Certolizumab pegol is a polyethylene-glycolated Fab' fragment of a humanized anti-TNF monoclonal antibody. Certolizumab pegol was evaluated in a phase 2, 12-week, double-blind, randomized, placebo-controlled, dose-response study in patients with moderate to severe CD (Schreiber et al. 2005). A total of 292 patients were randomized to receive subcutaneous cer-tolizumab 100,200, or 400 mg or placebo at Weeks 0,4, and 8. The primary endpoint was the percentage of patients with a clinical response (CDAI decrease of
> 100 or remission CDAI < 150) at Week 12. All certoli-zumab doses produced a significant clinical benefit over placebo by Week 2. The clinical response rates were highest for the 400-mg dose and were greatest at Week 10, although not significant at Week 12 (the primary endpoint). Among patients with elevated baseline C-reactive protein (CRP) levels, 53% of those treated with certolizumab 400 mg achieved clinical remission versus 18% of patients receiving placebo (p = 0.005). Adverse events were similar among groups.
In the PRECiSE 2, phase 3 study (Schreiber 2005), adult patients (N =668) with active CD who responded at Week 6 (CDAI decrease > 100 points from baseline) to open-label induction therapy with certolizumab 400 mg at Weeks 0,2, and 4, were randomized to maintenance therapy with certolizumab 400 mg or placebo every 4 weeks up to 24 weeks. Patients were stratified at baseline by CRP (<10 mg/l or > 10 mg/l) and by corti-costeroid and immunosuppressant use. The primary endpoint was the percentage of patients at Week 26 in the CRP > 10 mg/l stratum who maintained a clinical response after successful induction. Major secondary endpoints included remission (CDAI <150) in the CRP >10 mg/l stratum, and response and remission in the overall intention-to-treat (ITT) population. A total of 64% of patients responded to open-label induction therapy and were randomized. At Week 26, the clinical response rate (CDAI decrease > 100 points from baseline) in the CRP > 10 mg/l stratum was 62 % for certolizumab versus 34% for placebo (p <0.001). The clinical response rate at Week 26 in the overall ITT population was 63% for certolizumab versus 36% for placebo (p <0.001). Overall ITT population remission rates were 48% for certolizumab versus 29% for placebo (p <0.001). The most commonly reported adverse event was headache, which occurred with similar frequency among certolizumab and placebo groups. Results from the PRECiSE-1 phase 3 trial were recently presented. Similar to PRECiSE-2, certolizumab was more effective than placebo in achieving a clinical response among patients with CRP > 10 mg/l at baseline. Although there were trends toward greater efficacy in clinical remission results, differences between placebo and certolizumab did not achieve statistical significance in either the patients with CRP > 10 mg/l or among the overall ITT population (Sandborn et al. 2006). PRECiSE-3 and 4 are 24-month open-label trials to assess long-term safety that are currently ongoing.
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