Background and aims Pilot studies with visilizumab, a humanised monoclonal antibody to CD3, suggest efficacy for corticosteroid-refractory ulcerative colitis (UC). A placebo-controlled trial was... Show moreBackground and aims Pilot studies with visilizumab, a humanised monoclonal antibody to CD3, suggest efficacy for corticosteroid-refractory ulcerative colitis (UC). A placebo-controlled trial was warranted. Methods A randomised, double-blind, placebo-controlled study evaluated the efficacy of visilizumab induction treatment in 127 patients with severely active UC despite treatment with >= 5 days of intravenous corticosteroids. Patients received placebo or visilizumab 5 mu g/kg intravenously on days 1 and 2. Corticosteroids were tapered according to disease activity. Patients were followed up for 90 days. The primary end point was induction of response at day 45. Secondary end points included remission and mucosal healing at day 45, symptomatic response at day 15 and colectomy. Results Response at day 45 occurred in 55% of patients receiving visilizumab compared with 47% of those who received placebo (p=0.475). Remission at day 45 occurred in 8% of patients receiving visilizumab compared with 9% of those who received placebo (p=0.704). Mucosal healing at day 45 occurred in 29% of patients receiving visilizumab compared with 26% of those who received placebo (p=0.799). Symptomatic response at day 15 occurred in 82% of patients receiving visilizumab compared with 74% of those who received placebo (p=0.244). Colectomy was performed in 18% of patients receiving visilizumab compared with 7% of those who received placebo (p=0.130). Cardiac disorders and vascular disorders occurred more frequently in the patients who received visilizumab. Conclusion Visilizumab at a dose of 5 mu g/kg for two consecutive days was not effective for severe, corticosteroid-refractory UC and was associated with increased cardiac and vascular adverse events. (Registered at http://www.clinicaltrials.govNCT00279422/). Show less
Objective Semapimod, a small molecule known to inhibit proinflammatory cytokine activity, was studied to determine the optimal dose necessary to achieve a response in patients with moderate to... Show moreObjective Semapimod, a small molecule known to inhibit proinflammatory cytokine activity, was studied to determine the optimal dose necessary to achieve a response in patients with moderate to severe Crohn's disease (CD). Methods A randomised, double-blind, placebo-controlled trial (CD04) was carried out followed by an open-label extension study (CD05). The trial was conducted in international multicentre outpatient clinics and included patients with moderate to severe CD (Crohn's Disease Activity Index (CDAI) 250-400). Placebo was administered for 3 days; 60 mg semapimod intravenously for 1 day with placebo for 2 days; or 60 mg semapimod intravenously for 3 days. Participants who completed CD04 could participate in the open-label extension study, CD05, to receive up to five additional semapimod HCl 60 mg daily doses three times every 6-8 weeks. The main outcome measures were CDAI, Inflammatory Bowel Disease Questionnaire (IBDQ), Crohn's Disease Endoscopic Inflammation Score (CDEIS) and serum C-reactive protein (CRP) concentration. Results 152 patients were randomised in CD04. Responses for 1 and 3 day regimens were similar to placebo for CDAI (p=0.82), IBDQ (p=0.85), CDEIS (p=0.57) and CRP (p=0.40). The only noteworthy treatment-related safety finding was infusion reaction (phlebitis): 7.3, 34.8 and 62.7% for the placebo and 1 and 3 day semapimod treatment groups, respectively (p<0.001). In the open-label CD05 study (included 119 patients) a posthoc analysis showed that the mean CDAI improved in patients receiving 6 compared with <= 3 cumulative doses (204.1 +/- 83 vs 251.4 +/- 103.05, p=0.006). Conclusions Single and 3 day dosing of semapimod (<= 180 mg) was ineffective for the treatment of moderate to severe CD. However, cumulative dosing >= 360 mg was associated with decreased CDAI in a limited number of patients. Show less
Baert, F.; Moortgat, L.; Assche, G. van; Caenepeel, P.; Vergauwe, P.; Vos, M. de; ... ; N Holland Gut Club 2010
BACKGROUND & AIMS: Few prospective data are available to support the clinical relevance of mucosal healing in patients with Crohn's disease. This study examined whether complete healing,... Show moreBACKGROUND & AIMS: Few prospective data are available to support the clinical relevance of mucosal healing in patients with Crohn's disease. This study examined whether complete healing, determined by endoscopy, predicts a better outcome in Crohn's disease. METHODS: One-hundred thirty-three newly diagnosed and treatment-naive Crohn's disease patients were given either a combination of immunosuppressive therapy (azathioprine) and 3 infusions of infliximab or treatment with conventional corticosteroids. Patients given azathioprine were given repeated doses of infliximab for relapses, patients given corticosteroids were given azathioprine in cases of corticosteroid dependency and infliximab only if azathioprine failed. A representative subset of 49 patients from the initially randomized cohort underwent ileocolonoscopy after 2 years of therapy. Correlation analysis was performed between different clinical parameters including endoscopic activity (Simple Endoscopic Score) and clinical outcome 2 years after this endoscopic examination. Data were available from 46 patients 3 and 4 years after therapy began. RESULTS: Complete mucosal healing, defined as a simple endoscopic score of 0 after 2 years of therapy, was the only factor that predicted sustained, steroid-free remission 3 and 4 years after therapy was initiated; it was observed in 17 of 24 patients (70.8%) vs 6 of 22 patients with lesions detected by endoscopy (27.3%, Simple Endoscopic Score > 0) (P = .036; odds ratio = 4.352; 95% confidence interval, 1.10-17.220). Fifteen of 17 patients with mucosal healing at year 2 maintained in remission without further infliximab infusions during years 3 and 4 (P = .032; odds ratio = 4.883; 95% confidence interval, 1.144-20.844). CONCLUSIONS: Complete mucosal healing in patients with early-stage Crohn's disease is associated with significantly higher steroid-free remission rates 4 years after therapy began. Show less
