of interleukin-12 and interleukin-23, as induction and maintenance therapy in patients with ulcerative colitis is unknown.
METHODS: We evaluated ustekinumab as 8-week induction therapy and 44-week maintenance therapy in patients with moderate-to-severe ulcerative colitis. A total of 961 patients were randomly assigned to receive an intravenous induction dose of ustekinumab (either 130 mg [320 patients] or a weight-range-based dose that approximated 6 mg per kilogram of body weight [322]) or placebo (319). Patients who had a response to induction therapy 8 weeks after administration of intravenous ustekinumab were randomly assigned again to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 12 weeks [172 patients] or every 8 weeks [176]) or placebo (175). The primary end point in the induction trial (week 8) and the maintenance trial (week 44) was clinical remission (defined as a total score of ≤2 on the Mayo scale [range, 0 to 12, with higher scores indicating more severe disease] and no subscore >1 [range, 0 to 3] on any of the four Mayo scale components).
RESULTS: The percentage of patients who had clinical remission at week 8 among patients who received intravenous ustekinumab at a dose of 130 mg (15.6%) or 6 mg per kilogram (15.5%) was significantly higher than that among patients who received placebo (5.3%) (P<0.001 for both comparisons). Among patients who had a response to induction therapy with ustekinumab and underwent a second randomization, the percentage of patients who had clinical remission at week 44 was significantly higher among patients assigned to 90 mg of subcutaneous ustekinumab every 12 weeks (38.4%) or every 8 weeks (43.8%) than among those assigned to placebo (24.0%) (P = 0.002 and P<0.001, respectively). The incidence of serious adverse events with ustekinumab was similar to that with placebo. Through 52 weeks of exposure, there were two deaths (one each from acute respiratory distress syndrome and hemorrhage from esophageal varices) and seven cases of cancer (one each of prostate, colon, renal papillary, and rectal cancer and three nonmelanoma skin cancers) among 825 patients who received ustekinumab and no deaths and one case of cancer (testicular cancer) among 319 patients who received placebo.
CONCLUSIONS: Ustekinumab was more effective than placebo for inducing and maintaining remission in patients with moderate-to-severe ulcerative colitis. (Funded by Janssen Research and Development; UNIFI ClinicalTrials.gov number, NCT02407236.).
Background: Despite a growing number of new therapeutic options for inflammatory bowel disease (IBD), no clinical studies to date have directly compared two biologic agents. We performed a headto‐ head study of the efficacy and safety of vedolizumab (VDZ) and adalimumab (ADA) for treatment over 52 weeks in adults with moderately to severely active ulcerative colitis (UC). Methods: This was a phase 3b, double‐blind, double‐dummy, multicentre, active‐controlled trial enrolling patients with moderately to severely active UC (Mayo score 6 to 12 and endoscopic sub‐score ≥2) who had failed other conventional therapies (NCT02497469; EudraCT 2015‐000939‐33). Prior tumour necrosis factor (TNF) antagonist exposure was capped at 25% of the patient population. Patients were randomised 1:1 to either: (1) active VDZ intravenous (IV) infusions (300 mg)/placebo subcutaneous (SC) injections; or (2) placebo IV infusions/active ADA SC injections (160/80/40 mg). The dosing for each active drug followed the standard, approved regimens for induction and maintenance. Dose escalation was not permitted in either group. The primary endpoint was clinical remission, defined as a complete Mayo score ≤2 with no sub‐score >1 at week 52. Results: A total of 769 patients were randomised to VDZ (n = 383) or ADA (n = 386) at 330 sites in 37 countries and received at least one dose of study drug. At Week 52, VDZ showed significantly better rates of clinical remission (primary endpoint) and mucosal healing. Overall clinical remission rates at week 52 were 31.3% (n = 120/383) for VDZ and 22.5% (n = 87/386) for ADA (P = 0.0061). Mucosal healing (Mayo endoscopic sub‐score ≤1) at Week 52 was achieved in 39.7% (n = 152/383) of patients treated with VDZ and in 27.7% (n = 107/386) of patients treated with ADA (P = 0.0005). Corticosteroid‐free remission rates at Week 52 showed a numerical but non‐significant difference in favour of ADA. Overall, 62.7% and 69.2% of patients treated with VDZ and ADA, respectively, experienced an adverse event (AE). Serious AEs occurred in 11.0% and 13.7% of patients treated with VDZ and ADA, respectively. Exposure‐adjusted rates of infections were 33.5% and 43.5% in patients treated with VDZ and ADA, respectively; few infections were considered serious in either group. Conclusion: This is the first study to directly compare two biological agents in IBD. VDZ was superior to ADA in achieving clinical remission and endoscopic mucosal healing at Week 52, while VDZ and ADA were both generally safe and well‐tolerated, in patients with moderately to severely active UC.
Background: The objective was to evaluate the efficacy and safety of ustekinumab (UST) through Week 16 induction among patients with moderate‐severe UC randomised to UST in the UNIFI Phase 3 clinical trial. Week 8 induction data have been previously reported.1 Methods: Rates of overall clinical response and clinical remission among blinded patients randomised to IV UST induction were used to evaluate efficacy through Week 16. The number of patients who achieved each endpoint included patients who achieved the endpoint at Week 8 after initial IV UST induction and patients who achieved the same endpoint at Week 16 following a blinded dose of UST 90 mg SC at Week 8 if they were not in clinical response at Week 8. Results: Among patients randomised to UST at Week 0, 77.6% achieved clinical response within 16 weeks: 56.5% at Week 8 after IV induction and an additional 21.1% at Week 16 after receiving UST SC at Week 8. Among the Week 8 non‐responders to UST IV induction who received UST SC at Week 8, 57.9% achieved clinical response at Week 16. Among patients randomised to UST at Week 0, 18.8% achieved clinical remission within 16 weeks: 15.6% at Week 8 after IV induction and an additional 3.2% at Week 16 after receiving an additional UST dose at Week 8. Among the Week 8 non‐responders to UST IV induction who received UST SC at Week 8, 9.4% achieved clinical remission at Week 16. The proportions of patients who achieved clinical response within 16 weeks was lower for patients with a history of biological failure compared with nonbiological failure patients: 70.6% vs. 84.9% (Table 1). Similarly, the proportions of patients who achieved clinical remission during induction within 16 weeks were lower for biological failure patients compared with non‐biological failure patients: 13.3% vs. 24.7% (Table 2). The AE profile for patients who received a single UST IV dose and those with an additional UST dose SC at Week 8 were similar and consistent with the AE profile for patients that received PBO. Conclusions: UST is safe and effective induction therapy in patients with moderate‐severe UC. Similar to results from the Crohn's disease programme, these data support a clinical rationale for continuing treatment with UST through at least one SC dose 8 weeks after IV induction in patients with moderate‐severe UC. (Table Presented).
