Biologic therapy with antagonists to tumor necrosis factor

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1 CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2010;8: Reinduction With Certolizumab Pegol in Patients With Relapsed Crohn s Disease: Results From the PRECiSE 4 Study WILLIAM J. SANDBORN,* STEFAN SCHREIBER, STEPHEN B. HANAUER, JEAN FRÉDÉRIC COLOMBEL, RALPH BLOOMFIELD, and GARY R. LICHTENSTEIN # on behalf of the PRECiSE 4 Study Investigators *Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; Institute for Clinical Molecular Biology, Christian Albrechts University, Kiel, Germany; Department of Gastroenterology and Nutrition, University of Chicago Medical Center, Chicago, Illinois; Hepato-Gastroenterologie, Hôpital Claude Huriez, Lille, France; UCB Pharma, Slough, Berkshire, United Kingdom; and # University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania See related article, Thayu M et al, on page 430 in Gastroenterology. BACKGROUND & AIMS: We sought to determine the efficacy of certolizumab pegol reinduction in patients with active Crohn s disease who respond to induction therapy with certolizumab pegol and then relapse during continuous or interrupted maintenance therapy. METHODS: In the Pegylated Antibody Fragment Evaluation in Crohn s Disease: Safety and Efficacy (PRECiSE) 2 trial, 428 patients who responded to induction therapy with certolizumab pegol at week 6 were randomized to continuous therapy with certolizumab pegol or placebo (drug interruption) during weeks 6 to 26. Patients who relapsed before week 26 could enter PRECiSE 4, an ongoing open-label extension trial in which patients on continuous therapy underwent recapture with a single extra 400-mg dose of certolizumab pegol, and patients who relapsed after drug interruption underwent reinduction with certolizumab pegol 400 mg at weeks 0, 2, and 4 followed by maintenance with certolizumab pegol 400 mg every 4 weeks. Disease activity was measured by the Harvey Bradshaw Index. RESULTS: During PRECiSE 2, 124 patients had disease relapse and entered PRE- CiSE 4; 49 patients had received continuous therapy and 75 patients had drug interruption. At week 4 of PRECiSE 4, response rates were 63% in patients who relapsed on continuous therapy and 65% after drug interruption. Response was maintained in 55% and 59% of these responders, respectively, through week 52. CONCLUSIONS: Administration of 1 additional dose of certolizumab pegol to patients who relapsed on continuous maintenance therapy, and certolizumab pegol reinduction to those who relapsed after drug interruption, are effective strategies for treating patients who have relapsed after successful induction therapy with certolizumab pegol. Keywords: Anti-TNF Inhibitor; Relapsed Crohn s Disease; Certolizumab Pegol; PRECiSE 4. Biologic therapy with antagonists to tumor necrosis factor (TNF)-, including infliximab, adalimumab, and certolizumab pegol, is effective for the treatment of moderate to severe active Crohn s disease that is unresponsive to conventional therapy. 1 6 Previous studies have shown that these agents are effective for maintenance of response and remission in patients who respond to induction therapy. 1,2,5 Continuous maintenance therapy is more effective than drug interruption and is associated with lower rates of immunogenicity. 2,5,7 Nevertheless, some patients experience disease relapse despite continuous maintenance therapy, and other patients require drug interruption for a variety of reasons. Current treatment options for patients with relapsed Crohn s disease despite continuous maintenance therapy assuming that disease activity is confirmed as the cause of symptoms and surgery was considered inappropriate include the following: permanent dose escalation of the same drug (published information on infliximab and adalimumab), 8 10 switching to another drug within the TNF- antagonist class (published information on adalimumab and preliminary data on certolizumab pegol), 11,12 and switching to another drug outside the TNF- antagonist class (published information available on natalizumab). 13,14 At present, strategies to manage patients with active Crohn s disease who previously have responded to induction therapy with certolizumab pegol and then relapsed during continuous or interrupted maintenance therapy are lacking. The Pegylated Antibody Fragment Evaluation in Crohn s Disease: Safety and Efficacy (PRECiSE) 2 trial was a randomized, double-blind, placebo-controlled trial in which 428 patients with moderate-to-severe Crohn s disease who responded to induction therapy with certolizumab pegol at week 6 were randomized to continuous maintenance therapy with certolizumab pegol or drug interruption during weeks 6 to Induction therapy comprised 3 doses (400 mg) of certolizumab pegol at weeks 0, 2, and 4, and maintenance therapy comprised of 400-mg doses of certolizumab pegol every 4 weeks, beginning at week 8. Patients who relapsed before week 26 could enter PRECiSE 4, an ongoing open-label extension trial in which patients who lost response to continuous maintenance therapy underwent recapture with a single extra 400-mg dose, and patients who lost response after drug interruption underwent reinduction with certolizumab pegol 400 mg at weeks 0, 2, and 4. We report the results for PRECiSE 4 through week 52. Abbreviations used in this paper: CDAI, Crohn s Disease Activity Index; HBI, Harvey Bradshaw Index; PRECiSE, Pegylated Antibody Fragment Evaluation in Crohn s Disease: Safety and Efficacy; TNF, tumor necrosis factor by the AGA Institute /$36.00 doi: /j.cgh

2 August 2010 REINDUCTION WITH CERTOLIZUMAB PEGOL 697 Figure 1. Study design. CZP, certolizumab pegol. Methods Study Design PRECiSE 4 ( NCT ) is an ongoing open-label extension study that included patients who relapsed during the PRECiSE 2 trial and withdrew before week 26. Relapse was defined as an increase in the Crohn s Disease Activity Index (CDAI) score of at least 70 points above baseline (week 6 of PRECiSE 2) or a CDAI score higher than baseline (week 6 of PRECiSE 2) with an absolute score of at least 350 points. Patients could enroll in PRECiSE 4 after week 6 randomization (maintenance phase) of PRECiSE 2. Data are presented up to week 52 of PRECiSE 4. The methodology for PRECiSE 2 has been published previously. 5 All patients were age 18 years and older with moderate-to-severe Crohn s disease (defined by a CDAI score of points) affecting the terminal ileum, colon, or both the ileum and colon for at least 3 months duration before screening. Diagnoses were based on conventional radiologic, endoscopic, or histologic diagnostic criteria. In PRECiSE 4, patients received 3 doses of certolizumab pegol 400 mg (weeks 0, 2, and 4) followed by continuous maintenance treatment with certolizumab pegol 400 mg every 4 weeks. The cut-off date for this analysis was March 2006, by which time all patients remaining in the study had received a minimum of 12 months exposure to certolizumab pegol in PRECiSE 4. Because patients were receiving different treatments in PRE- CiSE 2, the data for this study have been analyzed to reflect the 2 distinct treatment groups for patients originally enrolled in PRECiSE 2 (Figure 1). Group A comprised patients randomized to placebo maintenance after induction with certolizumab pegol in PRECiSE 2 (drug interruption). Patients in this group received 3 induction doses of certolizumab pegol in PRECiSE 4 (ie, were re-induced). Group B comprised patients randomized to certolizumab pegol maintenance after induction with certolizumab pegol in PRECiSE 2 (continuous maintenance). For patients in this group, the 3 doses of certolizumab pegol administered at weeks 0, 2, and 4 in PRECiSE 4 effectively meant that patients received 1 additional dose of certolizumab pegol, which was referred to as recapture. Patients could withdraw from PRECiSE 4 at any time if they wished or if they required rescue therapy (defined as treatment with infliximab, major change in corticosteroid and/or immunosuppressant dose, surgery, or hospitalization) for exacerbation of Crohn s disease. The ethics committee or institutional review board at each study center approved the study. All participants gave written informed consent. Assessments Harvey Bradshaw index. The Harvey Bradshaw Index (HBI) was used as the measure of Crohn s disease activity in PRECiSE The CDAI requires a diary card to be completed by the patient 1 week before score calculation and also requires the measurement of hematocrit and body weight. In contrast, the HBI scoring information is obtained through a combination of patient-reported measures taken the day before each study visit and clinical assessments obtained during the study visit, making it a simpler alternative that is more suitable for long-term, follow-up studies. The HBI comprises 5 parameters: general well-being, abdominal pain, number of liquid stools per day, abdominal mass, and the presence of complications. In the PRECiSE 1 and 2 trials, the HBI was shown to be highly correlated (Pearson s correlation coefficient, r.80) with the CDAI. 16 These findings are supported by data from an earlier prospective study in patients with Crohn s disease (Pearson s correlation coefficient, r.93). 15 In PRECiSE 2, HBI scores were calculated at weeks 0 and 26. In PRECiSE 4, HBI was used to assess treatment efficacy at all clinical visits (ie, at weeks 0, 2, and 4, and every 4 weeks thereafter). An HBI response was defined as a reduction of 3 points or more from baseline (week 0 of PRECiSE 4) and clinical remission was defined as an HBI score of 4 points or fewer. HBI response and remission threshold values were determined from the correlation between the CDAI and HBI data at weeks 0 and 26 in PRECiSE Safety. Safety was assessed through physical examinations and clinical laboratory testing (hematology, serum biochemistry analyses, and urinalysis) at screening and at all study visits. For those withdrawing from the study, a safety follow-up visit was conducted 12 weeks after the last dose. In addition, a chest radiograph was obtained at week 52 of the study. Occurrence of adverse events was assessed by the investigator through observation and questioning of the patients. Adverse events were classified and descriptively summarized by primary

3 698 SANDBORN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 8, No. 8 Table 1. Patient Demographics at Baseline of the PRECiSE 2 Study (ITT Population) Baseline variable Group A (drug interruption) (n 75) Group B (continuous maintenance) (n 49) Mean age, y (SD) 38.5 (12.5) 36.2 (9.8) Male, n (%) 33 (44.0) 20 (40.8) Current smoker, n (%) 29 (38.7) 20 (40.8) Mean body mass index, kg/m 2 (SD) (6.10) (4.77) Mean duration of disease, y (range) 7.33 ( ) 9.97 ( ) Location of Crohn s disease, n (%) Terminal ileum 15 (20.0) 14 (28.6) Colon 25 (33.3) 11 (22.4) Ileocolon 30 (40.0) 22 (44.9) Resection performed, n (%) 25 (33.3) 21 (42.9) Previous infliximab therapy, n (%) 21 (28.0) 19 (38.8) Mean time in PRECiSE 2 before entering PRECiSE 4, wk ITT, intention to treat; SD, standard deviation. system organ class and preferred terms according to the Medical Dictionary for Regulatory Activities. Assays. Blood samples for the determination of certolizumab pegol plasma concentrations and antibodies to certolizumab pegol were collected at the following visits: weeks 0, 2, and 4, and every 4 weeks thereafter, withdrawal visit, or 12 weeks after the last dose. Certolizumab pegol plasma concentrations were measured by a validated enzyme-linked immunosorbent assay (unpublished data). Patients with 1 or more blood samples positive for antibodies were classed as antibodypositive, whereas the remainder were classed as antibody-negative. Patients who were positive at any time point throughout the study were deemed positive for the remainder of the study. Blood samples taken at weeks 24, 52, and 76, or withdrawal visit, and at the safety follow-up visit 12 weeks after the last dose, also were assayed for anti double-stranded DNA antibodies and antinuclear antibodies. Statistical Analyses Analyses were performed using the intention-to-treat population, which included all subjects who enrolled in the PRECiSE 4 study from PRECiSE 2, who received at least 1 injection of study drug (placebo or certolizumab pegol) in the maintenance phase of PRECiSE 2, and who provided at least 1 efficacy measurement after week 0 of PRECiSE 4. Response and remission analyses, safety, and plasma concentration data by anti certolizumab pegol antibody status are presented. The efficacy outcome variables of clinical response and remission (based on the HBI scores) are summarized by frequency. If patients did not provide data, withdrew, or received rescue therapy (infliximab, any change in corticosteroid and/or immunosuppressant dose, or surgery or hospitalization) during PRECISE 4, they were regarded as a nonresponder. As a secondary analysis, the proportion of patients achieving sustained response (reduction from baseline in total HBI score of 3 points at week 4 and for the visit of interest) or sustained remission (total HBI score of 4 at week 4 and for the visit of interest) was calculated. In addition, response and remission rates were analyzed in the subset of patients who were receiving concomitant corticosteroids or immunosuppressants or both at entry to the PRECISE 4 study. The relationship between the geometric mean plasma concentration of certolizumab pegol and HBI score by visit was examined post hoc in the intention-to-treat population using the Spearman s rank correlation coefficient. The safety population included all patients who enrolled in PRECiSE 4 from PRECiSE 2 and received at least 1 injection of study treatment (placebo or certolizumab pegol) in PRECiSE 4. This population was used for all summaries of the safety, pharmacokinetic, and autoantibody variables. Safety data were summarized using appropriate summary statistics. Results Patients and Demographics In PRECiSE 2, 428 of 668 patients (64%) responded to certolizumab pegol induction therapy at week 6 (CDAI 100- point clinical response) and were randomized to receive either certolizumab pegol or placebo maintenance treatment. 5 Of the 428 patients who responded, 260 successfully completed the study. Of the 168 patients who did not complete PRECiSE 2, a total of 124 patients entered PRECiSE 4; 75 were in group A (drug interruption group) and 49 were in group B (continuous maintenance group). Demographic and clinical characteristics at baseline for both groups are shown in Tables 1 and 2. A total of 55 patients (44%) who entered from PRECiSE 2 withdrew prematurely from PRECiSE 4 during the first 52 weeks of exposure. The reasons for withdrawal are summarized in Table 3. Fifty percent of patients who withdrew from PRECiSE 2 received certolizumab pegol reinduction within 4 to 5 weeks of their last dose. The mean time from the last dose in PRECiSE 2 to the first dose in PRECiSE 4 was days (minimum maximum, 6 34 d) in group A and days (minimum maximum, 6 38 d) in group B. Efficacy Reinduction with certolizumab pegol 400 mg at weeks 0, 2, and 4, or recapture with one additional dose of 400 mg for those on maintenance certolizumab, successfully re-established clinical response or remission in approximately two thirds of patients with moderate-to-severe Crohn s disease who had relapsed after initial response to certolizumab pegol. The rates of response and remission were similar in both groups over the course of the study. In group A, 49 patients (65.3%) responded by week 4 (Figure 2A); in group B, 31 patients (63.3%) were in

4 August 2010 REINDUCTION WITH CERTOLIZUMAB PEGOL 699 Table 2. Clinical Characteristics at Baseline of the PRECiSE 4 Study (ITT Population) Baseline variable Group A (drug interruption) (n 75) Group B (continuous maintenance) (n 49) Mean HBI score (range) 9.5 (1 18) 11.0 (0 28) Geometric mean CRP concentration, mg/l (range) 11.2 ( ) 8.4 ( ) Concomitant medications, n (%) Corticosteroids 11 (14.7) 7 (14.3) Immunosuppressants 10 (13.3) 3 (6.1) Corticosteroids and immunosuppressants 2 (2.7) 1 (2.0) Corticosteroids or immunosuppressants 19 (25.3) 9 (18.4) No corticosteroids or immunosuppressants 56 (74.7) 40 (81.6) ITT, intention to treat; CRP, C-reactive protein. response by week 4. At week 52, 28 patients (37.3%) in group A and 20 patients (40.8%) in group B were in response (Figure 2A). As early as week 4, 33 patients (44.0%) in group A and 14 patients (28.6%) in group B were in remission. At week 52, remission was similar in both groups: 27 patients (36.0%) in group A and 17 patients (34.7%) in group B (Figure 2B). The sustained response rate was 54.8% (17 of 31 patients) at week 52 among group B patients who showed a response at week 4. The corresponding value for group A patients was Table 3. Adverse Events and Discontinuations in Patients From PRECiSE 2 Entering PRECiSE 4 (Safety Population) Variable Group A (drug interruption) (n 75) n(%) Group B (continuous maintenance) (n 49) n(%) Any AE Total 64 (85.3) 45 (91.8) Mild 56 (74.7) 34 (69.4) Moderate 58 (77.3) 36 (73.5) Severe 21 (28.0) 12 (24.5) AE related to study drug 28 (37.3) 19 (38.8) Infections and infestations 49 (65.3) 25 (51.0) Serious AE 20 (26.7) 18 (36.7) Serious AE related to study drug 3 (4.0) 4 (8.2) Serious infections or infestations 5 (6.7) 4 (8.2) Malignancies a 0 1 (2.0) Injection site Pain 0 1 (2.0) Reactions 1 (1.3) 1 (2.0) Erythema 0 0 Burning 0 1 (2.0) Pruritis 0 0 Premature withdrawals 32 (42.7) 23 (46.9) AE leading to withdrawal 24 (32.0) 10 (20.4) Protocol noncompliance 2 (2.7) 1 (2.0) Patient decision 5 (6.7) 5 (10.2) Clinical decision 4 (5.3) 2 (4.1) Lost to follow-up evaluation 1 (1.3) 2 (4.1) Lack of improvement/disease 17 (22.7) 15 (30.6) deterioration Other 0 0 Deaths 0 0 AE, adverse event. a The reported malignancy was a basal cell carcinoma. 59.2% (29 of 49 patients). In those patients who were in remission at week 4, sustained remission rates at week 52 were 64.3% (9 of 14 patients) among group B patients and 54.5% (18 of 33 patients) among group A patients. In the small subpopulations of patients (range, 3 29) receiving either corticosteroids or immunosuppressants, response and remission rates at weeks 4 and 52 were generally similar to those observed in the total population (Supplementary Table 1). In the subpopulation receiving both corticosteroids and immunosuppressants, response and remission rates were higher in group B, but the number of patients was very small (n 3). Safety Certolizumab pegol was well tolerated in this study, and no new safety signals were observed. The incidence of adverse events was similar in both group A and group B (Table 3). There was a low incidence ( 2%) of injection-site reactions, such as burning, pain, and erythema, but no anaphylactic reactions were observed. Most treatment-emergent adverse events were of mild or moderate intensity and were considered by the investigators to be unrelated to the study drug (Table 3). The primary reasons for withdrawing from the study were adverse events, lack of improvement or deterioration of Crohn s disease, and patient decision. Serious adverse events occurred in 26.7% of patients in group A and 36.7% of patients in group B (Table 3). One case of basal cell carcinoma was the only malignancy to occur in the PRECiSE 2 patient population who entered into PRECiSE 4. This patient had received continuous maintenance therapy with certolizumab pegol in PRECiSE 2. The rate of serious infections was 6.7% in the drug interruption group and 8.2% in the continuous maintenance group. Autoimmune Antibodies Among the patients with data on the presence of autoimmune antibodies, the proportion with normal antinuclear antibody levels at baseline in PRECiSE 2 who tested positive during PRECiSE 4 was 4.7% at week 0 and 5.8% at week 52. The proportion of patients who were negative for anti doublestranded DNA antibodies at baseline in PRECiSE 2 and then tested positive during PRECiSE 4 was 1.0% at week 0 and 1.7% at week 52.

5 700 SANDBORN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 8, No. 8 Figure 2. (A) Response rates (reduction from week 0 in HBI score of 3) and (B) remission rates (HBI score of 4) in PRECiSE 4 (intention-to-treat population). Systemic Exposure to Certolizumab Pegol At week 0 of PRECiSE 4, the geometric mean plasma concentration of certolizumab pegol was g/ml in the drug interruption group and g/ml in the continuous exposure group. By week 52, the geometric mean plasma concentrations of certolizumab pegol were g/ml and g/ml in groups A (n 41) and B (n 24), respectively. There was no significant correlation between HBI score and geometric mean plasma concentration of certolizumab pegol at virtually all points from weeks 0 to 52. At weeks 4 and 52, the correlation coefficient for HBI score and geometric mean plasma concentration was and 0.104, respectively, in patients who received continuous maintenance therapy (group B), and and 0.067, respectively, in patients in the drug interruption group (group A). The geometric means of the certolizumab pegol plasma concentrations over time were generally lower in patients from both groups who were positive for anti certolizumab pegol antibodies than in patients who were antibody-negative (Figure 3). Discussion The PRECiSE 4 trial provides new information on treatment strategies to manage patients with active Crohn s disease who previously have responded to induction therapy with certolizumab pegol and then relapsed during continuous or interrupted maintenance therapy. Among patients who relapsed on continuous maintenance therapy, 63% responded at week 4 after a single extra dose of certolizumab pegol 400 mg, and 41% were in response at week 52. Among patients who relapsed after Figure 3. Geometric mean plasma concentration of certolizumab pegol (95% confidence interval) in patients with or without anti certolizumab pegol antibodies. (A) Group A (drug interruption group), (B) group B (continuous maintenance group). CZP, certolizumab pegol.

6 August 2010 REINDUCTION WITH CERTOLIZUMAB PEGOL 701 drug interruption, 65% were in response at week 4 after reinduction dosing with 3 doses of certolizumab pegol 400 mg, and 37% responded at week 52. Attenuation of response among patients who have responded to anti TNF- biologic therapy with infliximab, adalimumab, and certolizumab pegol and then continued the same agent as maintenance therapy is a relatively common clinical problem, occurring in approximately 60% of patients over 6 months. 1,2,5 The usual treatment strategy for this problem is to increase the dose from 5 to 10 mg/kg or to shorten the infusion interval for infliximab 2 and shorten the injection interval for adalimumab from 40 mg every other week to 40 mg weekly. 9,10 The results of the PRECiSE 4 study show that 1 additional injection of certolizumab pegol 400 mg (recapture) will result in a 63% response rate within 4 weeks. More importantly, this temporary dose intensification for only 4 weeks resulted in a durable benefit at 52 weeks in 41% of patients. Interestingly, similar observations have been reported in patients with psoriasis and rheumatoid arthritis under treatment with infliximab. 17,18 In patients who respond to recapture with certolizumab pegol and then relapse after receiving this additional dose, permanent dose intensification may be required. Although not addressed in the PRECiSE 4 study, the following 2 strategies could be considered in such cases: (1) splitting the dose from 400 mg every 4 weeks to 200 mg every 2 weeks (in a case series, 5 of 6 patients who received a split dose after disease relapse achieved clinical remission); 19 and (2) administering certolizumab pegol 400 mg every 2 weeks. The efficacy of this strategy has been investigated in the open-label rescue arm of the WELCOME phase IIIb, multicenter, 26-week trial. Safety results have been reported for this study and were similar for certolizumab pegol dosed every 2 weeks and every 4 weeks. 12 Certolizumab pegol 400 mg every 2 weeks has been shown to be well tolerated in patients with rheumatoid arthritis. 20 Dose interruption (episodic therapy) in patients who respond to anti TNF- biologics is not recommended. This strategy is less effective and results in more immunogenicity than continuous maintenance therapy. 7 Continuous maintenance therapy with anti TNF- agents has shown benefits in mucosal healing and a reduction in hospitalization rates. 8,21 Nevertheless, some patients will need to interrupt therapy for a variety of reasons. Data from the PRECiSE 4 trial show that patients who previously have been treated with certolizumab pegol and responded can be re-induced successfully with 400 mg at 0, 2, and 4 weeks followed by maintenance therapy with 400 mg every 4 weeks. Response and remission rates in those receiving either corticosteroids, immunosuppressants, or both, were not remarkably different from those observed in the study population as a whole. However, these data should be interpreted with caution because of the small patient numbers. The absence of a significant correlation between certolizumab pegol serum concentration and clinical response was not unexpected because the number of patients was relatively small, the patient population was selected and it was heterogenous with respect to concomitant immunosuppressive therapy, there were some missing data, and the study was not designed to assess this relationship. The adverse events observed in PRECiSE 4 are generally consistent with those reported in previous studies. 4,5 It is noteworthy that the rate of injection-site reactions was 2% or less, and the rate of new antinuclear antibodies and anti doublestranded DNA antibodies was less than 6%. In conclusion, recapture by administering 1 additional 400-mg dose of certolizumab pegol for patients who relapsed on continuous maintenance therapy, and reinduction for those who relapsed after drug interruption, are effective therapeutic strategies in patients with Crohn s disease who relapse after successful induction therapy with certolizumab pegol. Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at and at doi: / j.cgh References 1. Colombel JF, Sandborn WJ, Rutgeerts P, et al. Adalimumab for maintenance of clinical response and remission in patients with Crohn s disease: the CHARM trial. Gastroenterology 2007;132: Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn s disease: the ACCENT I randomised trial. Lancet 2002;359: Hanauer SB, Sandborn WJ, Rutgeerts P, et al. Human anti-tumor necrosis factor monoclonal antibody (adalimumab) in Crohn s disease: the CLASSIC-I trial. Gastroenterology 2006;130: Sandborn WJ, Feagan BG, Stoinov S, et al. Certolizumab pegol for the treatment of Crohn s disease. N Engl J Med 2007;357: Schreiber S, Khaliq-Kareemi M, Lawrance IC, et al. Maintenance therapy with certolizumab pegol for Crohn s disease. N Engl J Med 2007;357: Targan SR, Hanauer SB, van Deventer SJ, et al. A short-term study of chimeric monoclonal antibody ca2 to tumor necrosis factor alpha for Crohn s disease. Crohn s Disease ca2 Study Group. N Engl J Med 1997;337: Hanauer SB, Wagner CL, Bala M, et al. Incidence and importance of antibody responses to infliximab after maintenance or episodic treatment in Crohn s disease. Clin Gastroenterol Hepatol 2004; 2: Rutgeerts P, Feagan BG, Lichtenstein GR, et al. Comparison of scheduled and episodic treatment strategies of infliximab in Crohn s disease. Gastroenterology 2004;126: Sandborn WJ, Hanauer SB, Rutgeerts P, et al. Adalimumab for maintenance treatment of Crohn s disease: results of the CLAS- SIC II trial. Gut 2007;56: Sandborn WJ, Colombel JF, Rutgeerts P, et al. Benefits of dosage adjustment with adalimumab in Crohn s disease: an analysis of the CHARM trial. Gastroenterology 2008;134:A Sandborn WJ, Rutgeerts P, Enns R, et al. Adalimumab induction therapy for Crohn s disease previously treated with infliximab: a randomized trial. Ann Intern Med 2007;146: Sandborn WJ, Vermeire S, D Haens G, et al. WELCOME: a randomised, double-blind, controlled trial comparing certolizumab pegol 400 mg every 2 weeks with every 4 weeks for maintenance of response and remission in patients with moderate to severe Crohn s disease with secondary failure to infliximab. Gastroenterology 2009;136:A Sandborn WJ, Colombel JF, Enns R, et al. Natalizumab induction and maintenance therapy for Crohn s disease. N Engl J Med 2005;353: Targan SR, Feagan BG, Fedorak RN, et al. Natalizumab for the

7 702 SANDBORN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 8, No. 8 treatment of active Crohn s disease: results of the ENCORE Trial. Gastroenterology 2007;132: Harvey RF, Bradshaw JM. A simple index of Crohn s-disease activity. Lancet 1980;1: Vermeire S, Schreiber S, Sandborn WJ, et al. Determination of Harvey-Bradshaw index (HBI) definitions for response and remission using the CDAI data from PRECiSE 1 and PRECiSE 2. Gastroenterology 2007;132(Suppl 1):A Cassano N, Puglisi GA, Malara C, et al. Re-induction as a possible alternative modality of dose escalation of infliximab: a prospective evaluation in a small series of psoriatic patients. Int J Immunopathol Pharmacol 2007;20: Rahman MU, Strusberg I, Geusens P, et al. Double-blinded infliximab dose escalation in patients with rheumatoid arthritis. Ann Rheum Dis 2007;66: Fernandez-Blanco I, Hinojosa J. Efficacy of intensification therapy with certolizumab pegol in Crohn s disease patients included in a compassionate-use program. Am J Gastroenterol 2008;103 (Suppl 1):S Smolen JS, Landewe R, Mease P, et al. Efficacy and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis: the RAPID 2 study. A randomised controlled trial. Ann Rheum Dis 2009;68: Rutgeerts P, Diamond RH, Bala M, et al. Scheduled maintenance treatment with infliximab is superior to episodic treatment for the healing of mucosal ulceration associated with Crohn s disease. Gastrointest Endosc 2006;63: Reprint requests Address requests for reprints to: William J. Sandborn, MD, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota sandborn.william@mayo.edu; fax: (507) Acknowledgments A committee of academic investigators and UCB scientists designed the study. The trial was registered with clinicaltrials.gov (NCT ). Data were collected by ICON Clinical Research, Hampshire, United Kingdom, and were analyzed by UCB. The authors vouch for the veracity and completeness of the data and data analyses. Conflicts of interest The authors disclose the following: William Sandborn has received research support from and served as a consultant for UCB Pharma, Centocor, and Abbott Laboratories; Stefan Schreiber has received consulting fees from Abbott Laboratories, Schering-Plough and its subsidiary Essex Pharma, and UCB Pharma, has received lecture fees from Abbott Laboratories, Essex/Schering-Plough, and UCB Pharma, and has received research grant support from Abbott and UCB Pharma; Stephen Hanauer has served as a consultant to and has been involved in clinical research with Abbot Laboratories, Bristol-Myers Squibb, Centocor, Elan Pharmaceuticals, Ferring Pharmaceuticals, Genentech, Proctor and Gamble, Prometheus, Salix, Shire, and UCB Pharma, and has served as a consultant for AstraZeneca, GlaxoSmith- Kline, and Millennium Pharmaceuticals; Jean-Frédéric Colombel has received consulting fees and honoraria, has been involved in clinical research, and has received research support from UCB Pharma, Schering-Plough, Centocor, and Abbott Laboratories; Ralph Bloomfield is an employee of UCB Pharma; and Gary Lichtenstein has received consulting fees from Abbott Laboratories, Centocor, Ferring, Tanabe, Schering-Plough, Elan, Genentech, Given Imaging, Millennium Pharmaceuticals, Proctor and Gamble, Prometheus, Salix, Shire, UCB Pharma, and Wyeth, has received lecture fees from Abbott, Centocor, Proctor and Gamble, Salix, and UCB Pharma, and has undertaken research with Abbott, AstraZeneca, Bristol-Myers Squibb, Proctor and Gamble, Salix, and Shire. Funding This study was funded by UCB, Brussels. Medical writing assistance was provided by Sian Kneller, MSc, and Bill Kadish, MD, PAREXEL, and was funded by UCB, Brussels.

8 702.e1 SANDBORN ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 8, No. 8 Supplementary Table 1. Response and Remission Rates by Concomitant Crohn s Disease Medication Status Corticosteroids only Immunosuppressants only Immunosuppressants and corticosteroids Group A N 27 Group B N 14 Group A N 29 Group B N 4 Group A N 12 Group B N 3 Week 4 Response, n (%) 17 (63.0) 11 (78.6) 18 (62.1) 10 (71.4) 6 (50.0) 3 (100.0) Remission, n (%) 10 (37.0) 6 (42.9) 11 (37.9) 3 (21.4) 2 (16.7) 2 (66.7) Week 52 Response, n (%) 11 (40.7) 7 (50.0) 10 (34.5) 10 (71.4) 3 (25.0) 3 (100.0) Remission, n (%) 10 (37.0) 6 (42.9) 10 (34.5) 9 (64.3) 2 (16.7) 3 (100.0)