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Background Corticosteroids are the most efficacious drugs for inducing remission in active Crohn's disease, but their benefits are frequently offset by serious side effects. Budesonide is a corticosteroid with high topical antiinflammatory activity but low systemic activity because of extensive hepatic metabolism. We investigated the efficacy and safety of an oral controlled-ileal-release preparation of budesonide in patients with active Crohn's disease involving the ileum or ileum and proximal colon.
Methods In a double-blind, multicenter trial, 258 patients were randomly assigned to receive placebo or one of three doses of budesonide -- 3, 9, or 15 mg daily. The primary outcome measure was clinical remission, as defined by a score of 150 or less on the Crohn's disease activity index.
Results After eight weeks of treatment, remission occurred in 51 percent of the patients in the group receiving 9 mg of budesonide (95 percent confidence interval, 39 to 63 percent), 43 percent of those receiving 15 mg (95 percent confidence interval, 31 to 55 percent), and 33 percent of those receiving 3 mg (95 percent confidence interval, 21 to 44 percent), as compared with 20 percent of those receiving placebo (P<0.001, P = 0.009, and P = 0.13, respectively). Improvements in the quality of life, as measured by the patients' responses to the inflammatory bowel disease questionnaire, parallelled these remission rates. Location of disease, prior surgical resection, and previous use of corticosteroids did not affect the outcome. A total of 119 patients (46 percent) were withdrawn from the study before the trial ended, 96 because of insufficient therapeutic effects, 13 because of adverse reactions, and 10 because of noncompliance. Budesonide caused a dose-related reduction in basal and corticotropin-stimulated plasma cortisol concentrations but was not associated with clinically important corticosteroid-related symptoms or other toxic effects.
Conclusions In an eight-week trial, an oral controlled-release preparation of budesonide at an optimal daily dose of 9 mg was well tolerated and effective against active Crohn's disease of the ileum and proximal colon.
Budesonide is a corticosteroid structurally related to 16
-hydroxyprednisolone9. The drug has high topical antiinflammatory activity and low systemic activity as a result of its strong affinity for corticosteroid receptors and rapid hepatic conversion to metabolites with minimal biologic activity10. Aerosolized budesonide is effective therapy for asthma and allergic rhinitis11 and, when given as an enema, is as efficacious as other corticosteroids for distal ulcerative colitis12,13. In these settings, few adverse events and little change in patients' adrenal function have been noted.
Budesonide has been formulated into a coated-capsule preparation (Entocort CIR, Astra Draco, Lund, Sweden) that facilitates delivery of the medication to the terminal ileum and proximal colon, the most common sites of Crohn's disease. This preparation minimizes proximal drug absorption and allows a high concentration of drug to come in contact with inflamed intestinal mucosa14. Two pilot studies suggested a beneficial effect of budesonide in active Crohn's disease15,16. Therefore, we investigated the efficacy and safety of budesonide in patients with active Crohn's disease by comparing three dose levels of the drug with placebo in a randomized, double-blind trial.
Methods
Patient Selection
The study was performed at 27 Canadian centers between October 1991 and December 1992. Eligible patients were older than 18 years of age, with a confirmed diagnosis of active Crohn's disease, as defined by a score of 200 or higher on the Crohn's disease activity index. This index is based on the patient's symptoms (number of liquid stools, extent of abdominal pain, and general well-being), the occurrence of extraintestinal symptoms, need for antidiarrheal drugs, presence of abdominal masses, hematocrit, and body weight. Scores on the index range from 0 to 700. Scores between 151 and 400 are associated with disease that is mild to moderately active17; higher values indicate severe disease activity. The extent of disease had to be defined within 24 months before randomization; entry was restricted to patients with disease involving the ileum or ileum and colon, but not extending beyond the hepatic flexure. Patients who had undergone ileostomy or more extensive surgery than resection of the ileum and right colon and those with severe disease requiring imminent surgery were not enrolled in the study. Immunosuppressive drugs were allowed until 3 months before the study, corticosteroid treatment until 14 days before the study, and 5-aminosalicylates and metronidazole until the day before the study. People with diabetes mellitus, active infection, peptic ulcer disease, cancer, or clinically important cardiac or hepatic disease were ineligible, as were women who were pregnant or breast-feeding.
The study was approved by the institutional review board at each center and was conducted under the principles of the second Declaration of Helsinki. All participants gave informed written consent.
Study Medication
The budesonide formulation used is a gelatin capsule containing acid-stable microgranules composed of an inner sugar core surrounded by a layer of budesonide in ethylcellulose and an outer acrylic-based resin coating (Eudragit L100-55) that dissolves at a pH of 5.5 or higher. Absorption of this formulation in the ileocecal region ranges from 52 to 79 percent, with a systemic bioavailability of about 9 percent14. The placebo medication was identical in appearance to the investigational drug.
Evaluation Studies and Randomization
One week before randomization, the patients had a physical examination and sigmoidoscopy, and their radiographs and histories were reviewed. Stool samples were obtained to rule out enteric pathogens. A complete blood count, clinical chemistry tests, plasma cortisol determination (measured between 8 and 10 a.m.), and corticotropin stimulation test were performed. Quality of life was assessed with the inflammatory bowel disease questionnaire, which contains 32 questions grouped into four categories (systemic symptoms, bowel symptoms, emotional function, and social function); an increase over time of 30 points or more in the questionnaire score indicates a clinically important improvement in the quality of life18,19. The patients were assigned to a treatment group one week later if their score on the Crohn's disease activity index was at least 200 and they met all other inclusion and exclusion criteria.
The patients were randomly allocated to receive placebo, or one of three doses of budesonide -- 3, 9, or 15 mg daily. The patients were stratified according to treatment center and whether they had received corticosteroid treatment for longer than two weeks in the preceding year.
Intervention and Follow-up Schedule
Budesonide or placebo was given in two divided doses (morning and evening) before meals for eight weeks. Thereafter, patients who had been receiving 9 or 15 mg of budesonide had their drug dose reduced to 6 mg daily; the active drug was discontinued in those who had been receiving 3 mg of budesonide, but they continued to receive placebo capsules to preserve blinding. This gradual discontinuation of therapy was designed to minimize the risk of adrenal insufficiency.
Patients were seen at weeks 2, 4, 8, and 10 of the study. At each visit the patients had a physical examination, scores were calculated for the Crohn's disease activity index and inflammatory bowel disease questionnaire, a standardized adverse-events assessment was performed, and the laboratory studies performed at the beginning of the study were repeated. Compliance with the treatment regimen was assessed by pill counts. The corticotropin stimulation test was repeated at 10 weeks, and the results were reviewed by an endocrinologist who prescribed an additional two-week taper period of budesonide if adrenal suppression was demonstrated.
Other Interventions and Criteria for Withdrawal
During the study participants could take no other drugs for the treatment of Crohn's disease. If therapy with corticosteroids, 5-aminosalicylates, immunosuppressive agents, or antibiotics was initiated, the patient was withdrawn from the study. Patients could take loperamide to control diarrhea. To ensure patient safety, patients whose disease worsened or did not improve were withdrawn if their score on the Crohn's disease activity index exceeded 400 or had increased by 100 points at week 2 or exceeded 300 and had not decreased by 100 points at week 4 or thereafter. Patients could also be withdrawn from the study at any time if their physicians believed their condition had substantially deteriorated.
Outcome Measures
The primary outcome measure was remission, defined as a score of 150 or lower on the Crohn's disease activity index. Changes in the quality of life were assessed with the inflammatory bowel disease questionnaire. The serum concentrations of C-reactive protein and orosomucoid (1-acid glycoprotein) were used as measures of inflammation. Corticotropin stimulation tests were performed with a bolus intravenous injection of 250 µg of cosyntropin (Cortrosyn, Organon Canada, Toronto) between 8 and 10 a.m. Blood was drawn for measurements of plasma cortisol (Clinical Assays, Incstar, Stillwater, Minn.) at the time of cosyntropin administration and 30 and 60 minutes later. A normal response was defined as a base-line plasma cortisol concentration of at least 7.2 µg per deciliter (200 nmol per liter) and an increment above base line of at least 7.2 µg per deciliter, with an absolute value above 18.1 µg per deciliter (500 nmol per liter) at 30 or 60 minutes.
Statistical Analysis
We estimated that 240 patients would have to be studied to detect a 30 percent absolute difference in the proportion of patients entering remission while taking the most effective of the three doses evaluated (alpha = 0.05, beta = 0.20), assuming a response rate to placebo of 40 percent.
All patients who underwent randomization were included in the analyses. Three patients were included who had base-line scores of less than 200 on the Crohn's disease activity index (scores, 119, 189, and 153). The index was miscalculated in two of these patients because they were obese. The inclusion of the other patient was a clear protocol violation. The primary outcome measure was a comparison of remission rates (Crohn's disease activity index, 
150) at eight weeks among the four treatment groups, analyzed by the chi-square test20. The life-table method was used to compare the average length of time to remission in the four groups21. The base-line characteristics of the patients assigned to each group were compared in a descriptive fashion. Comparisons of changes in the score on the Crohn's disease activity index, the score on the inflammatory bowel disease questionnaire, and laboratory variables were performed by analysis of variance; if this analysis revealed significant differences, t-tests were used to compare the placebo group with the budesonide groups starting with the group receiving the highest dose20. The proportions of patients in each group who withdrew from the study, had adverse events, or had no response to the corticotropin stimulation test were compared by the chi-square test20. All outcome measures were analyzed with use of the last available value after the base-line measurement. All statistical analyses were two-sided, with an alpha error of 0.05.
Results
Patients
A total of 258 patients were randomly assigned to receive placebo or one of the three doses of budesonide. On average, 10 patients underwent randomization at each investigation site. The base-line characteristics did not differ significantly among the four groups (Table 1).
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A total of 119 patients (46 percent) did not complete the study (Table 2). Of these patients, 96 (81 percent) were withdrawn because of insufficient therapeutic effect. Insufficient effect was the reason for withdrawal in fewer patients receiving the 15-mg dose (28 percent) and the 9-mg dose (26 percent) of budesonide than the 3-mg dose (45 percent) or placebo (48 percent) (P = 0.014). Adverse events led to the withdrawal of 13 of the 119 patients (11 percent); the proportion withdrawn for this reason was similar in the active-treatment (10 of 192 patients, or 5.2 percent) and placebo (3 of 66 patients, or 4.5 percent) groups. Seven of these patients were withdrawn because of increased disease activity: an inflammatory abdominal mass in three patients (one each in the 15-mg, 9-mg, and placebo groups) and bowel obstruction in four patients (one in the 15-mg group, two in the 9-mg group, and one in the placebo group). The causes in the six other patients were epigastric pain, joint swelling, and heartburn (one patient each in the 15-mg group); headaches and abdominal pain (one patient each in the 3-mg group); and urticaria (one patient in the placebo group). Ten patients were withdrawn because of noncompliance. No patients were lost to follow-up.
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The response rates are shown in Figure 1. After eight weeks of treatment, remission occurred in 51 percent of the patients receiving 9 mg of budesonide daily (95 percent confidence interval, 39 to 63 percent) and 43 percent of those receiving 15 mg daily (95 percent confidence interval, 31 to 55 percent), as compared with 20 percent of those receiving placebo (P<0.001 and P = 0.009, respectively). The 33 percent rate of remission in the group receiving 3 mg of budesonide daily (95 percent confidence interval, 21 to 44 percent) was not significantly different from the rate in the placebo group (P = 0.13). The rate of remission in the 9-mg group was also significantly greater than that in the 3-mg group (P = 0.03). The time to remission did not differ between the 9-mg and 15-mg treatment groups (P = 0.70). Thus, a daily dose of 9 mg of budesonide was the lowest effective dose for the induction of remission.
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No significant differences between the four groups were found when changes in serum concentrations of orosomucoid and C-reactive protein from base line to the final visit were examined.
Subgroup Analysis
Two-way analysis of variance of remission rates showed no significant interaction between a beneficial effect of treatment and the patient's sex, severity of disease, location of disease, prior resection of diseased tissue, previous corticosteroid therapy, or smoking status.
Compliance
The mean rate of compliance of all patients who underwent randomization was 91 percent and was similar in all treatment groups (range, 89 to 95 percent).
Adverse Events
All reported adverse events were tabulated, whether or not they were considered to be related to the study medication. A total of 744 adverse events occurred in 215 of the 258 patients; events were reported for 88 percent of the patients given 15 mg of budesonide daily, 90 percent of those given 9 mg daily, 81 percent of those given 3 mg daily, and 76 percent of those given placebo. Reflecting the underlying disease, 41 percent (range, 37 to 49 percent) of the adverse events were classified as disorders of the gastrointestinal system; dyspepsia and nausea were the two most frequent events. The differences in the incidence of adverse events between the four groups were not significant.
Of the 744 events, 122 (16 percent) were classified as related to corticosteroids. The proportion of patients with corticosteroid-associated effects was not significantly different between the groups: 38 percent in the 15-mg group, 26 percent in the 9-mg group, 15 percent in the 3-mg group, and 26 percent in the placebo group. Although moon face was more common in the budesonide-treated patients than in those given placebo (7 percent vs. 2 percent, P = 0.001), the incidence of other symptoms and signs (acne, ankle edema, hirsutism, and buffalo hump) was similar in the two groups.
Serial comparisons of hematologic and biochemical variables showed no differences in the frequency or severity of abnormalities between the groups receiving active drug and the group receiving placebo.
Plasma Cortisol Responses to Therapy
The administration of budesonide at doses of 15 mg and 9 mg per day reduced the median plasma cortisol concentrations below base line (reference limit, 7.2 µg per deciliter) after two weeks of treatment (Table 3), and the concentrations remained below base line throughout the study. The median cortisol values in the group given 3 mg of budesonide daily and the group given placebo were not different from base-line values after eight weeks of treatment. After eight weeks of treatment, the proportion of patients with plasma cortisol values below the reference limit was higher in the 15-mg group (67 percent) and the 9-mg group (69 percent) than in the 3-mg group (30 percent) or the placebo group (14 percent). Before drug treatment, the proportion of patients with impaired responses to corticotropin stimulation was similar in the four groups: 13 percent in the placebo group, 21 percent in the 3-mg group, 13 percent in the 9-mg group, and 16 percent in the 15-mg group. After drug treatment, this proportion increased to 41 percent in the group given 15 mg of budesonide a day and to 50 percent in the group given 9 mg a day, as compared with 26 percent in the group given 3 mg a day and 19 percent in the group given placebo. The difference between the 9-mg group and the placebo group was significant (P = 0.006).
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We found that budesonide induced remission in patients with mild-to-moderately-active Crohn's disease at a significantly higher rate than placebo. Daily doses of 9 or 15 mg of budesonide produced similar responses. The antiinflammatory action of budesonide is primarily topical,9 whereas Crohn's disease damages all layers of the intestinal wall. Our findings suggest that a daily dose of 9 mg of budesonide may provide the maximal efficacy obtainable with a corticosteroid acting as a topical agent.
The 51 percent rate of clinical remission in the group of patients given 9 mg of budesonide a day in two divided doses is nearly identical to the rate reported in another study (52 percent), in which a 9-mg dose of budesonide given once daily was compared with prednisolone22. A single daily dose of budesonide may therefore be sufficient to achieve an optimal clinical response. In our study, analysis of the change in the score on the Crohn's disease activity index confirmed that the 9-mg dose of budesonide was the lowest effective dose. After two weeks of therapy, this score fell significantly in the groups of patients receiving 9 and 15 mg of budesonide per day; a near maximal reduction was reached by four weeks. Thus, the response to budesonide is rapid and similar to that after treatment of active Crohn's disease with oral corticosteroids3,6,7. Patients receiving 9 mg of budesonide daily had the greatest improvement in their quality of life. Scores on the quality-of-life questionnaire highly correlate with scores on the Crohn's disease activity index but provide a more comprehensive measure of patients' overall sense of well-being19. Improvements in social and emotional functions were noteworthy in our patients; such functions may be adversely affected by conventional oral corticosteroid treatment.
The proportion of patients who did not complete the study was relatively high (46 percent). The majority of patients (81 percent) were withdrawn because of insufficient therapeutic effect, primarily in the group given 3 mg of budesonide daily and the group given placebo. To minimize risk, the criteria for treatment failure were stringent.
Budesonide therapy was well tolerated: the frequency of adverse events was similar among budesonide-treated patients and those receiving placebo. Furthermore, the frequency of corticosteroid-associated events in patients receiving budesonide was not different from that in the placebo group. There was a greater frequency of moon face in the budesonide groups, which might imply a steroid-related effect. Alternatively, the clinical improvement may also improve nutritional status in some patients. The basal plasma cortisol concentrations were reduced in about 69 percent of the patients given 9 mg of budesonide daily in two divided doses -- a much higher percentage than that reported after once-daily treatment with 9 mg of budesonide22. This difference may reflect differential adrenal responses to single-dose regimens as compared with divided-dose regimens. Measurement of basal plasma cortisol concentrations has limitations as an indicator of pituitary-adrenal function23. Our results indicate, however, that after a dose of 9 mg of budesonide a day (in two divided doses) a substantial proportion of patients (50 percent) also had impaired adrenal function, as measured by a corticotropin stimulation test. The clinical importance of biochemical suppression of the hypothalamic-pituitary-adrenal axis after short-term corticosteroid administration is controversial, because tests of pituitary-adrenal function do not consistently correlate with responses to stress24. Nevertheless, corticosteroid supplementation seems prudent for patients receiving budesonide who require emergency surgery.
In conclusion, in our eight-week trial, an oral controlled-release preparation of budesonide at a dose of 9 mg per day was a well-tolerated and effective therapy for active Crohn's disease of the ileum and proximal colon.
Supported by a research grant from Astra Draco, Lund, Sweden.
Source Information
From the Department of Medicine, University of Toronto, Toronto (G.R.G.); the Departments of Medicine and Epidemiology and Biostatistics, University of Western Ontario, London (B.G.F.); the Department of Medicine, University of Montreal, Montreal (F.M.); the Department of Medicine, University of Calgary, Calgary, Alta. (L.R.S.); the Department of Medicine, University of Alberta, Edmonton (A.B.R.T.); the Department of Medicine, Dalhousie University, Halifax, N.S. (C.N.W.); and the Departments of Clinical Research and Development and Biostatistics and Data Processing, Astra Draco, Lund, Sweden (L.-G.N., T.P.). Members of the study group are listed in the Appendix.
Address reprint requests to Dr. Greenberg at Mount Sinai Hospital, 600 University Ave., Rm. 445, Toronto, ON M5G 1X5, Canada.
References
, 17-acetyl-substituted glucocorticoids. Mol Pharmacol 1984;25:70-78. [Abstract]
The investigators of the Canadian Inflammatory Bowel Disease Study Group are as follows: Participating investigators: University of Alberta, Edmonton: University Hospital, A.B.R. Thomson (chief investigator), V. Bain, R. Cherry, R. Fedorak, E. Lalor, R. Sherbaniuk, B. Yacyshyn, and P. Kierdekis; Royal Alexandra Hospital, R. Bailey and D. Meyer; University of British Columbia, Vancouver: University Hospital, H. Freeman (chief investigator) and Pauline Daws; Victoria General Hospital, S. Holland and M. Buytendorp; St. Paul's Hospital, S. Whittaker and A. Chang; University of Calgary, Calgary, Alta.: Foothills Hospital, L. Sutherland (chief investigator), N. Hershfield, K. MacCannell, J. Medding, L. Price, E. Shaffer, and N. Racicot; Calgary General Hospital, S. Bass (chief investigator), R. Bridges, P. Blustein, T. Lay, G. Van Rosendaal, and M. Watson; Dalhousie University, Halifax, N.S.: C.N. Williams (chief investigator), V. Vanzanten, D. Leddin, and J. Falkenham; Halifax Infirmary, R. Tanton (chief investigator) and P. Human; Camp Hill Hospital, G. Turnbull, G. Schep, and J. Woolnough; Laval University, Quebec, Que.: Hopital Saint-Francois d'Assise, C. Dallaire (chief investigator), B. Rosseau, and F. Bernard; Hotel-Dieu de Quebec, R. Dube (chief investigator), P. Pare, A. Morin, and D. Lafrance; McGill University, Montreal: Jewish General Hospital, J. Lichter (chief investigator) and M. Poleski; Montreal General Hospital, D. Cleland (chief investigator), D. Daly, G. Wild, and S. Finenbine; Royal Victoria Hospital, P. Belliveau (chief investigator), W. Dauphinee, S. Miskin, H. Sutherland, and C. Barber; McMaster University Health Sciences Centre, Hamilton, Ont.: J. Irvine (chief investigator), S. Collins, K. Croitoru, R. Hunt, S. Salina, and M. Donnelly; University of Manitoba, Winnipeg: St. Boniface Hospital, S. Baker (chief investigator) and A. Alvi; University of Montreal, Montreal: Hopital Maisonneuve-Rosemont, A. Archambault (chief investigator), G. Jobin, and M.L. Trouve; Hopital St. Luc, F. Martin (chief investigator) and M. Gagnon; Carleton University, Ottawa, Ont.: Ottawa Civic Hospital, R. Gillies (chief investigator), M. Champion, D. MacIntosh, D. Patel, A. Sekar, W. Thompson, and R. Fitzgerald; University of Saskatchewan, Saskatoon: Royal University Hospital, Saskatoon, L. Worobetz (chief investigator) and J. Osachoff; Pasqua Hospital, Regina, Sask.; J. McHattie (chief investigator) and J. Edwards; University of Toronto, Toronto: Mount Sinai Hospital, G.R. Greenberg (chief investigator), H. Steinhart, and A. Slater; St. Michael's Hospital, J. Baker (chief investigator), K.N. Jeejeebhoy, and G. McDermott; Sunnybrook Hospital, F. Saibil (chief investigator), L. Cohen, and S. Pearan; Toronto General Hospital, S.L. Wolman (chief investigator) and F. Habal; Women's College Hospital, S. Stafford; and University of Western Ontario, London: University Hospital, B.G. Feagan (chief investigator), W. Barnett, D. Bondy, J. McDonald, and M.B. Hopkins; Victoria Hospital, J. Howard, M. Belsheim, T. Ponich, W. Watson, and P. Gilmore; and St. Joseph's Hospital, R. Reynolds, D. Lloyd, I. Prokopiw, and L. Moyer.
Endocrinology Audit Investigators: University of British Columbia, Victoria: Victoria General Hospital, C. VonWestarp; University of Calgary, Calgary, Alta.: Foothills Hospital, S.L. Shumak; Dalhousie University, Halifax, N.S.: Halifax Infirmary Hospital, S.S.K. Reddy; University of Montreal, Montreal: Hopital St. Luc, R. Belanger; and University of Toronto, Toronto: Toronto General Hospital, S.R. George.
Industry Participants: Astra Draco, Lund, Sweden: L.G. Nilsson, C. Seidegard, and T. Persson; and Astra Pharma Canada, Toronto: R. Jenkins, Ph.D.
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