Introduction 1 2 3 4 5 6 7 8 9 10 11 13 14 15 13 16 8 17 18 19 20 21 22 23 24 25 18 Materials and methods Ethical conduct This study was approved by the Independent Ethics Committee/Institutional Review Board for each center before initiation. It was conducted in accordance with the International Conference for Harmonization Guidelines for Good Clinical Practice and the declaration of Helsinki (revised 1996). Written informed consent was obtained from each patient at screening before any study procedures were performed. Patients Adult patients (age ≥18 years) with moderate-to-severe active Crohn’s disease, as defined by a CDAI score of 220–450 points during the week before the administration of the first dose of study drug, were eligible for the study. Exclusion criteria included suspected or diagnosed abscess, a bowel perforation or evidence of non-inflammatory obstruction in 6 months before screening, extensive bowel resection, a functional colostomy or ileostomy, or a known history of tuberculosis. Concomitant medication was allowed, provided that doses were stable and could be continued for the 12-week double-blind period and the 8-week follow-up. Study design w v 1 Fig. 1 Study design (showing the total numbers of patients recruited into each treatment group)  Outcomes 26 26 27 7 28 7 Statistical analysis A sample size of 260 patients was calculated to give approximately 83% power to detect a true difference between treatment groups of 23% for the primary endpoint of the study, based on a placebo response rate of 12%. After screening, patients were to be randomized in a 1:1:1:1 ratio (65 patients to each of the four treatment groups). Therefore, 195 patients were to receive certolizumab pegol and 65 were to receive placebo. Efficacy was assessed for the intent-to-treat (ITT) population, which included all patients who received at least one injection and had at least one efficacy measurement after the first injection. Patients who terminated the trial prematurely were advanced to the end-of-study visit. The last observation carried forward method was used in cases where data were missing. P Results 21 Patients In total, 372 patients were screened of whom 292 patients were enrolled (CDAI score <220 points was the most common reason for screening failure). Of these 292 patients, 291 were included in the ITT population used to measure the efficacy endpoints according to CDAI scores [1 patient (400 mg group) was excluded because of missing efficacy data]. Baseline IBDQ scores were not obtained for one patient in the certolizumab pegol 100 mg treatment group. The ITT analyses for the HRQoL evaluations therefore included data for 290 patients. Seventy-five patients (25.7%) withdrew from the study by week 12. The majority of withdrawals were a consequence of lack of improvement/disease progression. Baseline CRP measurements were obtained for 290 of the 291 patients in the ITT population. Elevated baseline CRP levels (≥10 mg/l) were recorded for 119 patients (41.0%). One of these patients was the patient in the certolizumab pegol 100 mg treatment group who was excluded from analyses as a result of baseline IBDQ scores not being obtained. The subgroup analyses of IBDQ by baseline CRP status were therefore performed on data from 118 patients with an elevated baseline CRP concentration. 1 Table 1 Baseline demographic and clinical characteristics (intent to treat population used to measure efficacy endpoints according to Crohn’s Disease Activity Index scores)   n Certolizumab pegol n n  n Mean CDAI score (range) 291.5 (206–448) 299.2 (194–520) 310.7 (184–446) 304.5 (204–461) a 122.9 (61–190) b 122.9 (74–189) 126.5 (71–177) Geometric mean plasma CRP, mg/l (range) 7.268 (0.27–86.10) b 6.475 (0.17–127.00) 7.738 (0.35–128.28) n 28 (38.4) b 28 (38.9) 32 (44.4) n   Aminosalicylates 29 (39.7) 37 (50.0) 32 (44.4) 28 (38.9)   Anti-infectives 7 (9.6) 6 (8.1) 7 (9.7) 6 (8.3)   Antidiarrheals 10 (13.7) 19 (25.7) 16 (22.2) 12 (16.7)   Steroids 29 (39.7) 24 (32.4) 29 (40.3) 22 (30.6)   Codeine and derivatives 6 (8.2) 5 (6.8) 5 (6.9) 2 (2.8) Immunomodulators       Azathioprine 17 (23.3) 13 (17.6) 23 (31.9) 22 (30.6)   6-Mercaptopurine 4 (5.5) 9 (12.2) 2 (2.8) 2 (2.8)   Methotrexate 5 (6.8) 4 (5.4) 4 (5.6) 3 (4.2) CDAI CRP IBDQ n a b Clinical response P =  P =  21 P  Improvement in HRQoL P  P  2 P  P Fig. 2 IBDQ  3 P  3 2 3 Fig. 3 IBDQ a b c d  P  3 3 P =  3 2 Table 2 Proportion of patients achieving remission defined by Inflammatory Bowel Disease Questionnaire total score (≥170 points) n Week n Certolizumab pegol n n n 2 17.8 32.9 19.4 27.8 4 19.2 a 26.4 33.3 6 17.8 35.6* 30.6 38.9* 8 21.9 35.6 29.2 38.9* 10 27.4 43.8 36.1 47.2* 12 23.3 38.4 23.6 38.9* a p Discussion 29 10 21 22 23 21 30 22 23 31 32 Improvements in emotional well-being (e.g. depression, anxiety, irritability, and anger resulting from bowel problems) and systemic symptom domains were particularly marked with certolizumab pegol treatment. It appears that the improvements in these two domains of the IBDQ are largely responsible for the reported beneficial effect of certolizumab pegol on HRQoL. Overall, these findings suggest that certolizumab pegol alleviates the psychological symptoms associated with Crohn’s disease and improves a patient’s general well-being, in addition to providing clinical benefits in terms of CDAI response. 33 34 8 17 35 36 7 22 23 31 32 37 Conclusions This study demonstrates that the clinical efficacy of certolizumab pegol in patients with moderate-to-severe Crohn’s disease, which is evident within 2 weeks of injection, is paralleled by improvements in HRQoL. The benefits of certolizumab pegol were most pronounced at the highest dose tested (400 g). Improvements in emotional well-being and systemic symptoms appear to be largely responsible for the observed beneficial effect of certolizumab pegol on HRQoL.