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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflicts of interest
  8. Acknowledgements
  9. References
  10. Appendix

Background  More than 50% of patients with Crohn's disease become either steroid resistant or dependent. Accordingly, development of new treatments for steroid-dependent Crohn's disease is a research priority.

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

Methods  Patients with steroid-dependent Crohn's disease (n = 271) were enrolled in a 36-week, double-blind, placebo-controlled trial. Steroid dependence was defined as use of prednisolone or prednisone (15–40 mg/day) or budesonide (9 mg/day) for ≥8 weeks, a previous failed attempt to decrease or discontinue steroids within 8 weeks of screening, and a Crohn's Disease Activity Index score of ≤150 points. Patients were randomized to receive intravenous CDP571 10 mg/kg or placebo 8-weekly through to week 32. Steroids were then tapered using a defined schedule. The primary efficacy endpoint was the percentage of patients with steroid sparing, defined as discontinuation of steroid therapy without a disease flare (Crohn's Disease Activity Index score ≥220 points) at week 36.

Results  Steroid sparing occurred in 53 of 181 (29.3%) CDP571 patients and 33 of 90 (36.7%) placebo patients (P = 0.24). Adverse events occurred at similar frequencies in both treatment groups.

Conclusions  CDP571 was ineffective for sparing steroids in patients with steroid-dependent Crohn's disease. CDP571 was well tolerated.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflicts of interest
  8. Acknowledgements
  9. References
  10. Appendix

Steroids are highly effective for the induction of remission in patients with active Crohn's disease.1 However, the long-term prognosis of these patients is poor. More than 50% of patients become steroid-dependent or undergo a surgical resection within 1 year of commencing treatment with these agents.2 Although controlled trials have demonstrated that azathioprine and mercaptopurine are effective for maintenance of steroid-induced remission in patients with active Crohn's disease,3, 4 these agents have not been evaluated in steroid-dependent patients. Methotrexate is effective for the induction and maintenance of remission and for steroid-sparing in patients with steroid-treated Crohn's disease.5, 6 Nevertheless, for various reasons, acceptance of this drug by gastroenterologists has been modest.

Infliximab is an IgG1 chimeric monoclonal antibody to tumour necrosis factor-α (TNF-α) that is effective for the induction and maintenance of remission in patients with moderate to severe Crohn's disease.7, 8 Although a subgroup analysis within a maintenance study demonstrated that infliximab is effective for steroid sparing in patients,8 this indication has not been independently evaluated in steroid-dependent patients. Furthermore, infliximab is immunogenic and patients frequently develop human anti-chimeric antibodies (HACAs). These antibodies may cause infusion reactions and loss of efficacy.9–11

Consequently, humanized monoclonal antibodies were designed to reduce the immunogenicity associated with murine and chimeric antibodies. The process of humanization entails grafting a human antibody to the antigen binding complementarity determining regions (CDRs) of a murine antibody variable domain, resulting in a protein that is approximately 95% human.12 CDP571, a humanized monoclonal antibody specific to human TNF-α, was created by linking a human IgG4 antibody framework to the CDR of a murine TNF-α monoclonal antibody.13 Previous trials indicated that intravenous (i.v.) CDP571 might be effective for the short-term treatment of active Crohn's disease14, 15 and possibly for steroid sparing.16 A large-scale study subsequently demonstrated that i.v. CDP571 was effective for the short-term treatment of active Crohn's disease, but failed to demonstrate long-term efficacy over 28 weeks [(Sandborn, 2004 no. 1855)]. Post hoc analyses of the data from this study showed that CDP571 had both short- and long-term efficacy in a subgroup of patients with increased serum concentrations of C-reactive protein (CRP) [(Sandborn, 2004 no. 1855)]. Here we describe the results of a 36-week Phase-III trial in which patients with steroid-dependent Crohn's disease received i.v. CDP571 10 mg/kg or placebo 8-weekly through to week 32.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflicts of interest
  8. Acknowledgements
  9. References
  10. Appendix

Selection of patients

Eligible patients were at least 18 years of age and had steroid-dependent Crohn's disease defined as: (i) the requirement for steroid treatment with prednisolone or prednisone (15–40 mg/day), or budesonide (9 mg/day) for at least 8 weeks (although the dose could have been temporarily reduced during an attempt at steroid withdrawal), with a stable dose for at least 2 weeks prior to study entry; (ii) an unsuccessful attempt to decrease or discontinue steroid treatment, owing to disease flare within 30 days of the attempt, on at least one occasion in the 8 weeks prior to study entry. All patients had a baseline score of ≤150 points on the Crohn's Disease Activity Index (CDAI).17 The diagnosis of Crohn's disease was made using radiological, endoscopical, or histological evidence.

Patients with infection of a fistula (abscess); ulcerative colitis; bowel perforation or evidence of a non-inflammatory obstruction (within 6 months); obstructive symptoms owing to significant mechanical obstruction (within 3 months); small bowel resection >100 cm and/or more than the right colon resected (to avoid patients with significant postoperative diarrhoea that could confound measurement of the CDAI); or a colostomy or ileostomy (to avoid patients in whom stool frequency cannot be determined as this would confound measurement of the CDAI) were not eligible. In addition, patients were ineligible if they had an infectious enteritis or other serious infection; a clinically important chronic disease in the 3 months before study entry; previous history of blood dyscrasia (pancytopenia or aplastic anaemia) or demyelinating disease; current or previous malignancy other than successfully treated carcinoma of the cervix or basal cell carcinoma (> 5 years prior to entry); current or previous bowel dysplasia (5 years before screening); or clinically important allergies or multiple drug allergies. Furthermore, patients with drug or alcohol abuse, significant abnormal haematology or biochemical values, or a history of or concurrent tuberculosis, hepatitis, or human immunodeficiency virus were not entered. Pregnant and lactating women were also excluded. The institutional review board at each centre approved the study and all the participants gave written informed consent.

Steroid-tapering regimen

An attempt was made to discontinue patients’ existing steroid therapies within 4–9 weeks of starting treatment with CDP571 or placebo. A defined steroid-tapering schedule specific to the baseline dose was utilized (Figure 1). If at any time a patient required rescue therapy for a flare (CDAI ≥220 points), the dose of prednisolone, prednisone or budesonide was increased to the daily dose that the patient was receiving at the initial visit. Re-tapering was then resumed on the day of the next scheduled study infusion (unless the flare was within 2 weeks of the next scheduled infusion, in which case re-tapering was resumed after the following infusion 8 weeks later). The steroid dose was then tapered down to the daily steroid dose above that at which the disease had flared. If patients experienced a second flare, or could not be maintained on their dose of steroid at study entry, they were withdrawn from the study.

image

Figure 1. Dosing schedule and steroid withdrawal strategy.

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Concomitant medications

Treatment with azathioprine (minimum allowed dose 1.5 mg/kg/day) or mercaptopurine (minimum allowed dose 0.75 mg/kg/day) at a stable dose for ≥16 weeks, or methotrexate (minimum allowed dose 15 mg/weeks) at a stable dose for ≥12 weeks, was permitted. Patients who discontinued these agents in the 4 weeks prior to study entry were ineligible. Sulfasalazine, mesalamine, olsalazine, or balsalazide at a stable dose for ≥12 weeks was also permitted. Treatment with antibiotics at a stable dose for ≥8 weeks was also allowed provided that the patient agreed to continue the antibiotic during screening and throughout the 36-week trial. Patients who had received sodium cromoglycate, mycophenolate, or ciclosporin within 4 weeks of study entry were excluded, as were those who had been treated with >4 doses of an opioid-containing analgesic or non-steroidal anti-inflammatory drug [including cyclooxygenase (COX)-1 and COX-2 inhibitors] within 2 weeks of entry. Taking specific opioids (i.e. loperamide, diphenoxylate and codeine) for the control of diarrhoea was permitted.

Patients who had previously participated in a clinical trial of CDP571 or who had been treated with another biological anti-TNF-α therapy within 12 weeks of study entry were excluded. Patients who had previously received anti-TNF-α therapy and subsequently experienced either a lack of response to the first dose or an infusion reaction that was suspected or confirmed to be associated with an immune response (e.g. presence of HACA) were also ineligible. Other exclusion criteria included participation in a clinical trial involving an antibody, cytokine, or other immunomodulatory therapy in the 3 months prior to entry and participation in any other clinical trial within 1 month of study entry.

Study medication

Pharmacists at each centre prepared the i.v. infusions of CDP571 or placebo. Placebo was a 5% w/v solution of dextrose. CDP571 at a dose of 10 mg/kg body weight or placebo was administered to patients as a 2-h i.v. infusion using a 0.2 μm filter. CDP571 and placebo had a similar clear and colourless appearance. Patients received infusions every 8 weeks up to week 32.

Design of the study

This randomized, double-blind, placebo-controlled, parallel-group study was performed at 59 centres in Australia, Bulgaria, Canada, the Czech Republic, Hungary, Poland and the USA (see Appendix). The randomization procedure was stratified according to: (i) geographic region (Europe, the USA, Canada and Australia); and (ii) concomitant medication (treatment with at least one of azathioprine, mercaptopurine, methotrexate, corticosteroids, or antibiotics; and none of these treatments). After a 1- to 2-week screening period, eligible patients were randomly assigned in a 2 : 1 ratio to receive CDP571 or placebo. The randomization schedules for each of the two stratified groups were computer generated by an independent statistician.

Outcomes and statistical analyses

Disease activity was assessed at the baseline (randomization) visit, and at week 2, 4, 8, 12, 16, 24, 32 and 36. Using diary cards, patients recorded the frequency of loose stools, the extent of their abdominal pain and their general well-being in the 7 days before each visit. At each visit, a physical examination, fistula evaluation, quality of life assessment and laboratory tests were conducted and patients were asked whether adverse events had occurred. Clinical disease activity was assessed using the CDAI.17 Patients were assessed 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), or fistulae closure.18 Disease-specific health-related quality of life was assessed using the self-administered Inflammatory Bowel Disease Questionnaire (IBDQ).19, 20 Blood samples were taken for haematological and biochemical assessments and for measurement of plasma anti-CDP571 antibody (immunogenicity assay) and CRP concentrations.

Response measures

The efficacy intention to treat (ITT) population included 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. The primary efficacy endpoint was the percentage of patients with steroid sparing [defined as not experiencing a disease flare (CDAI ≥ 220 points) and no longer requiring steroid therapy at week 36]. Secondary efficacy endpoints included: the percentages of patients who had steroid sparing (as defined above) at week 16, 24 and 32; the time from baseline to the first increase in steroid therapy; the total amount of steroid taken during the study as a proportion of the amount taken if the patient had remained on their baseline dose throughout the study; the percentage of patients in the subgroup with fistulae who showed a closure of ≥ 50% or 100% of fistulae at any visit and on two consecutive visits over an 8-week period (closure defined as no drainage on gentle compression); the mean CDAI and IBDQ scores; and the median serum CRP concentration (week 0, 8, 16, 24, 32 and 36).

Safety measures

The safety population included all patients who received at least one dose of study treatment and had at least one postbaseline safety evaluation after the first infusion. All adverse events were recorded and graded according to Medical Dictionary for Regulatory Activities (MedDRA, Version 3.0, Reston, VA, USA) criteria. Infusion reactions were defined as any adverse events occurring within 2 h of the start of the infusion.

Other safety measures were laboratory data and the presence of antibodies to CDP571 at week 0, 8, 16, 24, 32 and 36. We also performed exploratory comparisons to determine the impact of concomitant therapy with immunosuppressive medications (azathioprine, mercaptopurine, or methotrexate) and past therapy with infliximab on the percentage of patients with steroid sparing at week 16, 24, 32 and 36.

Statistical methods

The percentages of steroid-dependent patients with steroid sparing at week 16, 24, 32 and 36 were summarized and compared between treatment groups using the Mantel–Haenszel test, adjusting for geographic region and concomitant medication usage. A Kaplan–Meier analysis of the time to the first increase in steroid therapy measured from baseline was also performed. In this analysis, the first increase in steroid therapy was considered an event. Patients with no reported events by week 36 were censored at this timepoint. Patients without events who withdrew from the study at any time during the period of analysis were censored at their time of withdrawal. The total steroid dose taken throughout the study, as a proportion of the amount the patient would have taken if retained on their baseline dose throughout the study, was compared between treatment groups using the van Elteren's test. Exploratory comparisons to determine the impact of concomitant immunosuppressive therapy or past therapy with infliximab on the percentage of patients who were steroid sparing at week 16, 24, 32 and 36 were performed using Fisher's exact test. Of the subgroup of patients with fistulae, the percentage showing a closure of ≥ 50% and 100% of fistulae at any visit and on two consecutive visits over an 8-week period at any time during the study, were summarized and comparisons made between treatment groups using Fisher's exact test. The mean CDAI and IBDQ scores and the median serum CRP concentrations, were presented graphically. For the analyses of CDAI scores, IBDQ scores and CRP concentrations, data for patients who were lost to follow up or who withdrew from the study because of deterioration in their condition or adverse events were shown using the last observation carried forward approach. Descriptive statistical techniques were used to summarize the adverse events by body system, preferred term and severity, as well as by body system, preferred term and relationship to study drug. The percentages of patients with antibodies to CDP571 were also summarized descriptively. All statistical tests were two-sided and P-values ≤0.05 were considered statistically significant.

Sample size

We estimated that 186 patients in the CDP571 group and 93 patients in the placebo group were needed to have 90% power to detect a true difference in the proportion of steroid-dependent patients who achieved steroid sparing at week 36, assuming a true difference of 17% and a placebo rate of 10%. These calculations are based on the observation from a previous Phase-II study of CDP571 for steroid sparing where 44% of patients treated with CDP571 were off steroid therapy at week 16 and 33% remained off steroid therapy at week 40.16 Because a similar success rate could not be assumed in a larger population, we made the assumption that a lower proportion of patients (27%) would remain off steroid therapy at week 36. We planned to recruit a total of 279 patients.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflicts of interest
  8. Acknowledgements
  9. References
  10. Appendix

The study was conducted between 30 November, 2000 and 13 May, 2002. Two hundred and ninety-eight patients were screened, of whom 271 were randomized: 90 patients received placebo and 181 received CDP571. These 271 patients comprised the ITT population. Two patients randomized to placebo did not have postbaseline safety evaluations; the remaining 269 patients comprised the safety population. Baseline characteristics were similar for the two treatment groups (Table 1). The disposition of participating patients is shown in Figure 2.

Table 1.  Baseline characteristics (safety population)
VariablePlacebo (n = 88)CDP571 10 mg/kg (n = 181)
  1. CI, confidence intervals; s.d., standard deviation; TNF-α, tumour necrosis factor-α.

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

  3. † Mesalamine, sulfasalazine and olsalazine.

White, n (%)87 (98.9)179 (98.9)
Male, n (%)47 (53.4)104 (57.5)
Mean (s.d.) age at entry, years34.7 (12.0)35.3 (12.7)
Mean (s.d.) weight, kg72.2 (16.0)70.2 (16.5)
Mean (s.d.) duration of Crohn's disease, years6.6 (6.2)6.4 (6.4)
Location of Crohn's disease*, n (%)
 Duodenum1 (1.1)10 (5.5)
 Ileum64 (72.7)135 (74.6)
 Caecum55 (62.5)102 (56.4)
 Ascending colon46 (52.3)86 (47.5)
 Transverse colon31 (35.2)73 (40.3)
 Descending colon43 (48.9)83 (45.9)
 Rectum29 (33.0)58 (32.0)
 Perianal12 (13.6)29 (16.0)
 Other6 (6.8)19 (10.5)
Open and draining perianal or abdominal enterocutaneous fistulae, n (%)8 (9.1)17 (9.4)
Previous intestinal resection, n (%)24 (27.3)60 (33.1)
Mean (s.d.) Crohn's Disease Activity Index score93 (47)94 (48)
Mean (s.d.) Inflammatory Bowel Disease Questionnaire score176 (26)171 (30)
Geometric mean (95% CI) C-reactive protein concentration, mg/L4.21 (2.91, 6.09)3.78 (2.97, 4.81)
Concomitant medications, n (%)
 Budesonide23 (26.1)32 (17.7)
 Prednisone or prednisolone67 (76.1)150 (82.9)
 1Azathioprine or mercaptopurine21 (23.9)44 (24.3)
 2Methotrexate2 (2.3)5 (2.8)
 3Antibiotics2 (2.3)14 (7.7)
 45-aminosalicylates†73 (83.0)130 (71.8)
 One or more of 1 or 223 (26.1)49 (27.1)
 One or more of 1, 2, 3, or 476 (86.4)146 (80.7)
Previous anti-TNF-α therapy, n (%)9 (10.2)19 (10.5)
image

Figure 2. Trial profile. aSome patients withdrew from the trial for more than one reason. A total of 38 patients in the placebo group and 70 patients in the CDP571 group withdrew before week 36.

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Major protocol violations were recorded for 152 (56.1%) patients (Table 2). The most common protocol deviation was errors in steroid titration, which occurred in 90 patients (33%). Forty-four patients (48.9%) in the placebo group and 73 patients (40.3%) in the CDP571 treatment group completed the study according to the protocol.

Table 2.  Major protocol deviations
VariableNumber of patients n (%)
  1. * In addition, protocol deviations occurred in three patients whose steroid dose was too low or incorrect on study entry, two patients who were taking long-term anti-antibiotics, two patients who had a ‘visit out of window’, one patient who withdrew after a second increase of steroid dose and one patient who did not have a chest X-ray performed until week 2.

Efficacy population271 (100)
Total major protocol deviations151 (56.1)
Errors in the titration of steroids. These errors included incorrect down-titration of steroids following flare, failure to stop titration following flare, incorrect steroid titration, incorrect timing of steroid titration and stopping down titration.90 (33)
Other steroid dosing errors. These errors included incorrect steroid dose or incorrect increase in dose, changing dose postflare and addition of a steroid.30 (11.1)
CDAI score was either out of range (>150) at the week 0 assessment or not calculated.25 (9.2)
Concomitant medications were changed during the study.16 (5.9)
Medications not allowed (e.g. methylprednisolone, intravenous hydrocortisone, triamcinolone, dexamethasone, prednisolone sodium phosphate, prednisone for an allergic reaction, and prednisolone combined with budesonide).16 (5.9)
Mesalazine dose was not stable for at least 12 weeks prior to screening, methotrexate dose was less than 15 mg/week, or azathioprine dose was less than 1.5 mg/kg/day or not stable for at least 16 weeks prior to screening.11 (4.1)
There were more than 5 weeks between week 32 and 36 assessments.9 (3.3)
Concomitant medications were not stable prior to infusion.8 (3.0)
Steroid dose was not stable for at least 2 weeks prior to the first infusion.5 (1.8)
The incorrect volume of CDP571 or placebo was infused.5 (1.8)
Miscellaneous9 (3.3)

Efficacy

The percentage of steroid-dependent patients who achieved steroid sparing at week 36 was not different between patients treated with CDP571 (53/181, 29.3%) and those who received placebo (33/90, 36.7%; P = 0.24) (Figure 3). Likewise, the percentages of steroid-dependent patients who achieved steroid sparing at week 16, 24 and 32 were not significantly different between the two treatment groups (Figure 3). Exploratory comparisons demonstrated that there were no significant differences in the primary outcome according to the stratification criteria of geographic region and concomitant medication use (data not shown).

image

Figure 3. Percentages of patients with steroid-dependent Crohn's disease treated with CDP571 10 mg/kg or placebo at week 0, 8, 16, 24 and 32 who showed steroid sparing (defined as patients who no longer required steroid therapy and who did not experience a disease flare [Crohn's Disease Activity Index (CDAI) score ≥220 points] at any postfirst infusion scheduled visit at which a CDAI score was available) (intention to treat population).

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The median time to first increase in steroid dose measured from baseline was 24.1 weeks in CDP571-treated patients and week 36 in placebo-treated patients (P = 0.38). The total amount of steroid taken during the study, as a proportion of the amount taken if the patient had remained on their baseline dose throughout the study, was similar in the two treatment groups (24% and 36% for the CDP571 and placebo groups, respectively). The median CRP concentrations at week 8, 16, 24, 32 and 36 were similar in the two groups (data not shown). The mean CDAI scores (Figure 4a) and the mean IBDQ scores (Figure 4b) at week 8, 16, 24, 32 and 36 were also similar for patients treated with placebo and CDP571.

image

Figure 4. Mean scores at each study visit since the start of the first infusion, according to treatment group (last observation carried forward) for the Crohn's Disease Activity Index (CDAI) (a) and Inflammatory Bowel Disease Questionnaire (IBDQ) (b) for patients treated with CDP571 10 mg/kg or placebo at week 0, 8, 16, 24 and 32 (intention to treat population; limits correspond to one standard deviation from the mean).

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At the start of the study, 17 (9.4%) patients in the CDP571 group and eight (8.9%) patients in the placebo group had at least one open fistula. No statistically significant differences were apparent between the percentages of patients treated with CDP571 or placebo who had closure of ≥50% (53% and 38% respectively) or 100% (41% and 25% respectively) of their fistulae at any visit.

Safety

Adverse events occurred at similar frequencies in the placebo and CDP571 groups (Table 3). Patients discontinued treatment because of an adverse event at similar frequencies in the placebo (10.2%) and CDP571 (12.7%) groups, most commonly owing to an exacerbation of Crohn's disease. The most frequently reported adverse events (>5%) in both treatment groups were similar (Table 3). Serious adverse events occurred in 6.8% of patients in the placebo group and 12.2% of patients in the CDP571 group (Table 3). No cancers occurred during the study. One patient treated with CDP571 died during the study, but the death was considered unrelated to the study medication. The patient underwent surgery for small intestinal obstruction complicated by ileal perforation and faecal peritonitis and died after 3 days because of gastrointestinal bleeding. There were no clinically significant changes in laboratory values in either treatment group.

Table 3.  Adverse events (safety population)
VariableNo. of patients (%)
Placebo (n = 88)CDP571 10 mg/kg (n = 181)
  1. * Six placebo patients experienced 18 serious adverse events, seven of which (cardiac failure, anaemia, myocardial ischaemia, pneumonitis, thyrotoxicosis, conjunctivitis and cataract) were reported in one patient. One placebo patient experienced gastric ulcer, one patient abdominal distension and pain, one patient Crohn's disease aggravated (two events) and pyrexia, one patient appendicitis and one patient deep limb venous thrombosis, anaemia, leucopenia, and pancytopenia.

  2. † Twenty-two CDP571-treated patients experienced a total of 38 serious adverse events. There was one patient with nine Crohn's disease related events, six patients with Crohn's disease aggravated (one with septicaemia escherichial), three patients with hypersensitivity, two patients with arthralgia, two patients with intestinal obstruction (one with peritonitis), and three patients with abdominal pain (one with vomiting and one with abdominal abscess). A further three patients experienced a serious adverse event of sinusitis, calculus, renal or ileitis aggravated. The remaining three patients each had three events: scrotal infection, venous thrombosis, and gastrointestinal haemorrhage in one case, and abdominal abscess, ileus and ileostomy in the other.

  3. ‡ None of the differences between the placebo and CDP571 groups was significant.

  4. § Infection was classified as a serious adverse event.

Patients with adverse events62 (70.5)128 (70.7)
Patients with serious adverse events6 (6.8)*22 (12.2)†
Patients with severe adverse events9 (10.2)32 (17.7)
Patients with possibly, probably, or definitely drug-related adverse events37 (42.0)76 (42)
Patients with adverse events leading to withdrawal9 (10.2)23 (12.7)
Deaths0 (0)1 (0.6)
Adverse events possibly or probably related to study treatment occurring in ≥5% of patients in at least one of the treatment groups‡
 Crohn's disease aggravated12 (13.6)34 (18.8)
 Headache11 (12.5)30 (16.6)
 Nausea4 (4.5)16 (8.8)
 Arthralgia3 (3.4)16 (8.8)
 Abdominal pain3 (3.4)14 (7.7)
 Dermatitis6 (6.8)12 (6.6)
 Sore throat2 (2.3)11 (6.1)
 Pyrexia3 (3.4)9 (5.0)
 Viral infection6 (6.8)8 (4.4)
 Upper respiratory tract infection6 (6.8)7 (3.9)
 Nasopharyngitis6 (6.8)6 (3.3)
 Back pain6 (6.8)6 (3.3)
 Urinary tract infection7 (8.0)5 (2.8)
Patients with adverse events occurring within 2 h of the start of the infusion
 Any13 (14.8)39 (22.8)
 Hypersensitivity07 (3.9)
 Urinary tract infection2 (2.3)4 (2.2)
 Headache2 (2.3)2 (1.1)
 Chest tightness02 (1.1)
 Flushing02 (1.1)
 Hypertension02 (1.1)
 Nausea02 (1.1)
 Taste disturbance02 (1.1)
 Urticaria02 (1.1)
Patients with infections
 Any infection32 (36.4)57 (31.5)
 Urinary tract infection7 (8.0)5 (2.8)
 Viral infection6 (6.8)8 (4.4)
 Upper respiratory tract infection6 (6.8)7 (3.9)
 Nasopharyngitis6 (6.8)6 (3.3)
 Sinusitis07 (3.9)§
 Influenza4 (4.5)1 (0.6)
 Abdominal abscesses02 (1.2)§
 Skin/subcutaneous tissue abscess01 (0.6)§
 Scrotal infection01 (0.6)§
 Escherichia coli sepsis01 (0.6)§

Infections occurred at similar frequencies in the placebo and CDP571 groups (Table 3); specific type of infections occurring at a frequency of ≥4.5% are tabulated. Serious infections occurred in six patients (3.3%) in the CDP571 group and none in the placebo group (Table 3); the specific types of serious infections are described in Table 3. No patient developed tuberculosis or other opportunistic infections.

Infusion reactions occurred in 13 (14.8%) patients in the placebo group and 39 (21.5%) patients in the CDP571 group (Table 3). Hypersensitivity reactions occurred in none of the patients in the placebo group and in 3.9% of patients treated with CDP571 (Table 3).

Anti-CDP571 antibodies

Of the 181 patients treated with CDP571, post-treatment samples were available for 164 patients, 10 (6.1%) of whom tested positive for anti-idiotype antibodies to CDP571. None of the patients who tested positive for antibodies were receiving concomitant treatment with immunosuppressive medications.

Sixty per cent of patients (6/10) in the CDP571 treatment group who tested positive for anti-CDP571 antibodies experienced an acute infusion reaction (one of whom also experienced a delayed hypersensitivity-like reaction), compared with 7% of patients (12/171) in the CDP571 group who tested negative for antibodies. Of the 10 patients in the CDP571 treatment group who tested positive for anti-CDP571 antibodies, CDP571 plasma concentrations measured pre-infusion were below the limit of quantification at all visits when anti-CDP571 antibodies were present (except for one instance in one patient, when the CDP571 plasma level was just above the limit of quantification).

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflicts of interest
  8. Acknowledgements
  9. References
  10. Appendix

Withdrawal of steroids while maintaining remission in patients with steroid-dependent Crohn's disease is an important unmet medical need. In this study, we found that CDP571 was ineffective as a steroid-sparing agent. Furthermore, no significant differences were identified between the two treatment groups in other efficacy endpoints, including the time to the first increase in steroid therapy; the total amount of steroid taken; the percentage of patients who showed a closure of ≥50% or 100% of fistulae at any visit or on two consecutive visits over an 8-week period; the mean CDAI and IBDQ scores; and the median serum CRP concentration. These findings contrast with those of a smaller study by Feagan et al.,16 who reported that 44% of steroid-dependent patients treated with CDP571 were able to withdraw from steroids without disease flare at week 40 (compared with the placebo rate of 22%). The current study involved a greater number of study centres and a higher proportion of patients from Eastern Europe than the trial conducted by Feagan et al.16 Hence, differences in the characteristics of the patients’ Crohn's disease, the duration of steroid use and the extent to which patients had previously attempted to withdraw from steroids may have been present. It is also notable that the current study had a high rate of protocol violations, which may have influenced the outcome. In particular, the steroid-tapering protocol was not followed correctly in many patients. A second possible reason that CDP571 failed to demonstrate efficacy is that the patients enrolled in the current trial were not truly steroid-dependent, thus leading to a higher than expected placebo response rate. In keeping with this possibility, the 36.7% response rate observed at week 36 was substantially higher than the placebo rates observed in previous trials of CDP571 (21.9% at week 16)16 and methotrexate (19% at 16 weeks).5

Finally, another possible reason why our study failed is that CDP571 is ineffective for the long-term treatment of Crohn's disease. Previous studies in patients with moderately to severely active Crohn's disease failed to demonstrate efficacy at week 24–28,15, 21 except in a selected subgroup of patients with baseline CRP concentrations ≥10 mg/L.21 These results are in contrast to those observed with infliximab, which is effective for maintenance of remission and steroid sparing in patients with moderately to severely active Crohn's disease.8 The apparent differences in efficacy between CDP571 and infliximab may, among other reasons, be due to differences in antibody binding affinity for TNF-α or immunoglobulin isotype.

Analysis of the adverse events associated with the administration of CDP571 showed that the antibody was well tolerated. It is notable that no cases of pneumonia or opportunistic infection occurred. One patient who received CDP571 died; however, this event was judged to be unrelated to treatment with the study medication. These findings are similar to those reported in other studies of CDP571 that included a total of 689 additional patients. Overall, no increased rate of serious infections, opportunistic infections, lymphoma or other cancers, autoimmune diseases, or death has been observed.14–16, 21, 22

The overall frequency of antibodies against CDP571 was low (6.1%). Data from this trial suggest that concomitant use of immunosuppressants reduced anti-CDP571 antibody formation to a nearly undetectable level. When antibodies do occur, they may be associated with relative increases in the rates of infusion reactions and loss of efficacy. These data are in contrast with data that have been reported for infliximab, where as many as 60% of re-treated patients have developed antibodies.9–11

In conclusion, CDP571 was ineffective for steroid sparing and maintenance of remission in patients with steroid-dependent Crohn's disease. A relatively high placebo response rate may have contributed to this outcome. CDP571 was well tolerated and demonstrated a low frequency of immunogenicity.

Conflicts of interest

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflicts of interest
  8. Acknowledgements
  9. References
  10. Appendix

Brian Feagan, William Sandborn and Gary Lichtenstein have served as consultants for UCB Pharma Limited. Jatin Patel is a former employee of Celltech (which subsequently merged with UCB Pharma Limited). Alison Innes is an employee of UCB Pharma Limited.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflicts of interest
  8. Acknowledgements
  9. References
  10. Appendix

This work was supported by UCB Pharma Limited, Slough, UK.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflicts of interest
  8. Acknowledgements
  9. References
  10. Appendix
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    Markowitz J, Grancher K, Kohn N, et al. A multicenter trial of 6-mercaptopurine and prednisone in children with newly diagnosed Crohn's disease. Gastroenterology 2000; 119: 895902.
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    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.
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    Feagan BG, Fedorak RN, Irvine EJ, et al. A comparison of methotrexate with placebo for the maintenance of remission in Crohn's disease. North American Crohn's Study Group Investigators. N Engl J Med 2000; 342: 162732.
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    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.
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    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.
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    Farrell RJ, Alsahli M, Jeen YT, et al. Intravenous hydrocortisone premedication reduces antibodies to infliximab in Crohn's disease: a randomized controlled trial. Gastroenterology 2003; 124: 91724.
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    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: 54253.
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    Winter G, Harris WJ. Humanized antibodies. Immunol Today 1993; 14: 2436.
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    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.
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    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.
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    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.
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    Feagan BG, Sandborn WJ, Baker JP, et al. A randomized, double-blind, placebo-controlled trial of CDP571, a humanized monoclonal antibody to tumour necrosis factor-alpha, in patients with corticosteroid-dependent Crohn's disease. Aliment Pharmacol Ther 2005; 21: 37384.
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    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.
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    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.
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    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.
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Appendix

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conflicts of interest
  8. Acknowledgements
  9. References
  10. Appendix

Appendix: Investigators

Australia

Bampton P, Flinders Medical Center, Bedford Park, SA, Australia

Gibson P, Royal Melbourne Hospital, Parkville, Vic., Australia

Hallam A, Peninsula Specialist Centre, Kippa-Ring, Qld, Australia

Jones B, The Liverpool Hospital, Liverpool, NSW, Australia

Lawrance I, Fremantle Hospital, Fremantle, WA, Australia

Masson J, Townsville General Hospital, Townsville, Qld, Australia

Radford-Smith G, Royal Brisbane Hospital, Herston, Qld, Australia

Riordan S, Prince of Wales Hospital, Randwick, NSW, Australia

Taupin D, The Canberra Hospital, Garran, Australian Capital Territory, Australia

Bulgaria

Krastev Z, Medical University, Sofia, Bulgaria

Stoynov S, DUB ‘Tzaritza Ioana’, Sofia, Bulgaria

Canada

Anderson F, Vancouver General Hospital, Vancouver, BC, Canada

Baker J, St Michael's Hospital, Toronto, ON, Canada

Bernstein C, Health Sciences Centre, Winnipeg, MB, Canada

Gregor J, London Health Sciences Center, London, ON, Canada

Czech Republic

Brabcovà O, Hospital with Out-patient Clinic, Kladno, Czech Republic

Cernoch J, Teaching Hospital Ostrava-Poruba, Ostrava-Poruba, Czech Republic

Gabalec L, District Hospital Usti nad Orlici, Usti nad Orlici, Czech Republic

Gregar I, Faculty Hospital – Internal Clinic, Olomouc, Czech Republic

Hàjek J, Internal Clinic B, Pardubice, Czech Republic

Krízovà V, Hospital Na Homolce, Prague, Czech Republic

Lukàs M, General Faculty Hospital, Prague, Czech Republic

Shonovà O, Hospital Ceské Budejovicde, Ceské Budejovicde, Czech Republic

Stehlik J, Gastroenterology Internal Clinic Masaryk's Hospital, Ústíi nad Lbem, Czech Republic

Vanek I, Hospital Blansko, Blansko, Czech Republic

Volfovà M, Faculty Hospital Hradec Králové, Hradec Králové, Czech Republic

Zavoral M, Central Military Hospital, Prague, Czech Republic

Zboril V, Internal Clinic – Gastroenterology, Brno-Bohunice, Czech Republic

Zdenek P, Faculty Hospital, Plzen-Lochotin, Czech Republic

Hungary

Kovacs A, Peterfy Hospital, Budapest, Hungary

Lakatos L, Veszprem County Hospital, Veszprem, Hungary

Lonovics J, Szent Gyorgyi Albert University, Szeged, Hungary

Nagy G, B.a.z. County Hospital, Miskolc, Hungary

Udvardy M, University Clinic (Debrecen), Debrecen, Hungary

Zagoni T, Semmelweis University, Szentkiralyi, Hungary

Poland

Bogdal J, Collegium Medicum of the Jagiellonian University, Cracow, Poland

Dzieniszewski J, Gastroenterology Clinic Brodnowski Hospital, Warsaw, Poland

Krasnodêbski IW, Surgery Gastroenterology Department, Warsaw, Poland

Kryszewski A, Medical Academy of Gdansk, Gdansk, Poland

Linke K, Internal Diseases Institute, Poznan, Poland

Marlicz K, Pomeranian Medical Academy, Szczecin, Poland

Paradowski L, Medical Academy, Wroclaw, Poland

Rydzewska G, Central Clinical Hospital of the Ministry of Internal Affairs, Warsaw, Poland

USA

Bickston S, University of Virginia Health System, Charlottesville, VA, USA

Breiter J, Center for Medical Research LLC, Manchester, CT, USA

De Villiers W, University of Kentucky Medical Center, Lexington, KY, USA

Elkin R, Regional Gastroenterology Associates of Lancaster Ltd, Lancaster, PA, USA

Eskreis D and Katz S, Long Island Clinical Research Assoc., Great Neck, NY, USA

Goff J, Rocky Mountain Clinical Research, Lakewood, CO, USA

Griffin M, Gastroenterology Specialties, PC, Lincoln, NE, USA

Hanauer S, University of Chicago, Chicago, IL, USA

Lichtenstein G, University of Pennsylvania Hospital, Philadelphia, PA, USA

Mula G, New Orleans Clinical Trial Management, Covington, LA, USA

Priebe W, Tacoma Digestive Disease Research, Tacoma, WA, USA

Pruitt R, Nashville Medical Research Institute, Nashville, TN, USA

Safdi M, Consultants for Clinical Research, Cincinnati, OH, USA

Sandborn W, Mayo Clinic, Rochester, MN, USA

Stanton D, Community Clinical Trials, Orange, CA, USA

Wolf D, Atlanta Gastroenterology Associates, Atlanta, GA, USA