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Keywords:

  • Infliximab;
  • Monoclonal antibody;
  • Steroid-refractory;
  • Tumor necrosis factor alpha;
  • Ulcerative colitis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

We report the experience of 11 patients (of 60 planned patients) enrolled in a double-blind, placebo-controlled clinical trial of infliximab in patients with severe, active steroid-refractory ulcerative colitis. The study was terminated prematurely because of slow enrollment. Patients having active disease for at least 2 weeks and receiving at least 5 days of intravenous corticosteroids were eligible to receive a single intravenous infusion of infliximab at 5, 10, or 20 mg/kg body weight. The primary endpoint used in this study was treatment failure at 2 weeks after infusion. Treatment failure was defined as 1) unachieved clinical response as defined by a modified Truelove and Witts severity score, 2) increase in corticosteroid dosage, 3) addition of immunosuppressants, 4) colectomy, or 5) death. Safety evaluations included physical examination, clinical chemistry and hematology laboratory tests, and occurrence of adverse experiences. Four of 8 patients (50%) who received infliximab were considered treatment successes at 2 weeks, compared with none of 3 patients who received placebo. Improvement in erythrocyte sedimentation rates and serum concentrations of C-reactive protein and interleukin-6 correlated with the clinical response observed in patients receiving infliximab. Infusion with infliximab produced no significant adverse events. Infliximab was well tolerated and may provide clinical benefit for some patients with steroid-refractory ulcerative colitis.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Current treatment of ulcerative colitis (UC) generally involves aminosalicylates, corticosteroids, and immunomodulators. About 10% of patients present with severe clinical symptoms requiring hospitalization and treatment with intravenous corticosteroids (1). Patients who fail to respond to intravenous corticosteroids may be treated with cyclosporine; however, 18% to 43% of patients may fail to respond (2,3). Treatment with cyclosporine may be associated with significant adverse effects. In patients who fail to respond to corticosteroids or cyclosporine, colectomy may be the only remaining therapeutic option.

In UC, as in other chronic inflammatory diseases, proinflammatory cytokines, such as tumor necrosis factor alpha (TNFα), interleukin (IL)-1, and IL-6, are thought to play a major role (4–8). TNFα, which acts early in the cytokine cascade, has been identified as a potential target for therapeutic intervention (9). Its association with inflammatory bowel disease (IBD) has been well documented in studies of both UC and Crohn's disease (CD) (6–8,10,11). In an animal model (i.e., cotton-top tamarins) of UC, neutralization of the biologic activity of TNFα with a monoclonal antibody was shown to produce a rapid improvement in the clinical condition of the animals (12). Perhaps the strongest evidence supporting the role of TNFα in IBD comes from clinical studies in which infliximab (formerly designated cA2) was used successfully to treat patients with CD unresponsive to standard antiinflammatory and immunomodulating therapies (13–15). Infliximab is a chimeric monoclonal anti-TNFα antibody that is highly specific for all soluble and membrane-bound forms of TNFα (16–18). The improvements seen in patients with CD treated with infliximab led to its administration to two patients with severe, steroid-refractive UC. A rapid clinical improvement with healing of endoscopic lesions was observed in one of these two patients (data on file, Centocor, Inc., Malvern, PA, U.S.A.).

On the basis of these observations, a multicenter, prospective, randomized, placebo-controlled study designed to assess the efficacy, safety, and tolerability of infliximab in the treatment of patients with severe UC was undertaken. However, the study was terminated for slow enrollment after the eleventh of 60 planned patients. We report the experience of these patients.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

All patients who participated in the trial were hospitalized for medical management of UC. Each patient provided written, informed consent before participation. Approval for the study protocol was granted by the appropriate institutional review board at each participating site. The study was conducted in three phases or periods—a preenrollment and screening period, a 2-week blinded treatment and evaluation period, and a 10-week follow-up period.

During the screening period, patients were evaluated to determine eligibility and baseline characteristics. Patients were eligible to participate if they were between 18 and 65 years of age and had active UC of at least 2 weeks duration that had been diagnosed and documented by standard clinical, endoscopic, and histologic methods. In addition, patients had received at least 7 days of corticosteroid therapy (≥ 40 to ≤ 60 mg/day, prednisone equivalent), of which at least 5 days included intravenous administration. Cyclosporine was not permitted within 3 months of enrollment. Other medications, including 5-aminosalicylates, antibiotics, 6-mercaptopurine, azathioprine, or antidiarrheal drugs, were permitted provided doses remained stable during the 2-week evaluation period. All patients had severe, active UC as defined by a modification of the Truelove and Witts classification of severity of UC (19). This score was previously used in a randomized controlled trial of cyclosporine in UC (2). All patients had a score of greater than 10. In addition, all patients had an endoscopic classification of moderately active or severe UC using the scoring system devised by Blackstone (20). Patients were excluded from participation in the study if they had UC that was so severe that endoscopy was contraindicated, or if they had toxic megacolon, perforation of the colon, or disease that did not extend beyond the rectum. All patients were tested for enteric stool pathogens and Clostridium difficile and were excluded for infection.

All medications administered during the screening period and throughout the 12-week trial were recorded. Patients were permitted to receive sulfasalazine, mesalazine, antibiotics, azathioprine, 6-mercaptopurine, or antidiarrheal drugs at stable doses. The treating physician was allowed to alter medications for the benefit of the patient; however, any changes in medications that met the criteria for treatment failure (addition of cyclosporine or other immunomodulators within 2 weeks of study infusion, or an increase in corticosteroid dosage) were to be considered as treatment failures, even if the patient's clinical status improved.

Patients who met the eligibility requirements were randomly assigned to receive a single, intravenous infusion of placebo or infliximab at 5, 10, or 20 mg/kg body weight. Infliximab was supplied in vials as a sterile, nonpyrogenic solution of 100 mg infliximab in 20 mL of 0.15 M sodium chloride, 0.001 M sodium phosphate pH 7.2, and 0.01% polysorbate 80. Identical placebo was supplied in 20 mL vials containing 0.1% human serum albumin. Infusion bottles of infliximab solution were prepared at each study site according to the assigned dose. An appropriate volume of infliximab or placebo was withdrawn from the vial and filtered through a low protein-binding 0.22-μM filter and then diluted to a final volume of 500 mL with normal saline. Study medication was infused through a low protein-binding 0.22-μm in-line filter over a 3-to 4-hour period.

Clinical response was assessed prior to the infusion of study medication and at 72 hours and 1, 2, 4, 6, and 12 weeks after infusion, or until treatment failure was observed. Patient weight, a modified Truelove and Witts severity assessment score, and physician and patient global evaluations were obtained at each assessment. Endoscopic and histologic responses were determined by sigmoidoscopy and biopsy within 7 days before the infusion of study medication and at 2 and 6 weeks after infusion. Endoscopic assessment of disease activity was scored as quiescent, mildly active, moderately active, or severe according to the Blackstone classification (20). Laboratory response was evaluated by erythrocyte sedimentation rate (ESR) and serum levels of C-reactive protein (CRP) determined immediately before infusion and at 72 hours and 1, 2, 4, 6, and 12 weeks following the infusion. Blood levels of TNFα and IL-6 were determined immediately before infusion and at 1 and 24 hours and 2, 4, and 6 weeks following the infusion.

The primary endpoint used in this study was treatment failure at 2 weeks after infusion of the trial medication. Treatment failure was defined as fulfilling one or more of the following criteria: 1) if within the 2-week period the patient failed to achieve a clinical response as defined by a modified Truelove and Witts score of < 10 and a 5-point reduction compared with baseline, 2) if the patient received a dosage of > 60 mg/day corticosteroids or was treated with cyclosporine A or other immunomodulators because of no improvement or worsening clinical condition, 3) if the patient underwent a nonelective colectomy, or 4) if the patient died as a result of UC. In addition, patients who underwent an elective colectomy were considered to be treatment failures.

Secondary endpoints measured at the 2-week evaluation included comparison of individual components of treatment failure, and change from baseline for the modified Truelove and Witts score, physician's and patient's global response evaluation, ESR, CRP levels, sigmoidoscopic ratings, and histologic disease activity scores. All patients considered to be treatment failures continued to be monitored for safety. Safety evaluations during the study period included measurements of vital signs, hematology and clinical laboratory measurements, and occurrence of adverse experiences.

A formal statistical analysis of the results was not performed because of the small number of patients participating in the study. Descriptive statistics are presented where applicable.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Although the study was designed to enroll a total of 60 patients, enrollment was terminated prematurely because of slow accrual. The demographic and baseline characteristics of the 11 patients enrolled in the trial are presented in Table 1. Of the patients enrolled, 10 (90.9%) were white and 8 (72.7%) were male. The duration of UC ranged from 0.9 to 36.2 years (median, 2.3 years) and the baseline modified Truelove and Witts scores ranged from 11 to 19 (median 12). Five of the 11 patients (45.5%) had an endoscopic assessment of moderately active disease and 6 patients (54.5%) had an endoscopic classification of severe disease. Five patients (45.5%) had extraintestinal manifestations of UC that included arthritis and arthralgia. The demographic and baseline characteristics of the patients were reasonably balanced across the four groups, with the exception of slightly higher modified Truelove and Witts scores in the placebo-treated patients. All patients were receiving corticosteroid therapy at baseline. Total duration of oral and intravenous corticosteroids prior to infusion ranged from 11 to 51 days (median duration 22 days). Duration of intravenous corticosteroid administered prior to treatment ranged from 5 to 17 days (median 10 days) at doses ranging from 200 to 300 mg hydrocortisone or the equivalent. Three patients (one each on placebo, 10, and 20 mg/kg infliximab) were also receiving hydrocortisone enemas. In addition, two patients were receiving azathioprine/6-mercaptopurine on entry. One patient treated with 10 mg/kg infliximab had begun 6-mercaptopurine 14 weeks prior; the other who received placebo had begun azathioprine 11 days prior to infusion. Neither were responders. Five patients (one placebo treated, one treated with 5 mg/kg infliximab, and three treated with 10 mg/kg infliximab) received oral aminosalicylates, and two patients (one placebo treated and one treated with 10 mg/kg infliximab) received rectal aminosalicylates. No patients received cyclosporine at baseline and all patients received the entire infusion of study medication.

Table 1. Patient demographic and baseline characteristics
 Infliximab
 Placebo5 mg/kg10 mg/kg20 mg/kgAll patients
Characteristic(n = 3)(n = 3)(n = 3)(n = 2)(n = 11)
Age (years)     
 Mean ± SD40.3 ± 16.043.7 ± 17.035.0 ± 3.538.0 ± 12.6
 Median39.037.037.037.0
 Range25–5731–6331–3720–4120–63
Gender     
 Male2 (66.7%)2 (66.7%)2 (66.7%)2(100%)10 (90.9%)
 Female1 (33.3%)1 (33.3%)1 (33.3%)0(0%)1 (9.1%)
Disease duration (years)     
 Mean ± SD4.0 ± 4.914.6 ± 18.83.8 ± 3.66.6 ± 10.3
 Median1.35.72.32.3
 Range1–9.72–36.21.3–7.90.9–4.10.9–36.2
Modified Truelove and Witts assessment score     
 Mean ± SD16 ± 313 ± 111 ± 013 ± 3
 Median16131112
 Range14–1912–1411–1111–1111–19
Endoscopic classification     
 Moderately active (Grade 3)2 (66.7%)1 (33.3%)1 (33.3%)1 (50%)5 (45.5%)
 Severe (Grade 4)1 (33.3%)2 (66.7%)2 (66.7%)1 (50%)6 (54,5%)

At the week 2 evaluation, none (0%) of the placebo-treated patients and four of eight infliximab-treated patients (50%) were classified as responders (Table 2). All three patients who received placebo underwent a colectomy by the week 2 evaluation. Of the four patients who received infliximab and were considered treatment failures at the week 2 evaluation, two (one each in the 10 mg/kg and 20 mg/kg groups) did not meet the modified Truelove and Witts criteria for a clinical response; one patient in the 5 mg/kg group received an increase in corticosteroid dosage to > 60 mg/day with a subsequent initiation of cyclosporine;, and one patient in the 10 mg/kg group underwent an elective colectomy. During the follow-up period, two patients who received 5 mg/kg infliximab (one who met the criteria for clinical response and one who was classified as a treatment failure at the week 2 evaluation) and one patient who received 10 mg/kg infliximab (classified as a treatment failure at the week 2 evaluation) underwent colectomies. Neither of the two patients who received 20 mg/kg infliximab underwent either elective or nonelective colectomy.

Table 2. Patients considered as treatment failures at the week 2 evaluation
 Infliximab
 Placebo (n = 3)5 mg/kg (n = 3)10 mg/kg (n = 3)20 mg/kg (n = 2)Infliximab-treated patients (n = 8)
Number of patients considered as treatment successes Reason for treatment failure0 (0%)2 (66.7%)1 (33.3%)1 (50%)4 (50%)
Failure to achieve clinical response00112
Received cydosporine A, >60 mg/day corticosteroids,     
or immunosuppressive agent added01001
Nonelective colectomy20000
Elective colectomy10101

Five of eight patients who received infliximab demonstrated a decrease of > 5 points from baseline in the modified Truelove and Witts scores at more than one evaluation visit (1). One patient treated with 20 mg/kg infliximab had modified Truelove and Witts scores of ≤ 4 and endoscopic assessments of quiescent disease, thus meeting the criteria for remission for the entire 12-week study period. The other patient who received 20 mg/kg infliximab did not meet the criteria for clinical response at the week 2 evaluation but did meet the criteria for clinical remission at week 6. Improvement was observed in five of six patients treated with infliximab who underwent sigmoidoscopic evaluations beyond the screening period.

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Figure 1. Modified Truelove and Witts severity scores in individual patients over time. A: placebo;B: 5 mg/kg infliximab;C: 10 mg/kg infliximab;D: 20 mg/kg infliximab.

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In general, decreases in ESR and serum levels of CRP correlated with improvement in modified Truelove and Witts scores for patients treated with infliximab. A substantial amount of variability was observed in serum TNFα concentrations in all patients treated with infliximab; however, circulating concentrations of IL-6 were substantially decreased in all but two of the infliximab-treated patients, whose IL-6 concentrations remained at baseline levels during the study period. In contrast, IL-6 concentrations increased in placebo-treated patients (data not shown).

All patients reported at least one adverse experience during the study. Most adverse experiences were mild or moderate in intensity. The most frequently reported adverse experiences in infliximab-treated patients were pruritus, headache, and urinary tract infection, each occurring in two patients. Five serious adverse experiences that required hospitalization or prolonged the hospital stay were reported in four patients. One patient treated with placebo had a colectomy performed within 9 days of infusion because of worsening symptoms. A second placebo patient was hospitalized 2 weeks following a colectomy with symptoms of decreased stoma output and ileus. One patient who received a 10 mg/kg infusion of infliximab developed cellulitis related to a skin wound and one patient who received 20 mg/kg infliximab developed a renal calculus. All serious adverse experiences resolved with appropriate treatment. Only the worsening symptoms of UC (diarrhea and blood in the stool) reported for one placebo-treated patient was assessed as being possibly related to study medication. One patient in the 5 mg/kg infliximab group reported dyspepsia of short duration, which occurred 3 hours after onset of infusion. No other adverse experiences associated with infusion were reported and no patients discontinued the infusion of study medication because of an adverse experience. No clinically significant abnormalities were reported in routine blood chemistries, urinalysis, hematologic parameters, or vital signs, and no patients died during the course of the study.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

TNFα has been identified as a key mediator in the pathogenesis of IBD (4–8,10,11). In this condition, the abnormal proinflammatory actions of TNFα appear to be localized and restricted to the gastrointestinal mucosa (11). As a result, neutralization of the biologic activity of TNFα has become a primary target for therapeutic intervention (9). Indeed, this approach has been supported by several clinical studies in CD that have used monoclonal antibodies against TNFα with success (14,15).

The efficacy of infliximab in the treatment of CD has been reported by several investigators. In an initial open-label study involving patients with steroid-refractory CD that lasted for an average of 4 months, a dramatic improvement in symptoms was observed within 1 week of a single infusion of infliximab (14). These observations were confirmed in a larger, placebo-controlled trial that involved 108 patients. In that study, a single infusion of infliximab (5, 10, or 20 mg/kg) resulted in a clinical response in 65% of treated patients (15). Other studies further evaluating the clinical efficacy of infliximab in the treatment of CD are in progress. In addition, a different monoclonal antibody against TNFα (CDP571) has demonstrated efficacy in the treatment of CD (21). It is not clear, however, if the magnitude and duration of response for this agent were as large as those observed with infliximab. Such differences might be attributed to specific characteristics of the antibodies such as binding affinity or on–off rates for binding to TNFα. The efficacy of CDP571 in the treatment of UC has been investigated in a small uncontrolled study (22). Consistent with the results of the current study using infliximab, a modest response to treatment was observed following a single infusion of CDP571.

Although only 11 patients participated in this study, the results from this study suggest that infliximab administered at 5, 10, or 20 mg/kg was well tolerated and may provide clinical benefit to patients with severe, steroid-refractory UC. All patients treated with placebo were considered treatment failures at the week 2 evaluation; however, only four of the eight patients treated with infliximab met the criteria for treatment failure. Five of eight infliximab-treated patients demonstrated decreases in modified Truelove and Witts disease severity scores, and five of six infliximab-treated patients who underwent sigmoidoscopic evaluations demonstrated improvement. Assessment of ESR and CRP levels (markers of the inflammatory process) also suggest that infliximab treatment may benefit patients. No differences among treatment groups were apparent with regard to the overall incidence of adverse experiences. The small number of patients in this trial precludes a definitive statement about the clinical response to infliximab; however, a larger, randomized, controlled trial is indicated to confirm the impression of benefit and to define the magnitude of the clinical response to infliximab in patients with UC.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Support for this study and writing of this article were made possible by an unrestricted educational grant from Centocor, Inc. Dr. Sands was supported in part by a National Institutes of Health Mentored Patient-Oriented Research Career Development Award (1 K23 DK02850-01K23).

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  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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