Two randomized placebo-controlled double-blind Phase III studies , PRECISE 1 and 2 (Pegylated antibody fragment evaluation in Crohn’s disease: safety and efficacy), evaluating the effectiveness of certolizumab against placebo, were the pivotal trials that led to regulatory approval for CD patients [13, 14]. Both these studies recruited in the same period (December 2003–May 2005), at different sites, patients with moderate-to-severe active disease (defined as a CDAI between 220 and 450) [15], despite the use of conventional drugs. Patients were eligible regardless disease’s location or behavior, albeit those ones who presented symptomatic strictures or active abscess were excluded. In the first study, 662 patients were randomized to receive subcutaneous doses of certolizumab 400 mg or placebo at week 0, 2, and 4 and then every 4 weeks trough week 26. In both arms, patients were centrally stratified according to their basal C-reactive protein (CRP) serum level (< or >10 mg/l). This design was arranged taking in account to the certolizumab phase II dose-finding study, reporting higher rates of clinical response at week 12 in patients with baseline elevated CRP level treated with 400 mg of certolizumab every 4 weeks [16]. Thus, the primary endpoint was clinical response (defined as a reduction of at least 100 points in CDAI score ) at week 6 and at both week 6 and 26 in the subgroups of patients with a baseline CRP level >10 mg/l. This endpoint was met by 37 % (54/145) of certolizumab treated patients versus 26 % (40/154) of control group (p-value = 0.04) and correspondingly, by 22 % (31/144) versus 12 % (19/154) (p-value = 0.05), respectively. Concerning to secondary aims, certolizumab was not more effective than placebo in inducing clinical remission (defined as a CDAI score of 150 points or less) at week 6 and at both week 6 and 26, in patients with baseline high level of CRP. Conversely, certolizumab was equally superior to placebo in inducing and maintaining clinical response in the overall population (regardless of the CRP level stratification) [13]. PRECISE 2 trial was specifically aimed to evaluate the efficacy of certolizumab as maintenance therapy. Therefore, 6-week responder patients to an open label induction with certolizumab (400 mg at week 0, 2, and 4), stratified according to their baseline CRP (< or >10 mg/l), were randomized to receive 400 mg of certolizumab or placebo every 4 weeks through week 26. After induction, 428 patients (64 %) achieved clinical benefit, of whom about 50 % had a baseline CRP >10 mg/l. The primary endpoint was clinical response (alike defined as in PRECISE 1) trough week 26 in 213 patients who responded to induction with a baseline CRP level >10 mg/l. This aim was reached by 62 % of patients (69/112) receiving certolizumab compared to 34 % on placebo treatment (34/101) (p < 0.001). Furthermore, in this specific population, patients on maintenance treatment with certolizumab were more likely to achieve clinical remission at week 26 (42 % in the certolizumab group versus 29 % of placebo one, p < 0.001). The differences between certolizumab and placebo were statistically significant, also considering clinical response and remission in all patients in the intention-to-treat population, regardless basal CRP level stratification (63 % versus 34 %, p < 0.001 and 48 % versus 29 %, p < 0.001, respectively). Moreover, the efficacy of certolizumab over placebo was confirmed in all subjects across subcategories, such as patients taking or not immunosuppressants or steroids and patients with or without previous experience with infliximab [14]. However, post hoc analysis showed that the likelihood of successful certolizumab treatment was increased when administered as first line biological therapy [17]. In PRECISE 2, continuous certolizumab treatment was associated with significant improvements in fistula closure. In particular, of 58 induction-responders (14 %) with an open draining fistula, 36 % of patients (10/28) treated with certolizumab achieved 100 % of fistula closure compared to 17 % (5/30) of the placebo ones [18]. After completing the PRECISE 1 and 2 studies, patients were eligible to enter into PRECISE 3, an open-label extension trials, in which a maintenance treatment with 400 mg of certolizumab every 4 weeks has been warranted for 7 years (362 weeks), aimed to evaluate long-term safety ([19], Fig. 33.2). Disease clinical activity was assessed at each available visit (every 4 weeks) with Harvey–Bradshaw Index (HBI) [20], defining clinical remission as an HBI score of 4 points or less. Patients, who experienced an exacerbation of disease and needed a dose-escalation or a rescue therapy, were considered to have treatment failure and were excluded from the efficacy analyses. Five hundred ninety-five patients entered the study, of whom 354 patients from PRECISE 1 and 241 from PRECISE 2. Patients were subdivided in three different categories, according to the drugs regimen received: (a) “First exposure” (n = 166): who were randomized to placebo in PRECISE 1; (b) “Re-exposure” (n = 100): who, after an open-label induction with certolizumab, were randomized to placebo in PRECISE 2; (c) “Continuous exposure group” (329): who were continuously treated with certolizumab in PRECISE 1 and 2. About 71 % of patients were treated with certolizumab for more than one year and the mean number of certolizumab doses was 41. During the years, 117 patients completed the follow-up, receiving certolizumab 400 mg every 4 weeks, while 478 patients discontinued from the study, mainly for adverse events (44.6 %) in the first year. Over 7 years, 88.2 % of patients experienced an adverse events and 40.3 % experienced a severe adverse event, without no significant differences among the three exposure groups. Opportunistic infections were reported in 114 patients (all of them concomitantly treated with steroids) and the malignant neoplasm incidence rate was 0.84 cases/100 patient-years. No new safety signals, no demyelinating disorders, congestive heart failure or lupus-like syndrome were reported. Clinical remission rates (secondary aim), assessed by observed cases analyses, and were 55 % (325/591) at week 0 of PRECISE 3 and 75.5 % (78/103) at year 7. Remission rates for the first exposure group were generally lower than the re-exposure group or the continuous group throughout all the study. All patients enrolled in PRECISE 2, who relapsed before week 26 and withdrew from the study, could enter PRECISE 4 [21, 22]. In this open-label extension, patients were again subdivided in two groups according to different treatment received in PRECISE 2: Group A, “drug interruption” patients randomized to placebo after open-label induction, who were reinduced with three doses of certolizumab 400 mg at week 0, 2, and 4; Group B, “continuous group” patients, randomized to certolizumab 400 mg every 4 weeks, who were “recaptured” with an additional dose after two weeks (week 0, 2, and 4). As in PRECISE 3, HBI has been preferred for treatment efficacy assessments for its greater convenience, adopting the same definitions for clinical response and remission. Of 428 patients enrolled in PRECISE 2, 168 patients (39 %) withdrew prematurely from the study. One-hundred twenty-four patients entered PRECISE 4, 75 from “drug interruption” and 49 from “continuous group”. The PRECISE 4 drop-out rate was 44 % (55 patients) within the first 52 weeks, (44 %). After week 4, 63 % of group A and 65 % of group B achieved clinical response that was maintained in 55 % and 59 % of them, respectively, through 52 weeks. No data are available beyond 52 weeks.

The Welcome trial, a multicenter 26-week phase III-b, was the first study specifically aimed to evaluate the effectiveness and the tolerability of certolizumab in patients with moderate-to-severe CD with history of exposure to infliximab. Patients needed to have a well-documented history of loss of response (lack of improving or worsening after at least two infusions at standard dose) or intolerance (only mild-moderate infusion reactions) to infliximab. After an open-label induction with certolizumab 400 mg at week 0, 2, and 4, patients in clinical response (CDAI score lower of at least 100 points from baseline) were randomized to a maintenance treatment with certolizumab 400 mg either every 4 weeks or every 2 weeks. The primary outcome was clinical response at week 6 that was met in 62 % of patients (334/539). Moreover at week 6, 69.2 % of patients experienced a 70-point or greater CDAI reduction and 39.3 % clinical remission (CDAI <150 points). At week 6, 168 and 161 responders were randomized to certolizumab every 4 and 2 weeks, respectively. Of these, only 47 % (79 patients) and 44.1 % (71 patients) completed the 26-week study. Overall, 38 % (126/ 329) achieved clinical response at week 26, without any significant differences between two groups (39.9 % versus 36.6 %, p = 0.55). Corresponding remission rates were 29.2 % and 30.4 %, respectively. After randomization, 38 % of patients relapsed and switched to open-label certolizumab every 2 weeks, with benefit in 71 % of them, who regained a 100-point CDAI reduction. Post hoc analysis showed relevant improvements in health-related quality of life and work productivity in both treatment groups as early as week 6, maintained through week 26 [23]. Certolizumab was well tolerated and serious drug-related adverse events were reported in 15 patients (2.8 %) during induction and 12 (3.2 %) during maintenance. A single case of malignant neoplasm occurred during the study [23].

This open-label multicenter single-arm study was the first aimed to evaluate the effectiveness of certolizumab in inducing and sustaining mucosal healing in patients with moderate-to-severe ileo-colonic CD. Eighty-nine patients with baseline active endoscopic disease (ulcers in at least two segments and a CDEIS score of 8 or greater) [24] were treated with certolizumab 400 mg at week 0, 2, and 4 and then every 4 weeks up to week 52. Endoscopic evaluations were performed at week 0, 10, and 54. Overall, 80 patients completed the 10-week period and 53 patients the 54-week one. The mean ± SD CDEIS score at baseline was 14.5 ± 5.3. At week 10, the mean change in CDEIS score (primary outcome) was 5.7 (95 % CI 4.6–6.8, p < 0.0001). With regard to secondary aims: endoscopic response (decrease of CDEIS score > 5 points), endoscopic remission (CDEIS score < 6), complete endoscopic remission (CDEIS < 3), and mucosal healing (absence of ulcerations) at week 10 were 54 %, 37 %, 10 %, and 4 %, respectively. At week 54 the corresponding rates were 49 %, 27 %, 14 %, and 8 %, respectively. The safety profile was consistent with that of previous CZP trials [25]. At week 8 and 54, certolizumab plasma concentrations were measured and related to endoscopic activity. Higher plasma concentrations at week 8 were associated with endoscopic response (p-value = 0.0016) and remission (p-value = 0.0302) at week 10. At week 54, the rates of endoscopic remission correlated with plasma concentrations (p-value = 0.0206) [26].