A Randomized, Placebo-Controlled Trial of Certolizumab Pegol (CDP870) for Treatment of Crohn’s Disease
2005; Elsevier BV; Volume: 129; Issue: 3 Linguagem: Inglês
10.1053/j.gastro.2005.06.064
ISSN1528-0012
AutoresStefan Schreiber, Paul Rutgeerts, Richard N. Fedorak, Munaa Khaliq–Kareemi, Michael A. Kamm, Michel Boivin, Çharles N. Bernstein, Michael Staun, Ole Østergaard Thomsen, Alison Innes,
Tópico(s)Microscopic Colitis
ResumoBackground & Aims: To investigate the efficacy and safety of certolizumab pegol (a polyethylene-glycolated Fab′ fragment of anti–tumor necrosis factor, CDP870) in Crohn's disease. Methods: In a placebo-controlled, phase II study, 292 patients with moderate to severe Crohn's disease received subcutaneous certolizumab 100, 200, or 400 mg or placebo at weeks 0, 4, and 8. The primary end point was the percentage of patients with a clinical response at week 12 (a Crohn's Disease Activity Index decrease of ≥ 100 points or remission [Crohn's Disease Activity Index ≤ 150 points]) in the intent-to-treat population. Results: All certolizumab doses produced significant clinical benefit over placebo at week 2 (placebo, 15.1%; certolizumab 100 mg, 29.7% [P = .033]; 200 mg, 30.6% [P = .026]; 400 mg, 33.3% [P = .010]). At all time points, the clinical response rates were highest for certolizumab 400 mg, greatest at week 10 (certolizumab 400 mg, 52.8%; placebo, 30.1%; P = .006) but not significant at week 12 (certolizumab 400 mg, 44.4%; placebo, 35.6%; P = .278). Patients with baseline C-reactive protein levels of 10 mg/L or greater (n = 119) showed clearer separation between active treatment and placebo (week 12 clinical response: certolizumab 400 mg, 53.1%; placebo, 17.9%; P = .005; post hoc analysis) owing to a lower placebo response rate than patients with C-reactive protein levels of less than 10 mg/L. Adverse events were similar among groups. Conclusions: Certolizumab 400 mg may be effective and is well tolerated in patients with active Crohn's disease. High placebo response rates in the large patient subgroup with low C-reactive protein levels may have obscured statistical separation between certolizumab and placebo. Ongoing phase III trials are necessary to establish the clinical efficacy of certolizumab. Background & Aims: To investigate the efficacy and safety of certolizumab pegol (a polyethylene-glycolated Fab′ fragment of anti–tumor necrosis factor, CDP870) in Crohn's disease. Methods: In a placebo-controlled, phase II study, 292 patients with moderate to severe Crohn's disease received subcutaneous certolizumab 100, 200, or 400 mg or placebo at weeks 0, 4, and 8. The primary end point was the percentage of patients with a clinical response at week 12 (a Crohn's Disease Activity Index decrease of ≥ 100 points or remission [Crohn's Disease Activity Index ≤ 150 points]) in the intent-to-treat population. Results: All certolizumab doses produced significant clinical benefit over placebo at week 2 (placebo, 15.1%; certolizumab 100 mg, 29.7% [P = .033]; 200 mg, 30.6% [P = .026]; 400 mg, 33.3% [P = .010]). At all time points, the clinical response rates were highest for certolizumab 400 mg, greatest at week 10 (certolizumab 400 mg, 52.8%; placebo, 30.1%; P = .006) but not significant at week 12 (certolizumab 400 mg, 44.4%; placebo, 35.6%; P = .278). Patients with baseline C-reactive protein levels of 10 mg/L or greater (n = 119) showed clearer separation between active treatment and placebo (week 12 clinical response: certolizumab 400 mg, 53.1%; placebo, 17.9%; P = .005; post hoc analysis) owing to a lower placebo response rate than patients with C-reactive protein levels of less than 10 mg/L. Adverse events were similar among groups. Conclusions: Certolizumab 400 mg may be effective and is well tolerated in patients with active Crohn's disease. High placebo response rates in the large patient subgroup with low C-reactive protein levels may have obscured statistical separation between certolizumab and placebo. 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Preventing antibodies to infliximab in patients with Crohn's disease) optimize not immunize.Gastroenterology. 2003; 124: 1140-1145Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar Certolizumab pegol (CDP870) hereafter referred to as certolizumab is a polyethylene glycolated Fab′ fragment of a humanized anti–TNF-α monoclonal antibody intended for subcutaneous administration. Subcutaneous delivery of the drug has cost and convenience advantages compared with intravenous dosing. Certolizumab has been constructed by grafting the short hypervariable complementarity-determining regions derived from the murine monoclonal antibody HTNF40 onto an otherwise virtually human Ig Fab′ fragment (IgG γ1κ). The engineered Fab′ fragment retains the biologic potency of the original antibody. The Fab′ fragment is linked via a maleimide to 2 cross-linked chains of polyethylene glycol that each have a molecular weight of 20 kilodaltons. This site-specific polyethylene glycolation increases the half-life of the antibody fragment to approximately 2 weeks in plasma, thereby reducing the frequency of required dosing. In phase II studies in patients with rheumatoid arthritis, certolizumab has been shown to be clinically effective and well tolerated.21Keystone E. Choy E.H. Kalden J. Klareskog L. Sany J. Smolen J. Smith J. Jain R. Burr A. Verburg K. CDP870, a novel, PEGylated, humanized TNF-α inhibitor is effective in treating the signs and symptoms of rheumatoid arthritis (RA). 2001Google Scholar, 22Choy E.H. Hazleman B. Smith M. Moss K. Lisi L. Scott D.G. Patel J. Sopwith M. Isenberg D.A. Efficacy of a novel humanized anti-TNF fragment (CDP870) in patients with rheumatoid arthritis) a phase II double-blinded, randomized, dose-escalating trial.Rheumatology (Oxford). 2002; 41: 1133-1137Crossref PubMed Google Scholar We have assessed the efficacy and safety of subcutaneous administration of certolizumab in a phase II, randomized, double-blind, placebo-controlled, dose-response study in patients with moderate to severe Crohn's disease. Eligible patients were at least 18 years old with a clinical diagnosis of Crohn's disease as confirmed by radiologic, endoscopic, or histologic evidence following established diagnostic criteria. Patients had moderate to severe disease, defined by a score of 220–450 points on the Crohn's Disease Activity Index (CDAI)23Best W.R. Becktel J.M. Singleton J.W. Kern Jr, F. Development of a Crohn's disease activity index. National Cooperative Crohn's Disease Study.Gastroenterology. 1976; 70: 439-444Abstract Full Text PDF PubMed Scopus (2946) Google Scholar over a 7-day screening period before the first study dose was administered. Patients were excluded from the study if they had a suspected or diagnosed abscess at screening, a bowel perforation or evidence of noninflammatory obstruction during the 6 months before screening, extensive bowel resection, a functional colostomy or ileostomy, a positive stool culture for enteric pathogens, or a known history of tuberculosis. Other exclusion criteria included treatment for Crohn's disease with sodium cromoglycate, mycophenolate, or cyclosporin within 4 weeks of study entry, or receipt of other anti-TNF therapy with a biologic agent within 12 weeks of screening. Patients were also excluded from the study if they had been treated previously with any anti-TNF agent and either had experienced an infusion reaction that was suspected or confirmed to be associated with an immune response, or had showed a lack of clinical response to the first dose. Any patients who had participated in another clinical trial with certolizumab were ineligible to take part in the study, as were those who had been involved in any other clinical drug trial within the 4 weeks before screening. All patients had an anteroposterior chest radiograph for tuberculosis at screening (or within the 12 weeks before screening) and at the final study visit. Concomitant medication was permitted if the patient was on a stable dose that could be continued throughout the 12-week duration of the double-blind phase of the study. The minimum stable treatment periods required before screening were as follows: 2 weeks for steroids (≤9 mg/day budesonide, ≤24 mg/day methylprednisolone, or ≤30 mg/day prednisone or prednisolone) and any topical anorectal treatment; 4 weeks for long-term anti-infectives and mesalamine or mesalamine analogs (eg, sulfasalazine, olsalazine, or balsalazide); and 8 weeks for the immunosuppressants azathioprine, 6-mercaptopurine, and methotrexate. Because certolizumab and placebo did not have the same color or viscosity, full blinding was not possible. Consequently, patients received their treatment from a nurse or physician who was not involved in the study. All other staff involved in the study remained blind to treatment. Certolizumab 100 mg, 200 mg, 400 mg, or placebo was administered subcutaneously. Certolizumab was supplied as a clear, colorless to pale yellow solution at a nominal concentration of 200 mg/mL in 50 mmol/L sodium acetate buffer and 125 mmol/L sodium chloride solution. Saline was used for dilution and for placebo injections. Each patient received 2 subcutaneous injections (1 mL each) at separate injection sites in the lateral abdominal wall or the outer upper thigh. Patients remained at the study site for 30 minutes after drug administration and any AEs were reported. Patients received the first dose at week 0 and further doses of the same medication at weeks 4 and 8. This was a phase II, multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-response study, recruiting patients from tertiary referral centers. The study was designed to assess the efficacy and safety of subcutaneous administration of certolizumab. It was conducted between February 15, 2001, and March 12, 2002, at 58 centers in a total of 10 countries (the number of centers in each country is shown in parentheses): Belgium (4), Canada (16), Denmark (6), Germany (8), Ireland (5), Russia (5), Serbia (5), South Africa (2), Sweden (4), and the United Kingdom (3). The 3 active treatment groups (certolizumab 100, 200, or 400 mg) were compared with placebo. At screening, patients were stratified into 1 of 2 groups according to whether or not they were receiving concomitant steroids, immunosuppressants, or long-term anti-infectives. They then were randomized to 1 of the 4 treatment groups (1:1:1:1 certolizumab 100 mg:certolizumab 200 mg:certolizumab 400 mg:placebo). The randomization code was prepared by an independent statistician and patients were assigned to treatment by the use of a randomization allocation schedule managed via an interactive voice response system. Efficacy assessments were performed every 2 weeks up until week 12, with a further 8-week follow-up evaluation for safety. Before dosing, demographic data were recorded for each patient, together with any significant past medical history and all concomitant diseases. Disease activity (by using the CDAI) was assessed prospectively in the week before screening, after 0, 2, 4, 6, 8, 10, and 12 weeks of treatment, and on withdrawal from the study (if appropriate). Patients kept a daily diary of their symptoms throughout the study. At weeks 0, 2, 4, 6, 8, 10, 12, and study end point, the patients' quality of life was assessed using the Inflammatory Bowel Disease Questionnaire (IBDQ).24Irvine E.J. Feagan B. Rochon J. Archambault A. Fedorak R.N. Groll A. Kinnear D. Saibil F. McDonald J.W. Canadian Crohn's Relapse Prevention Trial Study GroupQuality of life) a valid and reliable measure of therapeutic efficacy in the treatment of inflammatory bowel disease.Gastroenterology. 1994; 106: 287-296Abstract PubMed Google Scholar Our own translations were used in Russian, Serbian, and Afrikaans. Standard laboratory tests, including hematology, biochemistry, and urinalysis, together with measurement of serum C-reactive protein (CRP) levels, were performed at each visit up until week 20 or on withdrawal from the study. Investigators were blinded to the results of the CRP analyses. Certolizumab plasma concentrations were measured using an enzyme-linked immunosorbent assay with a lower limit of sensitivity of .41 μg/mL. AEs were monitored throughout the study. The duration and intensity of each event were recorded by the investigator, together with its putative relationship to the study drug, and its outcome and seriousness. Any patient requiring a change in baseline therapy or hospitalization to manage an exacerbation of the disease was considered to be a treatment failure and was withdrawn from the study. Written informed consent to participate in the trial was obtained from each patient and the independent ethics committee/institutional review board at each study center approved the protocol before commencement. The trial was performed in accordance with the International Conference on Harmonization Guidelines for Good Clinical Practice, which have their origins in the Declaration of Helsinki. A sample size of 260 patients was considered adequate for this study, with 65 patients being allocated to each treatment group. This would give approximately 83% power to detect a true difference of 23% between treatment groups for the primary end point (clinical response) based on a placebo response rate of 12%. The efficacy was analyzed for the intent-to-treat (ITT) population. This included all patients recruited who received at least 1 injection and had at least 1 efficacy measurement after the first injection. Patients who terminated the trial prematurely were advanced to the end-of-study visit. A clinical response was defined as a decrease in CDAI score of 100 points or greater or remission (CDAI score, ≤150 points). The primary efficacy end point was the percentage of patients achieving a clinical response at week 12. The percentage of patients who showed a clinical response at weeks 2, 4, 6, 8, and 10 was a secondary efficacy variable, as was the percentage of patients in remission at weeks 2, 4, 6, 8, 10, and 12. Statistical analyses of these outcomes were performed using the χ2 test to compare among the treatment groups and 95% confidence intervals (CI) were calculated. Mean CDAI scores and mean IBDQ scores, summed over all categories, were summarized at weeks 0, 2, 4, 6, 8, 10, and 12. Serum CRP concentrations (geometric means) at all time points were analyzed using descriptive statistics. (The geometric mean is the nth root of the product of n values.) All treatment comparisons for efficacy were made using a 2-sided significance level of .05. A closed testing procedure25Koch G.G. Gansky S.A. Statistical considerations for multiplicity in confirmatory protocols.Drug Inf J. 1996; 30: 523-533Google Scholar was used for the analysis of the primary end point. Results from patients receiving certolizumab 400 mg were compared with placebo. If the comparison was not significant at the 5% level, no further analysis was performed. If significance was apparent, comparisons of certolizumab 200 mg vs placebo and certolizumab 100 mg vs placebo were performed simultaneously. For the analysis of secondary end points, there was no adjustment for multiple efficacy end points. Additional subgroup analyses (including effect of stratum) were for exploratory purposes only and therefore no adjustments for multiplicity were made. The safety analysis (safety population) included all patients who received at least 1 dose of study medication and subsequently had a postbaseline safety evaluation. Actual values and changes from baseline relating to vital signs and laboratory data were analyzed using descriptive statistics. In an exploratory analysis, changes from baseline in IBDQ total score for each treatment group were compared with the placebo group by using a comparison of least-squares means. Least-squares means were adjusted for stratum, and pooled country and baseline IBDQ scores. In addition, patients were stratified according to baseline CRP concentrations of less than 10 mg/L or 10 mg/L or greater in an exploratory analysis. The percentage of patients with a clinical response and the percentage of patients in remission in the certolizumab- and placebo-treated groups were analyzed according to baseline concentrations of CRP. A further series of analyses was also performed using breakpoint baseline CRP concentrations of 5, 6, 7, 8, and 9 mg/L. The χ2 test was used to compare treatment groups. The trial profile for the participating patients is shown in Figure 1. A total of 292 patients were enrolled in the study. A total of 291 patients were included in the ITT population and received either certolizumab 100 mg (n = 74), 200 mg (n = 72), or 400 mg (n = 72), or placebo (n = 73). One patient who received certolizumab 400 mg did not provide any postinjection efficacy measurements and therefore was excluded from the ITT population before breaking the blind. The safety population comprised all 292 enrolled patients. The demographic characteristics of the patients at screening are shown in Table 1. The majority of the patients (96.6%) were Caucasian. Patient characteristics were generally well balanced among treatment groups, although the mean age of patients receiving certolizumab 200 mg (40.1 y) was slightly higher than in the other groups, in which the mean ages of patients ranged from 33.5 to 35.9 years. The greatest difference among the groups was a small preponderance of women in the placebo group (67.1%) in comparison with both the certolizumab 100 mg (52.7%) and 400 mg (55.6%) groups. The concomitant medications with which the patients were being treated were broadly similar in both the placebo and the certolizumab treatment groups (Table 2). The most notable difference was observed for overall glucocorticoid use: 39.7% for the placebo group vs 30.6% for the certolizumab 400-mg group. In the ITT population, 15.5% of the patients had concomitant medication with both immunomodulators and steroids, and 21.6% of the patients had received prior anti-TNF therapy with a biologic agent.Table 1Baseline Demographic Characteristics of Patients (ITT Population)VariablePlacebo (n = 73)Certolizumab100 mg (n = 74)200 mg (n = 72)400 mg (n = 72)Mean age, y (range)35.8 (19–64)33.5 (18–56)40.1 (19–71)35.9 (18–67)Sex, n (% of patients) Male24 (32.9)35 (47.3)22 (30.6)32 (44.4) Female49 (67.1)39 (52.7)50 (69.4)40 (55.6)Mean body mass index, kg/m2, (range)23.03 (16.3–38.6)23.06 (15.0–37.3)24.14 (16.2–40.7)22.73 (13.5–38.1)Mean duration of disease, y, (range)7.95 (.1–27.6)7.73 (0.0–31.8)8.84 (0.0–30.7)8.43 (.2–26.5)Previous anti-TNF therapy, n (% of patients)16 (21.9)18 (24.3)17 (23.6)12 (16.7)CRP concentrations Geometric mean, mg/L (range)7.3 (.3–86.1)6.2 (.2–141.0)aData missing for 1 patient.6.5 (.2–127.0)7.7 (.4–128.2) ≥10 mg/L, n (% of patients)28 (38.4)31 (42.5)aData missing for 1 patient.28 (38.9)32 (44.4)Disease site, n (% of patients) Duodenum1 (1.4)5 (6.8)2 (2.8)3 (4.2) Ileum54 (74.0)57 (77.0)51 (70.8)56 (77.8) Cecum37 (50.7)45 (60.8)32 (44.4)41 (56.9) Ascending colon31 (42.5)35 (47.3)35 (48.6)36 (50.0) Transverse colon33 (45.2)32 (43.2)33 (45.8)37 (51.4) Descending colon42 (57.5)39 (52.7)40 (55.6)47 (65.3) Rectum36 (49.3)36 (48.6)33 (45.8)32 (44.4) Perianal23 (31.5)20 (27.0)23 (31.9)21 (29.2) Other5 (6.8)9 (12.2)4 (5.6)7 (9.7)Resection performed, n (% of patients)27 (37.0)27 (36.5)25 (34.7)27 (37.5)a Data missing for 1 patient. Open table in a new tab Table 2Number (%) of Patients Receiving Concomitant Medication (ITT Population)Medication typePlacebo (n = 73)Certolizumab100 mg (n = 74)200 mg (n = 72)400 mg (n = 72)Aminosalicylates29 (39.7)37 (50.0)32 (44.4)28 (38.9)Antidiarrheals10 (13.7)19 (25.7)16 (22.2)12 (16.7)Anti-infectives7 (9.6)6 (8.1)7 (9.7)6 (8.3) Metronidazole6 (8.2)4 (5.4)4 (5.6)5 (6.9) Ciprofloxacin5 (6.8)4 (5.4)5 (6.9)3 (4.2)Codeine and derivatives6 (8.2)5 (6.8)5 (6.9)2 (2.8)Immunomodulators26 (35.6)26 (35.1)29 (40.3)27 (37.5) Azathioprine17 (23.3)13 (17.6)23 (31.9)22 (30.6) 6-mercaptopurine4 (5.5)9 (12.2)2 (2.8)2 (2.8) Methotrexate5 (6.8)4 (5.4)4 (5.6)3 (4.2)Glucocorticoids (overall)29 (39.7)24 (32.4)29 (40.3)22 (30.6) Systemic glucocorticoids20 (27.4)15 (20.3)22 (30.6)aOne patient received both systemic glucocorticoids and budesonide.16 (22.2) Budesonide9 (12.3)9 (12.2)8 (11.1)aOne patient received both systemic glucocorticoids and budesonide.6 (8.3)a One patient received both systemic glucocorticoids and budesonide. Open table in a new tab Eighteen patients (24.7%) in the placebo group withdrew from the study by week 12. The corresponding numbers for the certolizumab 100-, 200-, and 400-mg treatment groups were 22 (29.7%), 15 (20.8%), and 20 (27.4%) patients, respectively. In all groups, the majority of withdrawals were a consequence of disease progression. The percentage of patients reaching the primary end point (a decrease in CDAI score of ≥100 points or remission at week 12) in the ITT population is shown in Figure 2. An onset of effect was evident at 2 weeks postinjection, when all doses of certolizumab produced a statistically significant benefit compared with placebo (week 2: placebo, 15.1% [95% CI, 6.2–24.0] vs certolizumab 100 mg, 29.7% [95% CI, 18.6–40.8; P = .033]; 200 mg, 30.6% [95% CI, 19.2–41.9; P = .026]; 400 mg, 33.3% [95% CI, 21.8–44.9; P = .010]). Certolizumab also showed significantly higher efficacy compared with placebo at weeks 4 (400 and 200 mg), 8 (400 and 100 mg), and 10 (400 mg). Patients receiving certolizumab 400 mg showed the highest response rate at all time points, with the highest response observed at week 10 (52.8% [95% CI, 40.6–65.0] vs 30.1% [95% CI, 18.9–41.3] in the placebo group [P = .006]). At all time points, the rate of response among patients receiving certolizumab was higher than in those receiving pla
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