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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Study design
  7. Outcomes and statistical analyses
  8. Statistical methods
  9. Results
  10. Response to therapy
  11. Safety
  12. Discussion
  13. Acknowledgements
  14. References
  15. Appendix

Aim : To evaluate CDP571, a humanized monoclonal antibody to tumour necrosis factor-α, for the treatment of corticosteroid-dependent Crohn's disease.

Methods : Patients with corticosteroid-dependent Crohn's disease (use of prednisolone 15–40 mg/day or budesonide 9 mg/day for at least 8 weeks, a previous failed attempt to discontinue corticosteroids within 8 weeks, and Crohn's Disease Activity Index score 150 points or less) were enrolled in a 16-week, randomized, double-blind, placebo-controlled trial. The patients received intravenous CDP571 (20 mg/kg at week 0 and 10 mg/kg at week 8) or placebo. Corticosteroid therapy was decreased following a predefined schedule. The primary efficacy end-point was the percentage of patients with corticosteroid-sparing [i.e. no disease flare (Crohn's Disease Activity Index score ≥220 points) and no longer requiring corticosteroid therapy] at week 10. The major secondary efficacy end-point was corticosteroid-sparing at week 16.

Results : Seventy-one patients received treatment. Corticosteroid-sparing was achieved by 19 of 39 (48.7%) CDP571 patients and 13 of 42 (40.6%) placebo patients (P = 0.452) at week 10, and by 18 of 39 (46.2%) CDP571 patients and seven of 32 (21.9%) placebo patients (P = 0.032) at week 16. CDP571 therapy was well-tolerated and the incidence of serious adverse events was similar to placebo.

Conclusions : The CDP571 was effective for corticosteroid-sparing at week 16 but not week 10, and was well-tolerated in patients with corticosteroid-dependent Crohn's disease.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Study design
  7. Outcomes and statistical analyses
  8. Statistical methods
  9. Results
  10. Response to therapy
  11. Safety
  12. Discussion
  13. Acknowledgements
  14. References
  15. Appendix

Tumour necrosis factor-α (TNF-α) appears to play an important role in the pathogenesis of Crohn's disease.1–3 Accordingly, treatment with infliximab – a chimaeric IgG1 antibody directed towards TNF-α– ameliorates symptoms, maintains clinical remission, closes fistulae and heals intestinal ulcers in patients with active disease.4–9 Infliximab is also corticosteroid-sparing in patients with active Crohn's disease.7

Although infliximab is a substantial treatment advance, human antichimaeric antibodies (HACA) to the murine component of this drug may develop with repeated exposure.7, 10, 11 Serum sickness, infusion reactions and other events may occur, but the most important consequence of HACA formation is loss of drug efficacy from neutralizing antibodies.10, 11 Dose regimens of infliximab, which feature frequent, regular drug administration and the use of concomitant antimetabolite therapy,7, 12 may overcome this problem. However, this has implications both for the patient well-being and also the cost of treatments. Hence, other approaches are also warranted, and the synthesis of less immunogenic antibodies is one potential solution. CDP571 is a humanized monoclonal IgG4 antibody with specificity for TNF-α, which has been prepared by grafting the complementarity-determining regions from a rodent antibody onto a human antibody framework.13, 14 Approximately 95% of the amino acid sequence of this molecule is of human origin, it is less likely – in theory – to evoke an immune response than a chimaeric antibody.

In two phase II studies of patients with active Crohn's disease, the administration of CDP571 (5 mg/kg, 10 mg/kg 8-weekly or 12-weekly, and 20 mg/kg loading dose followed by 10 mg/kg 8-weekly or 12-weekly) was well-tolerated and had a beneficial effect on disease activity.15, 16 A phase III study of intravenous CDP571 10 mg/kg 8-weekly demonstrated short-term but not long-term efficacy in patients with active Crohn's disease, and a post hoc analysis suggested both short- and long-term efficacy in a subgroup of patients with elevated C-reactive protein (CRP) concentrations (≥10 mg/L) indicative of active inflammation.17 Here, we describe results from a 16-week randomized, double-blind, placebo-controlled phase II trial evaluating the efficacy and safety of CDP571 for the treatment of patients with corticosteroid-dependent Crohn's disease.

Patients

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Study design
  7. Outcomes and statistical analyses
  8. Statistical methods
  9. Results
  10. Response to therapy
  11. Safety
  12. Discussion
  13. Acknowledgements
  14. References
  15. Appendix

Adult patients (n = 82) with a previous diagnosis of Crohn's disease (based on radiological, endoscopic or histological evidence) were screened at 21 centres in the USA, Canada and the UK (Appendix 1). Key inclusion criteria were: age ≥18 years; Crohn's Disease Activity Index (CDAI) score ≤150 points (indicating remission);18 corticosteroid therapy with prednisolone or prednisone 15–40 mg/day or budesonide 9 mg/day to control symptoms for at least 8 weeks; at least one unsuccessful attempt to discontinue prednisolone, prednisone or budesonide therapy (defined as worsening symptoms within 30 days) within 8 weeks of study entry; and a stable corticosteroid dose (except during attempted withdrawal) for at least 2 weeks prior to screening.

Key exclusion criteria were: use of broad-spectrum antibiotics, mycophenolate mofetil, ciclosporin or sodium cromoglicate (sodium cromoglycate) within 1 month of screening; diagnosis of ulcerative colitis, extensive bowel resection (>100 cm of the small intestine or greater than an extended right hemicolectomy), a stoma, obstructive symptoms because of significant mechanical obstruction within the 3 months prior to study entry, radiographic evidence of fixed, non-inflammatory bowel obstruction within the 6 months prior to study entry, or history of bowel perforation; critical illness; active infections (including enteric pathogens); multiple drug allergies; other significant medical conditions (including malignancy, except carcinoma of the cervix or basal cell carcinoma of the skin); current or previous bowel dysplasia within 5 years prior to screening; significant abnormal haematology or biochemical values at study entry; history of hepatitis or human immunodeficiency virus; pregnancy or lactation; previous treatment with infliximab or other anti-TNF-α therapy (except CDP571), experimental immunomodulatory antibodies, cytokines or drugs (within the preceding 3 months), or participation in any other clinical trial (within the preceding 1 month); intravenous corticosteroids or corticotrophin (within 1 month); corticosteroid treatment for other diseases (except topical hydrocortisone or inhaled corticosteroids for pulmonary disease) within the preceding 6 months; and discontinued antimetabolite therapy within the preceding month.

Concomitant therapy with azathioprine (≥1.5 mg/kg/day), mercaptopurine (6-mercaptopurine; ≥0.75 mg/kg/day) or methotrexate (≥15 mg/weekly) was permitted if the dose had been stable for at least 3 months in the case of methotrexate and 4 months for the other therapies. Patients could also receive 5-aminosalicylate therapy with sulfasalazine, mesalazine or olsalazine (irrespective of the dose) if the dose had been stable for 3 months prior to screening. Female patients of child-bearing potential were required to utilize an effective means of birth control.

Study design

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Study design
  7. Outcomes and statistical analyses
  8. Statistical methods
  9. Results
  10. Response to therapy
  11. Safety
  12. Discussion
  13. Acknowledgements
  14. References
  15. Appendix

The study was randomized, double-blind and placebo-controlled in design, and was conducted between 4 June 1998 and 10 November 1999. All patients gave written informed consent, and the protocol was approved by the institutional review board at each institution.

Patients were screened in the clinic 7–14 days prior to receiving study treatment. At this time, eligibility criteria were assessed, a physical examination was performed, stool specimens were collected for microbiological examination, and blood samples obtained for haematological assessment and clinical chemistry. Patients were also instructed on the use of the diary cards necessary to record CDAI scores. Before receiving study treatment at week 0, additional blood was obtained for autoantibody assays [antinuclear antibody (ANA), anti-DNA antibody, and anticardiolipin IgG and anticardiolipin IgM antibodies], CRP concentration, erythrocyte sedimentation rate (ESR), and antibodies to CDP571 (immunogenicity assay). In addition, assessment for the presence of open and actively draining perianal or abdominal enterocutaneous fistulae (defined as open fistulae with either spontaneous drainage or the ability to express drainage with gentle compression)8 was performed, and the Inflammatory Bowel Disease Questionnaire (IBDQ)19, 20 administered.

The patients were randomly assigned (in a 1:1 ratio) by a computer-generated schedule created by an independent statistician to receive two intravenous infusions of either CDP571 or placebo. The randomization schedule was stratified according to whether or not the patient was receiving immunosuppressive therapy (azathioprine, mercaptopurine or methotrexate) at screening. Pharmacists at each centre prepared the intravenous infusions, which were administered to patients over 2 h using a 1.2 μm in-line filter. The placebo (a 5% w/v solution of dextrose) was identical in appearance to the active drug. A previous pharmacokinetic study demonstrated that the half-life for CDP571 at doses of 5, 10 and 20 mg/kg ranged from 11.1 to 14.3 days with a linear dose–response for the maximum concentration and area under the curve;13 and in a previous pilot study, a single intravenous dose of CDP571 5 mg/kg demonstrated a statistically significant improvement in disease activity (median CDAI score) after 2 weeks, but the effect of treatment was short-lived.15 Based on these data, in the current study patients were treated with a loading dose infusion (CDP571 20 mg/kg or placebo) at week 0 followed by a maintenance dose infusion (CDP571 10 mg/kg or placebo) at week 8, to ensure adequate plasma concentrations of CDP571 throughout each 8-week dosing interval.

Patients were seen in the clinic at weeks 2, 4, 8, 10 and 16. On each occasion, blood was obtained for laboratory tests, CDAI and IBDQ scores were collected, and patients were evaluated for the presence of open and actively draining perianal or abdominal enterocutaneous fistulae and whether previously present fistulae had closed (with closure being defined as no drainage on gentle compression). Patients were also questioned by the study nurse about the occurrence of adverse events, compliance with the study protocol for tapering corticosteroids and the use of other medications.

For patients who received concomitant antimetabolite therapy, the drug dose was held at a constant level throughout the study. No additional treatments for Crohn's disease were permitted during the study. The introduction of a new drug therapy or an increase in the dose of antimetabolite drug or corticosteroid was considered a treatment failure.

Corticosteroid therapy during the study.  A systematic attempt was made to withdraw all patients from corticosteroid therapy according to a predefined schedule (Figure 1). Worsening symptoms – requiring an increase in the prednisolone/prednisone or budesonide dose – were considered a treatment failure. Failure to discontinue corticosteroid therapy completely by week 10 was also considered a treatment failure.

image

Figure 1. Dosing schedule and corticosteroid withdrawal strategy.

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Measures of response.  The primary measure of response was the percentage of corticosteroid-dependent patients with ‘corticosteroid-sparing’, defined as the proportion of patients who: (i) no longer required corticosteroid therapy at week 10 (71 days after first infusion); (ii) did not experience a disease flare (CDAI score ≥220 points) at any postinfusion scheduled visit at which a CDAI score was available which occurred ≤71 days after the first infusion and (iii) did not withdraw from the study prior to day 71. The main secondary efficacy end-point was the percentage of patients able to spare corticosteroids (according to the definition above) at week 16. Other secondary end-points were: the median time to disease worsening (CDAI score ≥220 points); the median CDAI and IBDQ scores at weeks 0, 2, 4, 8, 10 and 16; the median CRP concentrations and ESR values at weeks 0, 2, 4, 8 and 16; the proportion of patients who developed autoantibodies (ANA, anti-DNA, anticardiolipin IgG and anticardiolipin IgM) at weeks 0, 10 and 16; and the presence of antibodies to CDP571 at weeks 0, 8, 10 and 16.

Although the study was not powered to compare the rate of fistulae closure between groups, the proportion of patients showing closure of at least 50 and 100% of fistulae at any visit and on two consecutive visits over a 6-week period were determined as measures of treatment response.8 Adverse events were assessed according to the Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART)21 classification; any relationship to study drug was judged by clinicians who were unaware of the treatment assignment. Infusion reactions were defined as any adverse events occurring within 2 h of infusion of the study medication. Exploratory comparisons were also performed to determine the impact of concomitant therapy with azathioprine, mercaptopurine or methotrexate on the percentage of patients who showed corticosteroid-sparing at weeks 10 and 16.

Statistical methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Study design
  7. Outcomes and statistical analyses
  8. Statistical methods
  9. Results
  10. Response to therapy
  11. Safety
  12. Discussion
  13. Acknowledgements
  14. References
  15. Appendix

In the primary analysis, the proportion of patients who successfully discontinued corticosteroid therapy without a worsening of their symptoms (corticosteroid-sparing) at week 10 was compared using the Mantel–Haenszel chi-squared test with adjustment for the design factor (stratification by immunosuppressant use). The same analysis was used for the main secondary end-point (proportion of patients with corticosteroid-sparing at week 16). The median time to disease worsening was estimated by the Kaplan–Meier product limit method and survival curves derived by this procedure were compared using the log-rank test. These analyses were performed based on the intention-to-treat (ITT) population (i.e. all patients who received at least one dose of study treatment and had at least one efficacy and/or quality of life measurement after the first study medication infusion). For continuous measures (median CDAI and IBDQ scores, CRP concentrations and ESR values), a repeated-measures anova based on ranks was used to compare the two treatment groups. For patients who prematurely withdrew from therapy, these scores were carried forward from the time of withdrawal or treatment failure. For the subgroup of patients with fistulae, the percentage showing a closure of at least 50 and 100% of fistulae at any visit and on two consecutive visits over a 6-week period at any time during the study were summarized and comparisons between treatment groups were made using Fisher's exact test. The proportion of patients who developed serum autoantibodies (ANA, anti-DNA, anticardiolipin IgG and anticardiolipin IgM) or an anti-idiotypic response to CDP571 was also compared using Fisher's exact test. The proportions of patients experiencing adverse events were compared using descriptive statistics by body system, preferred term and severity, as well as by body system, preferred term and relationship to study drug. A two-sided α-error of 0.05 was the criterion for statistical significance.

A power calculation was performed prior to initiation of the study. A relatively large treatment effect of >50% was anticipated based on a prior phase II study with another anti-TNF antibody (infliximab),5 and a placebo rate of <20% was anticipated based on the observed placebo rate of 19% in a study of methotrexate for steroid sparing.22 A total of 60 patients were to be randomized in a 1:1 ratio to receive either CDP571 or placebo. This sample size provided approximately 80% power with a two-sided significance level of 5% to detect a true difference between treatment groups of 38% in the percentage of patients who had not experienced a disease flare and who no longer required corticosteroid therapy at week 10, based on a placebo response rate of 17% and therefore an active response rate of 55%.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Study design
  7. Outcomes and statistical analyses
  8. Statistical methods
  9. Results
  10. Response to therapy
  11. Safety
  12. Discussion
  13. Acknowledgements
  14. References
  15. Appendix

Of the 82 patients screened and randomized, 11 patients went on to fail screening. Seventy-one patients received study medication in the blind treatment phase (CDP571, n = 39; placebo, n = 32); this comprised the ITT population. The demographic characteristics of the patients in the two treatment groups were similar, with the exceptions of age, baseline CDAI score, baseline IBDQ score and use of budesonide (Table 1). Approximately one-third of patients in each group were receiving treatment with immunosuppressants. Twenty patients (62.5%) who received placebo withdrew from the study prematurely during the blind treatment period compared with 20 patients (51.5%) who received CDP571 (P = 0.111) (Figure 2). The most common reason for discontinuation was progression of disease, which occurred in 17 patients (43.6%) who received CDP571 and 16 patients (50.0%) in the placebo group (P = 0.638). More patients who received CDP571 withdrew prematurely because of adverse events (CDP571: seven of 39, 17.9%) than those who received placebo (one of 32, 3.1%) (P = 0.065).

Table 1.  Baseline characteristics
 Placebo (n = 32)CDP571 (n = 39)
  1. * Indicates that P = 0.033 for placebo vs. CDP571.

  2. † Patients may have Crohn's disease involving more than one location.

  3. ‡ Indicates that P = 0.020 for placebo vs. CDP571.

  4. § Indicates that eight patients treated with placebo had baseline CDAI scores >150 points.

  5. ¶ Indicates that six patients treated with CDP571 had baseline CDAI scores >150 points.

  6. ** CRP levels <8 mg/L were recorded as 4 mg/L.

  7. †† Indicates that P = 0.035 for placebo vs. CDP571.

Caucasian [n (%)]28 (87.5)36 (92.3)
Male [n (%)]16 (50.0)21 (53.8)
Age at entry [mean (SD), years]38.8* (13.439)32.3 (9.22)
Weight (kg) [mean (SD)]74.12 (16.322)72.34 (20.206)
Duration of Crohn's disease [mean (SD), years]8.78 (8.516)8.31 (7.280)
Site of Crohn's disease† [n (%)]
 Duodenum6 (18.8)2 (5.1)
 Ileum28 (87.5)33 (84.6)
 Caecum13 (40.6)18 (46.2)
 Ascending colon13 (40.6)15 (38.5)
 Transverse colon15 (46.9)14 (35.9)
 Descending colon10 (31.3)16 (41.0)
 Rectum7 (21.9)12 (30.8)
 Perianal7 (21.9)9 (23.1)
 Other4 (12.5)5 (12.8)
Open fistulae [n (%)]4 (12.5)7 (17.9)
Previous intestinal resection [n (%)]12 (37.5)15 (38.5)
Crohn's Disease Activity Index score [median (range)]120.74‡ (32.0–277.3§)91.25 (14.0–180.3¶)
Inflammatory Bowel Disease Questionnaire score [median (range)]169.5‡ (108–209)182.5 (111–219)
C-reactive protein concentration (mg/L) [median (range)]**4.0 (4–31)4.0 (4–71)
Concomitant medications [n (%)]
 Budesonide1†† (3.1)8 (20.5)
 Prednisone or prednisolone31 (96.9)31 (79.5)
 Azathioprine or mercaptopurine or methotrexate10 (31.3)14 (35.9)
image

Figure 2. Patient disposition. *Some patients withdrew from the trial for more than one reason. A total of 20 patients in the placebo group and 20 patients in the CDP571 trial withdrew prior to week 16.

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Response to therapy

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Study design
  7. Outcomes and statistical analyses
  8. Statistical methods
  9. Results
  10. Response to therapy
  11. Safety
  12. Discussion
  13. Acknowledgements
  14. References
  15. Appendix

At the end of 10 weeks (primary end-point), 19 of 39 patients (48.7%) who were assigned to CDP571 treatment were successfully withdrawn from corticosteroid therapy without a worsening of disease activity (corticosteroid-sparing) when compared with 13 of 32 (40.6%) of those who received placebo (P = 0.452) (Figure 3). It should be noted that failure to withdraw from corticosteroids at week 10 did not necessarily mean that a patient was withdrawn from the trial. At the end of 16 weeks (main secondary end-point), 18 of 39 patients (46.2%) who were assigned to CDP571 treatment successfully achieved corticosteroid-sparing compared with seven of 32 (21.9%) in the placebo group (P = 0.032) (Figure 3). In an analysis of time to disease flare censoring at week 16 and excluding two patients in the placebo group with CDAI ≥220 points prior to first infusion, 13 of 30 (43.3%) patients who received placebo experienced a flare compared with 10 of 39 (25.6%) patients who received CDP571 (log-rank P = 0.023; Wilcoxon P = 0.022; both analyses were stratified by immunosuppressant use at study entry) (Figure 4). As data were censored at week 16 for more than 50% of patients in each treatment group [placebo 17 of 30 (56.7%) vs. CDP571 29 of 39 (74.4%)], median times to disease flare cannot be calculated. Exploratory comparisons demonstrated that the rates of corticosteroid-sparing at weeks 10 and 16 in the subgroup of patients not receiving immunosuppressants in the placebo group [11 of 22 (50%) at week 10 and seven of 22 (32%) at week 16] were similar to the CDP571 group [13 of 25 (52%) at week 10 and 11 of 25 (44%) at week 16]. By comparison the rates of corticosteroid-sparing at weeks 10 and 16 in the subgroup of patients receiving immunosuppressants in the placebo group [two of 10 (20%) at week 10 and zero of 10 (0%) at week 16] were lower than in the CDP571 group [six of 14 (43%) at week 10 and seven of 14 (50%) at week 16], but these differences were not significant. Additional exploratory analyses using logistic regression methods did not demonstrate an association between age, the baseline CDAI score, the baseline IBDQ score, or use of budesonide and corticosteroid-sparing at the primary or major secondary end-points.

image

Figure 3. Percentage of patients with corticosteroid-dependent Crohn's disease at weeks 10 and 16 who showed corticosteroid-sparing (intention-to-treat population).

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image

Figure 4. Survival curves demonstrating time to disease worsening using the Kaplan–Meier product limit method, according to treatment group. All patients with no flare by week 16 were included in the analysis as censored observations (at 112 days); withdrawals prior to week 16 without flare were also censored in the analysis (at the time of withdrawal).

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Disease activity and quality of life.  A number of patients in both treatment groups had CDAI scores >150 points at the prefirst infusion visit and were therefore recorded as minor protocol deviations. Baseline median CDAI values were lower in the CDP571 group (91.25 points) compared with the placebo group (120.74 points) indicating less severe symptoms in the active group before treatment. In the CDP571 group, the median CDAI scores tended to remain <150 points throughout the study (Figure 5a). The placebo patients demonstrated a similar median increase in CDAI score to the CDP571 patients at week 16 (14.3 points and 14.9 points, respectively). However, data from only 12 of 32 (37.5%) of the original placebo cohort were available at week 16 because of premature withdrawals. An additional last observation-carried forward (LOCF) analysis was performed to take into account the significant amount of missing data at later visits, particularly in the placebo group. The LOCF analysis showed that the placebo patients demonstrated a greater median increase in CDAI score relative to the CDP571 patients at week 16 (33.4 points and 19.0 points, respectively).

image

Figure 5. (a) Median Crohn's Disease Activity Index (CDAI) scores and (b) Inflammatory Bowel Disease Questionnaire (IBDQ) scores at each study visit, according to treatment group (last observation carried forward), for the intention-to-treat population (error bars represent interquartile ranges).

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At the start of the study, the median IBDQ score in the placebo group was lower than in the CDP571 group (169.5 points and 182.5 points, respectively), indicating slightly better quality of life amongst the CDP571 patients before treatment. IBDQ scores showed fluctuations from visit to visit, however, in general, the results at week 16 were very similar to those seen at baseline (placebo median: 171.0 points, CDP571 median: 181.5 points). Again, it should be noted that week 16 data were available from 41% of placebo patients and 56% of CDP571 patients. The corresponding LOCF summaries support the main analysis (placebo median: 169.0 points, CDP571 median: 181.0 points; Figure 5b).

Laboratory markers of inflammation.  The median CRP concentrations at weeks 0, 2, 4, 8 and 10 were similar between treatment groups (data not shown). There was an overall trend towards increased ESR over the course of the study in both treatment groups, with lower median values in patients treated with CDP571 than placebo at all visits (data not shown).

Effects on fistulae.  At the start of the study, seven (17.9%) patients in the CDP571 group and four (12.5%) patients in the placebo group had at least one open fistula. Based on these 11 patients, the percentages of patients with at least one closure of open fistulae present at prefirst infusion, closure of at least 50% of open fistulae present at prefirst infusion, and closure of 100% of open fistulae present at prefirst infusion were similar between the two treatment groups (Figure 6).

image

Figure 6. Percentage of the patient subgroup with draining fistulae at baseline who experienced fistula closure (defined as no drainage on gentle compression) according to treatment group. Seven patients in the CDP571 treatment group and four patients in the placebo treatment group had draining fistulas at baseline.

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Safety

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Study design
  7. Outcomes and statistical analyses
  8. Statistical methods
  9. Results
  10. Response to therapy
  11. Safety
  12. Discussion
  13. Acknowledgements
  14. References
  15. Appendix

The two treatment groups were similar with regard to the proportion of patients who experienced any adverse event, serious adverse events, adverse events leading to withdrawal from the study, severe adverse events and adverse events possibly related or probably related to the study medication (Table 2). No adverse events during the blind treatment period were judged to be definitely related to the study medication by the blinded adjudicators. The most frequent (≥5%) adverse events possibly or probably related to the study medication were generally similar between the two treatment groups (Table 2). The percentage of patients with infusion reactions (defined as adverse events occurring within 2 h of the start of the study medication infusion) was 12.8% (five of 39) for those patients treated with CDP571, compared with 9.4% (three of 32) for those treated with placebo (Table 2). Overall, the most common adverse events reported during the blind treatment phase were abdominal pain [placebo: 7 (21.9%); CDP571: 14 (35.9%)], flu syndrome [placebo: 6 (18.8%); CDP571: 9 (23.1%)], headache [placebo: 6 (18.8%); CDP571: 6 (15.4%)], asthenia [placebo: 7 (21.9%); CDP571 5 (12.8%)] and infection [placebo: 6 (18.8%); CDP571: 5 (12.8%)]. No patients developed pneumonia, tuberculosis or opportunistic infections during the study, and no cases of lymphoma were observed. A single patient who had thyroid nodules at the time of randomization was diagnosed with a papillary cancer of the thyroid 2 weeks after receiving the first infusion of CDP571. This occurrence was ruled to be unrelated to the study drug by the patient's doctor. No patients died during the study. There were no clinically significant changes in laboratory values in either treatment group. Overall, patients who received CDP571 were no more likely to experience adverse events than those who received placebo. In particular, the percentage of patients who had an infection-related adverse event was almost identical between the groups.

Table 2.  Adverse events by treatment group
 Number of patients (%)
Placebo (n = 32)CDP571 (n = 39)
Number of adverse events112177
Patients with adverse events25 (78.1)35 (89.7)
Patients with serious adverse events3 (9.4)4 (10.3)
Patients withdrawn due to adverse events1 (3.1)7 (17.9)
Deaths00
Patients with severe adverse events7 (21.9)8 (20.5)
Patients with possibly, probably or definitely drug-related adverse events17 (53.1%)24 (61.5%)
Adverse events possibly or probably related to study treatment occurring in ≥5% of patients in at least one of the treatment groupsPossibleProbablePossibleProbable
 Flu syndrome5 (15.6)02 (5.1)0
 Asthenia5 (15.6)000
 Abdominal pain4 (12.5)05 (12.8)0
 Headache4 (12.5)05 (12.8)0
 Vasodilation1 (3.1)03 (7.7)1 (2.6)
 Dizziness3 (9.4)04 (10.3)0
 Antinuclear antibody2 (6.3)1 (3.1)1 (2.6)2 (5.1)
 Diarrhoea1 (3.1)03 (7.7)0
 Nausea003 (7.7)0
 Dry skin003 (7.7)0
 Abscess2 (6.3)000
 Infection1 (3.1)02 (5.1)0
 Pain002 (5.1)0
 Cardiolipin antibodies0002 (5.1)
Patients with any adverse events occurring within 2 h of infusion start3 (9.4) 5 (12.8) 

Overall, the placebo treatment group had less follow-up time in the blind treatment period because of having a somewhat higher withdrawal rate and earlier withdrawal time relative to the CDP571 group. This must be a consideration when comparing adverse event rates between the two groups.

Autoantibodies and CDP571 antibodies.  One patient in the CDP571 group showed both ANA and anti-DNA seroconversion to positive on at least one occasion during the blind treatment period. No patients developed new seropositivity for anticardiolipin IgG or anticardiolipin IgM. No patients with autoantibodies developed clinical manifestations of lupus or any other autoimmune disease. Only one of 39 patients (2.6%) treated with CDP571 tested positive for anti-CDP571 (anti-idiotypic) antibodies during the 16-week study.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Study design
  7. Outcomes and statistical analyses
  8. Statistical methods
  9. Results
  10. Response to therapy
  11. Safety
  12. Discussion
  13. Acknowledgements
  14. References
  15. Appendix

Corticosteroid dependency following induction therapy with corticosteroids in patients with Crohn's disease occurs frequently; two population-based studies have demonstrated that over 50% of patients who initially respond to corticosteroid therapy will be corticosteroid-dependent or undergo surgery within 1 year.23, 24 Long-term corticosteroid therapy is associated with significant morbidity25, 26 and, consequently, corticosteroid dependency in patients with Crohn's disease is a major clinical problem. Although treatment with the purine antimetabolites or methotrexate may reduce or eliminate the use of corticosteroids in patients with corticosteroid-dependent Crohn's disease,22, 27, 28 these drugs have important limitations. The purine antimetabolites are most frequently prescribed for this indication, but have a relatively slow onset of action and only 40% of patients who receive these compounds will enter remission as defined in this study (it should be noted that one-third of patients in the current study were corticosteroid-dependent despite regular antimetabolite therapy). Azathioprine and mercaptopurine, on the other hand, are associated with bone marrow suppression and pancreatitis,29 whereas methotrexate is unsuitable for use in female patients of child-bearing potential, has a risk of hepatic toxicity, and may cause hypersensitivity pneumonitis.30 The chimaeric anti-TNF-α monoclonal antibody infliximab was effective for corticosteroid withdrawal in a subgroup of patients with moderate to severely active Crohn's disease who were taking corticosteroids at the time it was initiated; however, infliximab has not been studied in a corticosteroid-dependent patient population.7 Thus, the identification of a safe and effective corticosteroid-sparing agent for the treatment of patients with corticosteroid-dependent Crohn's disease remains an important goal.

The 10-week time-point was too early for CDP571 to have had a sufficient anti-inflammatory effect to allow complete withdrawal of corticosteroids. The effect of a second dose of CDP571 at 8 weeks made it possible to wean patients off corticosteroids – a meaningful and statistically significant difference was observed between active treatment and placebo regarding the proportions of patients who were able to spare corticosteroids. Prior to study entry, all patients required corticosteroids to control their symptoms. At the end of the 16-week blind treatment period, approximately twice as many patients who received CDP571 successfully discontinued corticosteroid therapy without experiencing an exacerbation of disease activity compared with those who received placebo (46.2% vs. 21.9%, respectively). Similarly, as corticosteroid therapy was withdrawn, the time to worsening of symptoms (i.e. time to first disease flare) was significantly prolonged in patients who were assigned to the active treatment. However, there were no apparent differences between the treatment groups for other secondary end-points – including the CDAI and IBDQ scores, CRP concentrations and ESR values – and various measurements of fistulae closure. These results may, in part, reflect the difficulties encountered in defining and identifying corticosteroid-dependent patients with Crohn's disease in the clinical setting. It remains uncertain whether the corticosteroid-sparing effect observed with CDP571 in this short-term study has any lasting clinical relevance – a longer term study, in which patients are treated for at least 6 months after corticosteroid withdrawal, would be required to determine this more conclusively. This is particularly true in light of results from a phase III study of intravenous CDP571 (10 mg/kg every 8 weeks) that demonstrated short-term efficacy – but no effect in the longer term – in patients with active Crohn's disease.17

Analysis of the adverse events associated with the administration of CDP571 showed it to be well-tolerated. Notably, there were no cases of pneumonia, opportunistic infection or death. These favourable safety data are similar to those reported in other studies of CDP571 for treatment of active Crohn's disease.15–17, 31 The frequency of anti-idiotypic responses associated with CPD571 therapy was low. In fact, only one of 39 patients (2.6%) tested positive (at a low titre), indicating a low rate of immunogenicity.

In conclusion, CDP571 was effective for corticosteroid-sparing at week 16 but not week 10 in the treatment of patients with corticosteroid-dependent Crohn's disease. CDP571 was well-tolerated.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Study design
  7. Outcomes and statistical analyses
  8. Statistical methods
  9. Results
  10. Response to therapy
  11. Safety
  12. Discussion
  13. Acknowledgements
  14. References
  15. Appendix

The study was supported by a research grant from Celltech, Slough, UK. William Sandborn, Brian Feagan and Stephen Hanauer have served as consultants for Celltech. Patricia Heath is a former employee of Celltech. Sara Cameron is an employee of Celltech.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Study design
  7. Outcomes and statistical analyses
  8. Statistical methods
  9. Results
  10. Response to therapy
  11. Safety
  12. Discussion
  13. Acknowledgements
  14. References
  15. Appendix
  • 1
    Schreiber S, Nikolaus S, Hampe J, et al. Tumour necrosis factor alpha and interleukin 1beta in relapse of Crohn's disease [see comment]. Lancet 1999; 353: 45961.
  • 2
    Baert FJ, D'Haens GR, Peeters M, et al. Tumor necrosis factor alpha antibody (infliximab) therapy profoundly down-regulates the inflammation in Crohn's ileocolitis. Gastroenterology 1999; 116: 228.
  • 3
    Beutler BA. The role of tumor necrosis factor in health and disease. J Rheumatol 1999; 26 (Suppl. 57): 1621.
  • 4
    van Dullemen HM, van Deventer SJ, Hommes DW, et al. Treatment of Crohn's disease with anti-tumor necrosis factor chimeric monoclonal antibody (cA2). Gastroenterology 1995; 109: 12935.
  • 5
    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: 102935.
  • 6
    Rutgeerts P, D'Haens G, Targan S, et al. Efficacy and safety of retreatment with anti-tumor necrosis factor antibody (infliximab) to maintain remission in Crohn's disease. Gastroenterology 1999; 117: 7619.
  • 7
    Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 2002; 359: 15419.
  • 8
    Present DH, Rutgeerts P, Targan S, et al. Infliximab for the treatment of fistulas in patients with Crohn's disease. N Engl J Med 1999; 340: 1398405.
  • 9
    Sands BE, Anderson FH, Bernstein CN, et al. Infliximab maintenance therapy for fistulizing Crohn's disease. N Engl J Med 2004; 350: 87685.
  • 10
    Baert F, Noman M, Vermeire S, et al. Influence of immunogenicity on the long-term efficacy of infliximab in Crohn's disease. N Engl J Med 2003; 348: 6018.
  • 11
    Farrell RJ, Alsahli M, Jeen YTJ, Falchuk KR, Peppercorn MA, Michetti P. Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn's disease: a randomized controlled trial. Gastroenterology 2003; 124: 91724.
  • 12
    Maini R, St Clair EW, Breedveld F, et al. Infliximab (chimeric anti-tumour necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomised phase III trial. ATTRACT Study Group. Lancet 1999; 354: 19329.
  • 13
    Stephens S, Emtage S, Vetterlein O, et al. Comprehensive pharmacokinetics of a humanized antibody and analysis of residual anti-idiotypic responses. Immunology 1995; 85: 66874.
  • 14
    CDP571. Anti-TNF monoclonal antibody, BAY 103356. Drugs in R&D 1999; 1: 2535.
  • 15
    Stack WA, Mann SD, Roy AJ, et al. Randomised controlled trial of CDP571 antibody to tumour necrosis factor-alpha in Crohn's disease. Lancet 1997; 349: 5214.
  • 16
    Sandborn WJ, Feagan BG, Hanauer SB, et al. An engineered human antibody to TNF (CDP571) for active Crohn's disease: a randomized double-blind placebo-controlled trial. Gastroenterology 2001; 120: 13308.
  • 17
    Sandborn WJ, Feagan BG, Radford-Smith G, et al. CDP571, a humanised monoclonal antibody to tumour necrosis factor alpha, for moderate to severe Crohn's disease: a randomised, double-blind, placebo-controlled trial. Gut 2004; 53: 148593.
  • 18
    Best WR, Becktel JM, Singleton JW, Kern F Jr. Development of a Crohn's Disease Activity Index. National Cooperative Crohn's Disease Study. Gastroenterology 1976; 70: 43944.
  • 19
    Irvine EJ, Feagan B, Rochon J, et al. Quality of life: a valid and reliable measure of therapeutic efficacy in the treatment of inflammatory bowel disease. Canadian Crohn's Relapse Prevention Trial Study Group. Gastroenterology 1994; 106: 28796.
  • 20
    Irvine EJ, Feagan BG, Wong CJ. Does self-administration of a quality of life index for inflammatory bowel disease change the results? J Clin Epidemiol 1996; 49: 117785.
  • 21
    Department of Health and Human Services, Food and Drug Administration (FDA). COSTART: Coding Symbols for Thesaurus of Adverse Reaction Terms, 5th edn. Rockville, MD: Department of Health and Human Services, Food and Drug Administration (FDA), 1995.
  • 22
    Feagan BG, Rochon J, Fedorak RN, et al. Methotrexate for the treatment of Crohn's disease. The North American Crohn's Study Group Investigators. N Engl J Med 1995; 332: 2927.
  • 23
    Munkholm P, Langholz E, Davidsen M, Binder V. Frequency of glucocorticoid resistance and dependency in Crohn's disease. Gut 1994; 35: 3602.
  • 24
    Faubion WJ, Loftus EJ, Harmsen WS, Zinsmeister AR, Sandborn WJ. The natural history of corticosteroid therapy for inflammatory bowel disease: a population-based study. Gastroenterology 2001; 121: 25560.
  • 25
    Kusunoki M, Moeslein G, Shoji Y, et al. Steroid complications in patients with ulcerative colitis. Dis Colon Rectum 1992; 35: 10039.
  • 26
    Akerkar GA, Peppercorn MA, Hamel MB, Parker RA. Corticosteroid-associated complications in elderly Crohn's disease patients [see comment]. Am J Gastroenterol 1997; 92: 4614.
  • 27
    Candy S, Wright J, Gerber M, Adams G, Gerig M, Goodman R. A controlled double blind study of azathioprine in the management of Crohn's disease. Gut 1995; 37: 6748.
  • 28
    Markowitz J, Grancher K, Kohn N, Lesser M, Daum F. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn's disease. Gastroenterology 2000; 119: 895902.
  • 29
    Present DH, Meltzer SJ, Krumholz MP, Wolke A, Korelitz BI. 6-Mercaptopurine in the management of inflammatory bowel disease: short- and long-term toxicity. Ann Intern Med 1989; 111: 6419.
  • 30
    Kremer JM, Alarcon GS, Lightfoot RW Jr, et al. Methotrexate for rheumatoid arthritis. Suggested guidelines for monitoring liver toxicity. American College of Rheumatology. Arthritis Rheum 1994; 37: 31628.
  • 31
    Hanauer S, Present D, Targan SR, Kam L, Patel J, Sandborn WJ. CDP571, a humanized monoclonal antibody to TNF-a, is well tolerated in Crohn's disease patients with previous hypersensitivity to infliximab. Gastroenterology 2003; 124: A-517.

Appendix

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Patients
  6. Study design
  7. Outcomes and statistical analyses
  8. Statistical methods
  9. Results
  10. Response to therapy
  11. Safety
  12. Discussion
  13. Acknowledgements
  14. References
  15. Appendix

Appendix 1. Investigators

Canada
  • 1
    Andre Archambault, Hospital Maisonneuve-Rosemont, Montreal, QE, Canada
  • 2
    Jeffrey Baker, St Michael's Hospital, Toronto, ON, Canada
  • 3
    Charles Bernstein, Health Sciences Centre, Winnipeg, MB, Canada
  • 4
    Laurington DaCosta, Hotel-Dieu Hospital, Kingston, ON, Canada
  • 5
    Chrystian Dallaire, Centre Hospitalier Universitaire de Quebec, Quebec, QE, Canada
  • 6
    Brian Feagan and James Gregor, London Health Sciences Centre, London, ON, Canada
  • 7
    Lloyd Sutherland, University of Calgary, Health Science Centre, Calgary, AB, Canada
United Kingdom
  • 1
    Douglas Chalmers, Leeds General Infirmary, Leeds, Great Britain, UK
  • 2
    John Hunter, Addenbroke's Hospital, Cambridge, Great Britain, UK
  • 3
    Michael Kamm, St Mark's Hospital, Northwick Park, Middlesex, Great Britain, UK
  • 4
    Andrew Williams, St John's Hospital, Livingston, Scotland, UK
USA
  • 1
    Simmy Bank, Long Island Jewish Medical Centre, Long Island, NY, USA
  • 2
    Fabio Cominelli, University of Virginia Health Sciences Centre, Charlottesville, VA, USA
  • 3
    Charles Elson, University of Alabama at Birmingham, Birmingham, AL, USA
  • 4
    Stephen Hanauer, University of Chicago, Chicago, IL, USA
  • 5
    Gary R. Lichtenstein, University of Pennsylvania Hospital, Philadelphia, PA, USA
  • 6
    Daniel Present, Mount Sinai Medical Center, New York, NY, USA
  • 7
    Vance Rodgers, Scripps Clinic, La Jolla, CA, USA
  • 8
    William J. Sandborn and William J. Tremaine, Mayo Clinic, Rochester, MN, USA
  • 9
    Stephan Targan, Cedars Sinai Medical Center, Los Angeles, CA, USA
  • 10
    Douglas Wolf, Atlanta Gastroenterology Associates, Atlanta, GA, USA